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Gutnikov, Sergei A. "Behavioural studies of the NMDA system in rats." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294382.
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Wilson, John A. "The role of N-methyl D-aspartate (NMDA) receptor antagonists in neuropathic pain." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/25324.
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The aim of this thesis is to investigate the use of NMDAR antagonists in preventing naturopathic sensitisation. The chronic constriction injury (CCI) model of neuropathic pain is used to study the role of NMDARs in the development of neuropathic pain and subsequent modulation. Behavioural effects are assessed in association with changes in NMDAR subtypes. Memantine and ketamine (NMDAR antagonists) are shown to attenuate typical behavioural responses (thermal hyperalgesia and cold allodynia) to nerve injury. In addition, NMDAR antagonist pre-treatment is shown to effect the subsequent NMDAR subunit expression, with improved susceptibility to subsequent NMDAR antagonist treatment. The clinical use of epidural ketamine as a preventative drug prior to lower limb amputation is investigated in a double blind randomised placebo controlled study. No significant effects on the incidence of post-amputation pain were found, although the overall incidence of pain was lower than in comparable studies. Ketamine is shown to improve peri-operative analgesia and have long lasting effects (up to one week) on sensory processing in the remaining stump. In summary, NMDAR antagonists seem to be effective in attenuating neuropathic pain in animal models. The promise shown in these studies has not translated into a reduction in post-amputation pain in a clinical study. Ketamine remains a clinically useful drug in peri-operative pain management but the role of ketamine and other clinically available NMDAR antagonists in the prevention of neutropathic sensitisation is still not clearly defined.
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Dutta, Arpan. "The effect of NMDA receptor antagonists and antidepressants on resting state in major depressive disorder." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/the-effect-of-nmda-receptor-antagonists-and-antidepressants-on-resting-state-in-major-depressive-disorder(0c1dd1fc-ff39-43fb-92c0-7b108e4f6230).html.
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Introduction: The aim of the project was to investigate the effects of antidepressants on brain networks whilst at rest. My hypothesis was that antidepressants work by reversing persistent activity in the brain’s default mode network (DMN). The DMN is implicated in self-reflection and rumination in MDD. The methodologies and results of studies of resting state networks in MDD and the effects of antidepressants are reviewed in the thesis. Increasing evidence implicates glutamate in the action of antidepressant drugs. Whether there are illness related changes in glutamate function is unresolved, largely because of the lack of techniques for assessing it. Ketamine and other NMDA antagonists have improved MDD symptoms within 24 hours though the effects are short lasting. The molecular neural networks involved in ketamine’s putative antidepressant effects are unclear. The thesis reviews the evidence. Much evidence implicates ACC as a site of action of antidepressant effects but whether this is through its regulation of the DMN or other networks is not known. This thesis compares the effect of ketamine and citalopram on ACC-related systems. Method: The thesis combines two systematic reviews of the effects of MDD and antidepressant drugs on i) resting state networks (53 studies) and ii) glutamate neurotransmission (45 studies of clinical efficacy of ketamine). There are two experimental chapters. The first describes investigation into two rapid acting antidepressant drugs acting via glutamate mechanisms. 54 unmedicated cMDD were scanned across two centres on 3T MRI scanners while being infused with placebo (0.5% saline), 0.5mg/kg ketamine or 100mg AZD6765 over 1 hour. fMRI resting state data between drug treatments was compared for the final 25 minutes of the drug infusion and for a 25 minute resting state scan a day later. The second experimental chapter examines whether these effects were shared by citalopram, a standard antidepressant. 67 unmedicated cMDD, rMDD and HC were administered citalopram 7.5mg i.v. and scanned on a 1.5T MRI scanner. In a second study 63 cMDD and HC were administered i.v. citalopram 7.5mg or placebo (0.5% saline). fMRI resting state data for the final 12 ½ minutes following drug infusion was compared. Independent Component Analysis was performed using the Group ICA for fMRI toolbox. The resting component with the highest spatial correlation to the ACC was used. Brain maps of the intensity of the selected component were constructed for each individual. Group averages were calculated and compared using SPM. Regional analysis was performed using Marseille Boite a Regions d'interet. Results: On day 1 AZD6765 significantly increased mean intensity of ACC resting component in the right insula, right IPL and left cingulate gyrus greater than ketamine or placebo. Ketamine increased mean intensity of ACC resting component greater than placebo in the right lentiform nucleus and left mFG. Significantly decreased mean intensity of ACC resting component in the left insula in the AZD6765 group compared to placebo was noted. On day 2 AZD6765 increased mean intensity of ACC resting component greater than ketamine and placebo in the left and right lentiform nuclei. AZD6765 reduced mean intensity of the ACC resting component in the left and right MFG. The first citalopram study revealed reduced mean intensity of ACC resting component in cMDD compared to rMDD and HC in PCC. rMDD had reduced mean intensity of ACC resting component in the precuneus compared to HC. In the second study, citalopram had no effect in HC but normalised precuneus activity in cMDD producing a significant drug x group interaction. Conclusions: The acute antidepressant effects of citalopram are modulated by changes in the bilateral precuneus. The precuneus is central to connectivity with other regions in MDD. It has a prominent role in the DMN and is linked to rumination. The mechanism of the antidepressant effects of AZD6765 is different from those of ketamine and citalopram. The insula, IPL, MFG, cingulate gyrus and lentiform nuclei are all regions implicated in MDD suggesting antidepressant effects. The rapid antidepressant effects of AZD6765 are possibly due to a resetting of the interface between DMN and salience networks.
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Brazaitis, Casmira T. "In vivo and in vitro studies of positive allosteric modulation of the NMDA receptor." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/10495.
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Dysfunction of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to the cognitive deficits of many neurodegenerative diseases and psychiatric disorders. Cognitive symptoms of Alzheimer's disease can be treated with NMDA receptor antagonists or drugs targeting the cholinergic system; however, there are no effective treatments for cognitive deficits of schizophrenia or Huntington's disease. With the discovery of a potent and selective allosteric modulator of the NMDA receptor, there is the possibility of new treatments based on NMDA receptor functional-enhancement through neuroactive steroids, closely related in structure to the endogenous neurosteroid, cerebrosterol. The aim of this thesis was to examine steroidal modulation of the NMDA receptor both in vitro and in vivo. In chapter 2, NMDA receptor enhancement of both the synthetic and endogenous neuroactive steroids was assessed in neurons maintained in cell culture using calcium imaging techniques. Sulphation of the steroids greatly increased the efficacy of NMDA receptor enhancement compared to the unsulphated steroids. Chapters 3 and 4 investigate the potential for neuroactive steroids to treat cognitive impairments of Huntington's disease. Using a mouse model, tests were selected that were analogous to those in which patients are impaired; however, no impairments were found in the mouse model. Chapter 5, therefore, used a different model of cognitive impairment – namely, rats with a set-shifting impairment, as is seen in many psychiatric and neurological disorders, including Huntington's disease – to assess the effect of the synthetic steroid administration. Unfortunately, the rats did not show the expected impairment. The lack of reliable animal models compromised testing the efficacy of these promising NMDA receptor positive allosteric modulators. Nevertheless, the promising in vitro results suggest that there could still be therapeutic potential. In addition, the compound is a useful research tool for exploring NMDA receptor function in health and disease.
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Tarrés, Gatius Mireia. "Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/669917.
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Sub-anesthetic doses of ketamine evoke rapid and persistent antidepressant effects in treatment-resistant depressed patients through still poorly-known mechanisms. Ketamine also evokes transient psychotomimetic effects, shared by other non-competitive NMDA-R antagonists such as phencyclidine (PCP) and dizocilpine (MK-801), which are used as pharmacological models of schizophrenia. Previous studies indicate that PCP activates thalamo- cortical circuits after the blockade of NMDA-R in GABAergic neurons of the reticular nucleus (RtN). Given that one of the sites of action of non-competitive NMDA-R antagonists is the RtN and that the GluN2C subunit is expressed in this nucleus, our working hypothesis was that the psychotomimetic and the antidepressant-like effects induced by non-competitive NMDA-R antagonists would be partly attenuated in absence of the GluN2C subunit.
All three NMDA-R antagonists induced psychotomimetic effects in both genotypes. While locomotor activity was increased in GluN2CKO mice, stereotyped behaviors like circling and ataxia signs (falls, hindlimb abduction) were dramatically attenuated, suggesting a better motor coordination in absence of the GluN2C subunit. In agreement, GluN2CKO mice spent more time on the rotarod compared to WT mice after PCP or MK-801 administration. However, there were no genotype differences in the PPI test, showing that the GluN2C subunit is not involved in sensory gating. Moreover, PCP and MK-801 evoked a general pattern of c-fos activation, except in cerebellum, where significant reductions and genotype differences were noted. Ketamine reduced the immobility time in male and female WT and GluN2CKO mice in tests used for the screening of antidepressants, showing that the GluN2C subunit does not contribute to the antidepressant-like effects induced by ketamine in both sexes. This acute antidepressant-like effect might be mediated by a transient increase of serotonin, but not glutamate, in the medial prefrontal cortex. Moreover, ketamine increased c-fos expression in the thalamus of female but not male mice, while reductions were only present in the cerebellum of male mice, suggesting sex-differentiated effects of ketamine. Regarding NMDA-R subunits distribution, deletion of the GluN2C subunit led to minor changes in the expression of GluN2A, GluN2B or GluN2D subunits, suggesting that it was not systematically replaced by any other GluN2 subunits. However, it produced remarkable changes in the expression of the GluN1 subunit in cerebellar and thalamic areas, which may contribute to the behavioral and molecular differences between both genotypes.
In conclusion, the GluN2C subunit appears to be strongly involved in motor components of the behavioral syndrome induced by non-competitive NMDA-R antagonists, while the antidepressant-like effects of ketamine are preserved. Its genetic deletion results in an improved motor coordination after NMDA-R blockade. This supports the presence of GluN2C‐containing NMDA‐R in cerebellar circuits controlling motor activity and equilibrium, which are sensitive to the action of ketamine, PCP, and MK-801. Overall, the present study supports the involvement of cerebellar GluN2C subunits as a key element in the psychotomimetic actions of non- competitive NMDA-R antagonists. The differential role of the GluN2C subunit in mediating the psychotomimetic and antidepressant effects of ketamine identifies this subunit as a potential target for preventing the emergence of pro-psychotic effects while keeping a full antidepressant action.La ketamina, la fenciclidina (PCP) y la dizocilpina (MK-801) son antagonistas no competitivos del receptor NMDA y se utilizan como modelos farmacológicos de esquizofrenia ya que su administración evoca unos síntomas parecidos a los de un estado psicótico. Además, la ketamina también ejerce un efecto antidepresivo rápido y sostenido en el tiempo en pacientes depresivos resistentes a los tratamientos convencionales. Estudios previos han demostrado que PCP actuaría preferencialmente sobre neuronas GABAérgicas del núcleo reticular del tálamo, bloqueando su efecto inhibidor y, en consecuencia, activando circuitos tálamo-corticales. Dado que la subunidad GluN2C del NMDA-R se expresa en dicho núcleo talámico, en esta tesis hemos estudiado la posible implicación de la subunidad GluN2C en los efectos psicotomiméticos y antidepresivos inducidos por los antagonistas no competitivos del NMDA-R, bajo la hipótesis de trabajo de que estos efectos serían menores en ausencia de dicha subunidad. El tratamiento agudo con MK-801, PCP y ketamina indujo efectos psicotomiméticos en ratones WT y GluN2CKO. No obstante, la intensidad de las rotaciones (movimiento estereotipado), el número de caídas y el arrastrado de patas traseras (signos de ataxia) fueron significativamente menores en los ratones GluN2CKO, sugiriendo una mejor coordinación motora en ausencia de la subunidad GluN2C. De acuerdo con estos resultados, en los ratones GluN2CKO observamos un mayor tiempo de permanencia en el rotarod en comparación con los ratones WT tras la administración aguda de MK-801 o PCP. Sin embargo, no encontramos diferencias de genotipo en el test de la inhibición pre-pulso, sugiriendo que la subunidad GluN2C no estaría relacionada con la regulación sensoriomotora. La administración de MK-801 y PCP provocó un aumento generalizado de la expresión del gen c-fos en el cerebro de los ratones WT y GluN2CKO, excepto en el cerebelo, dónde se observaron reducciones y diferencias de genotipo en su expresión. Respecto a los efectos antidepresivos, ketamina redujo el tiempo de inmovilidad en machos y hembras WT y GluN2CKO, sugiriendo que la subunidad GluN2C no está involucrada en la acción antidepresiva de ketamina. Además, ketamina aumentó la liberación de serotonina en la corteza prefrontal en ambos géneros, sugiriendo que el efecto antidepresivo podría estar relacionado con este neurotransmisor. En comparación con MK-801 y PCP, el patrón de expresión de c-fos después de la administración de ketamina no fue tan intenso y se observaron diferencias de género. En conclusión, este trabajo demuestra que existe una disociación en cuanto a la participación de la subunidad GluN2C en los efectos motores y el efecto antidepresivo inducidos por antagonistas no competitivos del NMDA-R. Debido a que la subunidad GluN2C se encuentra altamente expresada en el cerebelo y que ésta es un área involucrada en coordinación motora, los NMDA-R de cerebelo podrían jugar un papel importante en el mecanismo de acción de MK-801, PCP y ketamina.
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Mathé, Jan M. "The phencyclidine model of schizophrenia : dysregulation of brain dopamine systems induced by NMDA receptor antagonists : an experimental study /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980930math.
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Hillhouse, Todd. "Dissociable antidepressant-like and abuse-related effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 in rats." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3326.
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The noncompetitive NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in patients suffering from major depressive disorder. However, abuse liability is a concern. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA receptor antagonists, this study evaluated the effects of ketamine, MK-801, and phencyclidine in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects [differential-reinforcement-of-low-rate (DRL) 72 s schedule of food reinforcement] and abuse-related drug effects [intracranial self-stimulation (ICSS)]. Under DRL 72 s, ketamine produced an antidepressant-like effect by increasing reinforcers, decreasing responses, and producing a rightward shift in the peak location of the interresponse time (IRT) distributions. Phencyclidine produced a modest antidepressant-like effect by increasing reinforcers and decreasing responses, but did not shift the IRT distributions. In contrast, MK-801 produced a psychostimulant-like effect by decreasing reinforcers, increasing responses, and producing a leftward shift in the peak location of the IRT distributions. The antidepressant-like effects of ketamine on the DRL 72 s procedure do not appear to be mediated by inhibiting the reuptake of serotonin via serotonin transporters or antagonism of 5-HT2 receptors. Additionally, the dissociable effects of ketamine and MK-801 in the DRL 72 s procedure may be mediated by 5-HT2 receptors. Following acute administration, ketamine produced only dose- and time-dependent depression of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. In contrast, MK-801 and phencyclidine effects produced dose- and time-dependent facilitation of ICSS by MK-801. Taken together, our findings provide further evidence that expression of these antidepressant-like and abuse-related effects of ketamine, phencyclidine, and MK-801 may be related to NMDA receptor affinity.
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Wang, Yachao [Verfasser], and Dirk [Akademischer Betreuer] Hermann. "Post-acute delivery of NMDA or GABAA α5 receptor antagonists promotes neurological recovery and peri-infarct brain remodeling after transient focal cerebral ischemia in mice / Yachao Wang ; Betreuer: Dirk Hermann." Duisburg, 2019. http://d-nb.info/1191692272/34.
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Berry, Jennifer N. "THE MESOCORTICOLIMBIC DOPAMINE PATHWAY RECONSTITUTED IN VITRO: GLUTAMATE RECEPTORS AND CORTICOSTEROID-METHAMPHETAMINE NEUROTOXICITY." UKnowledge, 2013. http://uknowledge.uky.edu/psychology_etds/28.
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Stress promotes the use of methamphetamine and other recreational substances and is often implicated in relapse to stimulant use. Thus, it is of critical importance to examine the consequences of the co-occurance of stress and methamphetamine use. Activity of the glutamatergic N-methyl D-aspartate (NMDA) receptor system appears to be involved in the neurotoxic effects of both chronic stress and methamphetamine exposure. The current studies investigated the hypothesis that chronic pre-exposure to the stress hormone corticosterone (CORT) results in an increase of NMDA receptor activity and that this will potentiate the neurotoxic effects of methamphetamine (METH). Co-cultures of the ventral tegmental area, nucleus accumbens, and medial prefrontal cortex were pre-exposed to CORT (1 μM) for 5 days prior to co-exposure to METH (100 μM) for 24 hours to investigate the combined effects on neurotoxicity and protein density of NMDA receptor subunits. The combination of CORT and METH resulted in significant neurotoxicity within the medial prefrontal cortex compared to either CORT or METH alone. The CORT+METH-induced toxicity was attenuated by co-exposure to the NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 50 μM) during the 24 hour CORT and METH co-exposure. Although CORT alone did not significantly alter the density of the NR1 and NR2B subunits of the NMDA receptor, METH exposure for 24 hours resulted in a significant loss of the polyamine sensitive NR2B subunit. Co-exposure to CORT and METH also resulted in decreased extracellular glutamate while not significantly altering extracellular dopamine. These results suggest an enhancement of NMDA receptor systems or downstream effectors in areas of the mesolimbic reward pathway following chronic pre-exposure to CORT, which leads to enhanced neuronal vulnerability to future excitotoxic insults. This may be of critical importance as use of psychostimulants such as METH and other drugs of abuse may produce excitotoxic events in these areas, thus further compromising neuronal viability.
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Deshpande, Laxmikant Sudhir. "Glutamate Excitotoxicty Activates a Novel Calcium Permeable Ion Channel in Cultured Hippocampal Neurons." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/688.
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Glutamate excitotoxicity is the predominant mechanism implicated in neuronal cell death associated with neurological disorders such as stroke, epilepsy, traumatic brain injury and ALS. Excessive stimulation of NMDA subtypes of glutamate receptors leads to protracted intracellular calcium elevations triggering calcium mediated neurotoxic mechanisms culminating in delayed neuronal cell death. In addition, glutamate excitotoxicity induces a NMDA dependent extended neuronal depolarization mediated by continuous calcium influx that correlates with delayed neuronal death. Attempts to prevent neuronal death by blocking calcium entry into the neurons using calcium channel blockers or NMDA receptor antagonists have failed to provide any beneficial effects in clinical trials. Thus, calcium continues to enter the neurons despite the presence of calcium entry blockers. This phenomenon is known as the "calcium paradox of stroke" and represents a major problem in developing effective therapies for treatment of stroke. Here employing a combination of patch clamp recordings, fluorescent calcium imaging and neuronal cell death assays in well-characterized in vivo and in vitro models of glutamate excitotoxicity, we report the discovery of a novel calcium permeable ion channel that is activated by excitotoxic glutamate injury and mediates a calcium current that is an early initiating step in causing neuronal death. Blocking this calcium permeable channel with high concentrations of Zn2+ or Gd3+ by removing extracellular calcium for a significant time period after the initial injury is effective in preventing calcium entry, apoptosis and neuronal death, thus accounting for the calcium paradox. This injury induced-calcium permeable channel provides a unique mechanism for calcium entry following stroke and offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.
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Jezequel, Julie. "Impact of psychotomimetic molecules on glutamatergic N-Methyl-D-Aspartate receptors surface trafficking." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0232/document.
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Les récepteurs glutamatergiques de type N-Méthyl-D-Aspartate (RNMDA) jouent un rôle majeur dans de nombreux processus physiologiques, et leur implication dans la physiopathologie de certains troubles neuropsychiatriques tels que la schizophrénie est suggérée par un robuste faisceau de données cliniques et précliniques. Cependant, les mécanismes cellulaires et moléculaires conduisant à une telle dérégulation des RNMDA restent inexpliqués. La diffusion membranaire, mécanisme de contrôle spatial et temporel de la distribution des RNMDA à la surface des neurones, constitue un puissant régulateur de la transmission synaptique. Mon projet de thèse repose ainsi sur l’hypothèse originale qu’une altération de la diffusion de surface des RNMDA jouerait un rôle central dans l’émergence de troubles psychotiques. Afin d‘explorer cette piste, j’ai étudié l’impact de molécules aux propriétés psychomimétiques (i.e induisant un état psychotique) sur la diffusion de surface des RNMDA. Les résultats obtenus au cours de ma thèse démontrent que des molécules psychomimétiques, aux modes d’action distincts (antagonistes du RNMDA et autoanticorps anti-RNMDA), perturbent la diffusion membranaire ainsi que la localisation synaptique des RNMDA, conduisant à terme à des défauts de transmission glutamatergique. Mon travail de thèse propose donc qu’un défaut de diffusion membranaire des RNMDA conduirait à des altérations fonctionnelles pouvant contribuer à l’émergence de troubles psychotiques. L’ensemble de mon travail apporte ainsi un regard nouveau sur la mécanistique des troubles psychotiques et ouvre la voie à de nouvelles pistes thérapeutiquesGlutamatergic N-Methyl-D-Aspartate receptors (NMDAR) play a key role in many physiological processes, and their implication in the pathophysiology of several neuropsychiatric disorders is now well established. Multiple lines of evidence converge towards a dysregulation of the NMDAR in psychotic disorders such as schizophrenia (SCZ). However, the molecular and cellular deficits underlying NMDAR dysfunction remain misunderstood. By tightly controlling NMDAR synaptic localization, surface trafficking represents a powerful regulator of synaptic transmission. Could an alteration of NMDAR surface trafficking underlie NMDAR dysfunction and contribute to the emergence of psychotic disorders? To tackle this question, my PhD project aimed at investigating the impact of different psychotomimetic molecules on NMDAR surface trafficking. In the first part of my project, I explored the impact of NMDAR autoantibodies (NMDAR-Ab) from SCZ and healthy subjects. My results revealed that NMDAR-Ab from SCZ patients rapidly disturb NMDAR synaptic trafficking and distribution, through a loss of NMDAR-EphrinB2 receptor interaction, eventually preventing the induction of synaptic plasticity. In the second part of my PhD project, I showed that psychotomimetic NMDAR antagonists also alter NMDAR synaptic mobility and localization. Downregulation of PSD proteins expression prevented NMDAR antagonists-induced deficits, suggesting that such alterations ensue from modifications of NMDAR intracellular interactions. Taken together, these results demonstrate that psychotomimetic molecules profoundly impact NMDAR surface trafficking, supporting a pathogenic role of this unsuspected process in the emergence of psychotic symptoms
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Bradford, Andrea Marie. "Molecular pharmacology of a novel NR2B-selective NMDA receptor antagonist." Thesis, Durham University, 2006. http://etheses.dur.ac.uk/2736/.
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The NMDA receptor is a heteromeric ligand-gated ion channel in the central nervous system (CNS). There are three families of NMDA receptor subunits with various combinations of NRl, NR2A-D and NR3A֊B subunits producing unique receptors with distinctive pharmacological and biochemical properties. Pharmacological and functional properties of the NMDA receptor are highly dependent on the composition of the receptor complex. The NMDA receptor is the focus of drug development for therapy and prevention of numerous neurological and psychiatric disorders. The focus of this thesis was to investigate NMDA receptor subtype selectivity of NMDA antagonists, in particular, RGH-896, a novel NR2B֊selective antagonist. The study has utilised radioligand binding competition binding assays with RGH-896 in native, recombinant and immunopurified NMDA receptor preparations. In addition, ligand autoradiography has been employed to quantify and delineate the regional distribution of [^3H] RGH-896 binding sites in rodent and human brain tissue. This study provides the first evidence that [3H] RGH-896 binds to a distinct binding site which displays a significantly lower affinity for spermidine compared to the [^3H] Ro 25,6981 binding site. In addition, the low sensitivity of [^3H] MK-801 for unlabelled RGH-896 compared to prototypical NR2B ligand ifenprodil is further evidence for the difference in binding sites. Novel immunopurification studies using [3H] RGH-896, in contrast to [3H] CP 101,606, binds to NR2B-containing receptors irrespective of NMDA receptor subunit combinations. Ligand autoradiography in human brain has shown a surprising overall preservation of NR2B receptors in dementia with Lewy bodies (DLB) patients compared to age matched controls in the anterior cingulate cortex (ACC). However, this study has revealed the first evidence of an upregulation of NR2B receptors in ACC of DLB cases related to severity of auditory, but not visual hallucinations.
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Montezuma, Karina. "Efeito de antagonistas do receptor NMDA sobre a metilação do DNA." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-24102016-163014/.
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A depressão é uma doença com alta incidência na população mundial e os antidepressivos atualmente disponíveis não são completamente eficazes. Esses fármacos apresentam uma latência de 2-4 semanas para induzir uma melhora significativa dos sintomas e cerca de 45% dos pacientes não respondem ao tratamento, cujo mecanismo é baseado na facilitação da neurotransmissão monoaminérgica no SNC. Por outro lado, recentemente tem sido demonstrado que a ketamina, antagonista do receptor de glutamato do tipo NMDA induz um efeito antidepressivo rápido e sustentado em animais e pacientes. No entanto, o uso dessa droga para o tratamento da depressão possui diversas limitações e, assim, o entendimento dos mecanismos subjacentes à sua ação antidepressiva pode contribuir para o desenvolvimento de novas e melhores alternativas terapêuticas. Estes mecanismos parecem ser mais complicados do que simplesmente o bloqueio do receptor NMDA, dado que tal bloqueio com o antagonista MK-801, por exemplo, induz efeito tipo-antidepressivo no teste do nado forçado (FST) por até 3 horas, mas sem reproduzir os efeitos prolongados da ketamina. Por isso, a cascata de eventos neuroquímicos iniciada após a administração de ketamina que culmina com a regulação da expressão gênica e síntese de proteínas relacionadas aos processos de plasticidade neural têm sido alvo de grande investigação a fim de se compreender o mecanismo de ação subjacente ao efeito antidepressivo rápido e sustentado dessa droga. A expressão desses genes pode ser modulada por mecanismos epigenéticos, como a metilação do DNA, um processo realizado por DNA metiltransferases (DNMTs), que também tem apresentado grande relevância para a neurobiologia da depressão. Diante disso, o presente estudo teve como objetivo avaliar os efeitos da administração de antagonistas do receptor NMDA, ketamina e MK-801, em doses e protocolos de tratamento que promovam efeito tipo-antidepressivo no FST, sobre a metilação do DNA em estruturas encefálicas importantes para a neurobiologia da depressão, em animais submetidos ou não ao estresse de nado forçado. Para tanto, primeiramente, foram delineados protocolos experimentais para análise do efeito tipo-antidepressivo destas drogas: Em ratos, administração sistêmica aguda de S(+)-ketamina 10 mg/Kg ou MK-801 0,025 mg/Kg 23 horas após a sessão pré-teste e 1 hora ou 7 dias antes da sessão teste do FST, permitiu a análise de um efeito tipo-antidepressivo rápido e sustentado induzido pela ketamina e apenas rápido pelo MK-801. Em seguida, utilizando estes protocolos, avaliou-se os efeitos do estresse do pré-teste do FST e do tratamento com tais antagonistas do receptor NMDA sobre os níveis de metilação global do DNA e expressão de DNMT3a e DNMT3b no córtex frontal, hipocampo ventral e dorsal dos animais. Foram encontradas alterações nas quantificações realizadas, sugerindo que o estresse e o tratamento podem induzir efeitos importantes sobre a metilação do DNA nas estruturas analisadas. Além disso, o tratamento com ketamina ou MK-801 parecem induzir efeitos diferenciais em algumas regiões, o que poderia estar associado aos efeitos também distintos que apresentam sobre a ação antidepressivaAlthough depression presents a high incidence in the world population, currently available antidepressants exhibit a latency of 2-4 weeks to induce a significant improvement of symptoms and around 45% of patients do not respond to these drugs. On the other hand, it has been recently shown that ketamine, a NMDA receptor antagonist, induces a rapid and sustained antidepressant effect in animals and patients. However, the use of this drug for depression treatment has several limitations and, thus, the understanding of the mechanisms underlying its antidepressant action could present a significant importance for the development of new and better therapeutic alternatives. These mechanisms appear to be more complex than the initial blockade of the NMDA receptor, since such blockade by MK-801, for example, reduces the immobility time of mice submitted the forced swimming test (FST) for up to 3 hours, without reproducing the sustained effects of ketamine. Therefore, the cascade of neurochemical events that are initiated after ketamine administration that culminate in the regulation of gene expression and syntehsis of proteins related to neuronal plasticity has been the focus of intense investigation. These genes, in turn, can be modulated by epigenetic mechanisms such as DNA methylation, a process performed by DNA methyltransferase (DNMTs), which has also shown a high relevance to the neurobiology of depression and its treatment. Based on that, the present study aimed at investigating the effects induced by ketamine and MK-801, at doses and treatment protocols that promote antidepressant-like effect in the FST, upon DNA methylation in brain structures of animals submitted or not to the forced swim stress. The first experimental protocols were designed for the analysis of acute and sustained drug-induced antidepressant-like effects: In rats, acute systemic administration of S(+)-Ketamine 10 mg/Kg or MK-801 0.025 mg/Kg 23 hours after the pretest session and 1 hour or 7 days before the test session of FST was investigated. Based on these protocols, the effects of stress (FST) and of treatment with NMDA receptor antagonists were investigated on global DNA methylation levels and DNMT3a and Dnmt3b expression in the rat frontal cortex, ventral and dorsal hippocampus. Both, stress and treatment, induced changes in DNA methylation and DNMT3 expression in some of the brain regions analised. In addition, treatment with MK-801 and ketamine seem to induce differential effects in some areas, which could also be associated with different effects that they present on antidepressant action.
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MacQueen, David A. "Non-competitive NMDA receptor antagonist impairs olfactory memory span in rats." View electronic thesis (PDF), 2009. http://dl.uncw.edu/etd/2009-1/macqueend/davidmacqueen.pdf.
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Simma, Narasimhulu [Verfasser], and Ursula [Akademischer Betreuer] Bommhardt. "The role of NMDA-receptors (NMDARs) and NMDAR antagonists in murine T- and B-lymphocyte function / Narasimhulu Simma. Betreuer: Ursula Bommhardt." Magdeburg : Universitätsbibliothek, 2015. http://d-nb.info/1081981423/34.
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Rao, Rahul Ramesh. "The uncompetitive NMDA receptor antagonist memantine blocks compulsive eating of palatable food." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12200.
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Thesis (M.A.)--Boston UniversityBinge-eating disorder is one of the most prevalent illnesses in the U.S. today and is characterized by short periods of excessive consumption of palatable food. Our study sought to explore the role of the glutamatergic system, one of the key neural pathways associated with reward-related learning and motivation, in binge-eating. We trained male rats to consume either a highly palatable diet or a standard chow diet within a limited time frame (1 hr/day) on a fixed ratio 1 (FR1) schedule of reinforcement. The palatable- fed rats quickly developed “bingeing” behavior and exhibited compulsive eating and risk- taking behavior when faced with an aversive environment. We evaluated the effects of systemic administration of the uncompetitive NMDA receptor antagonists, ketamine and memantine, and found that memantine significantly decreased FR1 responding and compulsive eating of palatable food, but not chow, and reduced the difference in risk- taking behavior between the palatable-fed and chow-fed groups. Site-specific injections of memantine into the nucleus accumbens, a key region of reward processing, also decreased responding for food selectively in the bingeing rats. These findings, taken together, implicate the glutamatergic system within the mesolimbic reward pathway in modulating neuroadaptive mechanisms that lead to the development of binge-eating disorder and suggest a potential pharmacological strategy to combat this debilitating disease.
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Ulmen, Adam Richard. "The NMDA receptor antagonist MK-801 renders pavlovian fear conditioning state-dependent." Kent State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1430140456.
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Banks, Paul James. "Molecular mechanisms of NMDA receptor antagonism and neuroprotection by general anaesthetics." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516551.
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Chopra, Bela. "Characterisation of the binding of two novel glycine site antagonists to NMDA receptors." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392169.
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Pozzi, Laura. "Role of the transcription factor creb in the nmda receptor antagonist-induced attention deficits." Thesis, Open University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542446.
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Moradabbasi, Arman. "Läkemedelsbehandling av opioid-inducerad hyperalgesi med NMDA-receptor antagonister och opioidrotation : - en litteraturstudie." Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-106298.
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Gomes, Felipe Villela. "Tratamento repetido com canabidiol atenua alterações comportamentais e moleculares em um modelo de esquizofrenia baseado no antagonismo dos receptores NMDA." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-05012016-224242/.
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Dados pré-clínicos e clínicos indicam que o canabidiol (CBD), um composto não-psicotomimético presente na planta Cannabis sativa, induz efeitos tipo-antipsicóticos. No entanto, poucos estudos em animais de laboratório investigaram as propriedades antipsicóticas do tratamento repetido com CBD. As alterações comportamentais induzidas pelo tratamento repetido com antagonistas dos receptores glutamatérgicos do tipo N-metil-D-aspartato (NMDA) têm sido propostas como um modelo animal de esquizofrenia. Evidências sugerem que uma hipofunção dos receptores NMDA estaria envolvida nos sintomas positivos, bem como nos sintomas negativos e cognitivos da esquizofrenia. Assim, no presente estudo, nós avaliamos se o tratamento repetido com CBD atenuaria as alterações comportamentais e moleculares induzidas pela administração crônica de um desses antagonistas, o MK-801. Camundongos C57BL/6J receberam injeções intraperitoneais diárias de MK-801 (0,1, 0,5 ou 1 mg/kg) durante 14, 21 ou 28 dias. Vinte e quatro horas após a última injeção, os animais foram submetidos ao teste de inibição pelo pré-pulso (PPI). Posteriormente, foi avaliado se o tratamento repetido com CBD (15, 30 e 60 mg/kg) atenuaria o prejuízo no teste de PPI induzido pelo MK-801 (1 mg/kg; por 28 dias). O tratamento com CBD iniciou-se no sexto dia após o início da administração de MK-801 e continuou até o final do tratamento. Nós também avaliamos se o tratamento com CBD atenuaria as alterações comportamentais induzidas pelo MK-801 nos testes de interação social e reconhecimento de objeto. Imediatamente após os testes comportamentais, os cérebros dos animais foram removidos e processados para posterior avaliação de alterações moleculares. Foram avaliadas as alterações na expressão das proteínas FosB/FosB e parvalbumina, um marcador de atividade neuronal e uma proteína de ligação ao cálcio expressa em uma subclasse de interneurônios GABAérgicos, respectivamente. Alterações na expressão do RNAm para o gene da subunidade obrigatória GluN1 do receptor NMDA (GRN1) também foram avaliadas. Adicionalmente, um número crescente de estudos indica que condições neuroinflamatórias e células gliais, como microglia e astrócitos, parecem estar envolvidas na patogênese da esquizofrenia. E, devido ao fato que o CBD, além de suas propriedades antipsicóticas, também induz efeitos anti-inflamatórios e neuroprotetores, nós também avaliamos possíveis alterações na expressão de NeuN (um marcador neuronal), Iba-1 (um marcador de microglia) e GFAP (um marcador de astrócitos) induzidas pelos tratamentos. Os efeitos do CBD foram comparados àqueles induzidos pelo antipsicótico atípico clozapina. A administração de MK-801, na dose de 1 mg/kg, por 28 dias induziu um prejuízo no teste de PPI, um efeito atenuado pelo tratamento repetido com CBD (30 e 60 mg/kg). Adicionalmente, o CBD também foi capaz de atenuar os prejuízos nos testes de interação social e reconhecimento de objeto induzidos pelo MK-801. Além das alterações comportamentais, o tratamento repetido com MK-801 aumentou a expressão da proteína FosB/FosB e diminuiu a expressão da parvalbumina no córtex pré-frontal medial (CPFm). Uma diminuição da expressão do mRNA para GRN1 no hipocampo também foi observada. O tratamento com MK-801 resultou ainda em aumento no número de astrócitos GFAP-positivos no CPFm e na porcentagem de células microgliais Iba-1-positivas apresentando um fenótipo reativo no CPFm e hipocampo dorsal, mas sem alterar o número total de células Iba-1-positivas. Nenhuma alteração no número de células NeuN-positivas foi observada. Assim como para as alterações comportamentais, as alterações moleculares induzidas pelo MK-801 também foram atenuadas pelo CBD. Entretanto, o CBD por si só não induziu qualquer efeito. Além disso, os efeitos do CBD foram semelhantes àqueles induzidos pelo tratamento repetido com clozapina. Estes resultados indicam que o tratamento repetido com o CBD, semelhante à clozapina, atenuou as alterações comportamentais tipo-esquizofrenia e as alterações moleculares observadas após a administração repetida de um antagonista dos receptores NMDA. Estes dados reforçam a proposta de que o CBD possui propriedades antipsicóticas. Embora os possíveis mecanismos de ação envolvidos nesses efeitos não estejam completamente elucidados, eles poderiam envolver as propriedades antiinflamatórias e neuroprotetoras do CBD. Além disso, nossos dados suportam a visão de que a inibição da microglia ativada pode ser benéfica para a melhora dos sintomas da esquizofreniaPreclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate NMDA receptor antagonists have been proposed as an animal model of schizophrenia-like symptoms. Evidence suggests that NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. In the present study we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular changes induced by chronic administration of one of these antagonists, MK-801. Male C57BL/6J mice received daily intraperitoneal injections of MK-801 (0.1, 0.5 or 1 mg/kg) for 14, 21 or 28 days. Twenty-four hours after the last injection animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30 and 60 mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1 mg/kg; 28 days). We also evaluate if the repeated CBD treatment would attenuate the MK-801-induced behavioral changes in social interaction and novel object recognition tests. CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the behavioral tests, the mice brains were removed and processed to evaluate molecular changes. We measured changes in FosB/FosB and parvalbumin expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in the mRNA expression of the NMDA receptor GluN1 subunit gene (GRN1) were also evaluated. Additionally, an increasing number of data has linked schizophrenia with neuroinflammatory conditions, and glial cells, such as microglia and astrocytes, have become increasingly attractive as candidates accounting for the pathogenesis of schizophrenia. And besides its antipsychotic properties, CBD also induces anti-inflammatory and neuroprotective effects. Thus, we also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. MK-801 administration at the dose of 1 mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60 mg/kg) attenuated MK801-induced PPI impairment. CBD treatment also attenuated the impairment in social interaction and NOR tests induced by MK-801 treatment. Besides behavioral disruption, MK-801 treatment increased FosB/FosB expression and decreased parvalbumin expression in the mPFC. A decreased mRNA level of GRN1 in the hippocampus was also observed. Repeated MK-801 treatment also increased the number of GFAP-positive astrocytes in the mPFC and increased the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. In addition, no change in the number of NeuN-positive cells was observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDA receptor antagonist. These data reinforce the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms
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Anderson, Paul Michael. "Oscillations dans la bande de fréquence gamma dans des modèles de rongeurs pour la schizophrénie." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ025/document.
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La schizophrénie est un trouble mental débilitant qui se caractérise par des perturbations de la pensée, des émotions et de la cognition. Ces processus d’intégration fonctionnelle sont généralement associés à des oscillations bioélectriques cérébrales synchrones dans la bande de fréquence gamma (30-80 Hz), lesquelles sont aussi altérées chez des patients souffrant de schizophrénie. Ce travail de thèse vise à développer des méthodes et des outils pour étudier les mécanismes neuronaux sous-tendant les altérations de ces oscillations physiopathologiques. Pour ce faire, nous avons développé des modèles de rongeurs de laboratoire pour la schizophrénie. Nous avons démontré que des modifications génétiques ou pharmacologiques conduisent à des perturbations des oscillations gamma et que des médicaments antipsychotiques peuvent les modulerSchizophrenia is a debilitating mental disorder that is characterised by a breakdown in normal thought processes, blunted emotional responses and a variety of cognitive difficulties. Gamma frequency (30 – 80 Hz) oscillations are associated with many processes that are disrupted in people with schizophrenia memory, perception and attention. This thesis aimed to develop methods and tools to investigate the basic mechanisms that underlie the alterations in gamma frequency brain activity that are observed in patients suffering from schizophrenia. To do this we developed a variety of experimental animal models for schizophrenia. We successfully demonstrated that both genetic and pharmacological changes lead to alterations in gamma oscillations and that antipsychotic medications can modulate them
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Dorville, Agnès. "Optimisation des propriétés des antagonistes des récepteurs N-méthyl-D-aspartate et cholecystokinine-B par modélisation moléculaire." Paris 5, 1993. http://www.theses.fr/1993PA05P608.
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Miller, Laurence L. "A competitive NMDA receptor antagonist potentiates the effects of morphine on spatial and discrimination learning /." Electronic version (PDF), 2005. http://dl.uncw.edu/etd/2005/millerl/laurencemiller.pdf.
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Harris, L. J. W. "The short and long term effects of neonatal NMDA receptor antagonist treatment : a model for schizophrenia?" Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275312.
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Molina, Leonardo A. "Alteration of neural dynamics in the rat medial prefrontal cortex by an NMDA antagonist." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Neuroscience, c2012, 2012. http://hdl.handle.net/10133/3264.
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NMDA receptor antagonists such as Ketamine and PCP are potent psychoactive drugs used recreationally. This class of drug induces a number of phenomena in humans similar to those associated with schizophrenia including reduced selective attention, altered working memory, thought disorders and hallucinations. These psychotomimetic drugs have thus been used as a longstanding model to study this disease in animals. Importantly, such animal models allow for recording of brain activity using invasive techniques that are inappropriate in humans. Previous electrophysiological studies have shown that MK-801, a potent non-competitive NMDA receptor antagonist, increases gamma-frequency oscillations and produces a state of disinhibition in the prefrontal cortex of rats wherein the activity of putative excitatory pyramidal neurons increases while the activity of putative inhibitory interneurons decreases. These features are relevant to schizophrenia because molecular evidence suggests dysfunction of inhibitory cortical interneurons, while electroencephalographic recordings show altered gamma-frequency oscillations in this disease. It has been hypothesized that the disinhibited cortical state produces “noisy” information processing, but this has not been directly observed in the interaction of neuronal firing in either humans or animal models. We therefore tested this hypothesis by examining the synchronization of neural activity in the NMDA receptor antagonist model of schizophrenia. We used high-density electrophysiological recordings in the medial prefrontal cortex of freely moving rats before and after systemic injection of MK-801. Analysis of these recordings revealed that drug administration: (i) increases gamma power in field potentials in a manner dissociated from increased locomotion; (ii) does not change the gamma power in multi-unit activity; (iii) decreases spike synchronization among putative pyramidal neurons in the gamma range (30ms), and despite of this it (iv) does not change the synchronization between gamma-range field potentials or between sum-of-spikes and field potentials. These effects in synchronization may be revealing of potent cognitive effects associated with NMDA receptor antagonism, and may reflect impaired communication processing hypothesized to occur in schizophrenia.xi, 42 leaves : ill. ; 29 cm
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Gueremy, Thomas. "Agonistes et antagonistes au site glycine du récepteur NMDA : structures, propriétés et perspectives thérapeutiques." Paris 5, 1993. http://www.theses.fr/1993PA05P229.
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Willins, David L. "The role of excitatory amino acid receptors in the basal forebrain in the locomotor response produced by psychostimulants and the non-competitive NMDA receptor antagonist MK801 /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487779439846962.
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Blom, Emma-Clara. "Ketamine for treatment-resistant depression : Moving away from conventional antidepressants." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-20177.
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An increasing amount of research suggests Ketamine in subanaesthetic doses to be an effective antidepressant for Major Depressive Disorder (MDD) and Treatment-Resistant Disorder (TRD). After the finding that NMDA-receptor antagonists may hold antidepressant effect, several studies have suggested Ketamine to have great effect in relief of depressive symptoms. A time lag between biological and behavioural effects have been shown in currently available antidepressants and are not guaranteed to be efficient; only 30% of patients reach adequate response. The aim for this thesis is to systematically review available studies on the efficiency of Ketamine's antidepressant effects in patients with TRD. Scopus, Web of Science, and PubMed were the databases searched for relevant research regarding the subject. Six articles were included in the analysis. A compilation of the results presented a moderate to large effect size for Ketamine compared to placebo at 24 hours through day seven. It is of immense weight that prolonged adverse effects and possible abuse are taken into consideration for future research, as well as how to sustain the dramatic acute antidepressant effect of Ketamine.
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Greyling, Yolande. "N-methyl-D-aspartate (NMDA) and sigma receptor antagonism as neuroprotective strategy for polycyclic amines / Yolande Greyling." Thesis, North-West University, 2008. http://hdl.handle.net/10394/4202.
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Polycyclic cage compounds and their effects on different receptors and receptor channels have been studied extensively. It is evident that these compounds may prove to be of great value in future treatment of neurodegenerative diseases. Although many of the mechanisms involved in the process of neurodegeneration are still not fully elucidated, researchers are getting closer to identifying more and new possible targets for drug treatment.
In this study the focus was mainly on the effect of polycyclic cage compounds on calcium homeostasis, a key process in neurodegeneration. The role of sigma receptors in calcium homeostasis was also evaluated. As can be seen in the literature, these receptors are an exciting new prospect for drug targeting and treatment of not only neurodegenerative diseases but tumor related illnesses as well.
A series of pentacycloundecane derivatives containing sigma bias substituents were selected and synthesised using reductive amination. Their effect on intracellular calcium in synaptoneursomes, were evaluated using fluorescent techniques and their affinity for sigma receptors was determined through a radio ligand binding study on Sprague-Dawley rat liver membranes. The difference between the oxa-and aza derivatives as well as the effect of chain length between the cage and the piperidine moiety on calcium influx and binding affinity were evaluated.Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2009.
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Miller, Jonathan P. "Effects of the NMDA Receptor Antagonist MK-801 on the Timing and Temporal Processing of Short-Intervals in Rats." Bowling Green State University / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1131043294.
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Elhallaoui, Menana. "Modélisation moléculaire d'antagonistes non compétitifs du récepteur NMDA [N-Méthyl-D-aspartate]." Bordeaux 2, 1994. http://www.theses.fr/1994BOR2B003.
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Martin, Elodie. "Etude de l'impact des antagonistes du récepteur N-méthyl-D-aspartate (NMDA) dans la douleur neuropathique." Thesis, Université Clermont Auvergne (2017-2020), 2017. http://www.theses.fr/2017CLFAS012.
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Les antagonistes du récepteur N-méthyl-D-aspartate (NMDA) comme la kétamine, le dextrométhorphane et la mémantine sont utilisés pour la prise en charge de la douleur neuropathique. La kétamine est très efficace contre les douleurs neuropathiques réfractaires aux traitements conventionnels. Cependant, son utilisation est limitée du fait de nombreux effets indésirables. Un relais antalgique est alors proposé. Ce travail de thèse s’insère dans un programme de recherche dédié aux antagonistes du récepteur NMDA dans la prise en charge de la douleur neuropathique. Le premier objectif était d’évaluer dans une étude clinique randomisée, en simple insu, en groupes parallèles, contrôlée versus placebo, les effets antalgiques du dextrométhorphane et de la mémantine, administrés en relais de la kétamine chez 60 patients souffrant de douleurs neuropathiques d’origine périphérique. L’impact de ces traitements sur le statut cognitivo-émotionnel des patients et leur qualité de vie a également été examiné, ainsi que la modulation des effets de ces médicaments par le polymorphisme génétique impliqué dans le métabolisme (CYP2D6, CYP3A4,5), la biodisponibilité et l’élimination (NR1I2) de ces deux molécules. En parallèle une étude mécanistique centrée sur le dextrométhorphane a été réalisée chez vingt volontaires sains (étude randomisée, en double aveugle, en groupes croisés). L’objectif était d’étudier dans un modèle d’hyperalgie induite par le froid « Freeze injury » les caractéristiques pharmacologiques et mécanistiques déterminant les effets anti-nociceptifs, centraux et cognitifs du dextrométhorphane ainsi que le polymorphisme génétique impliqué dans leur modulation. Chez les patients, les effets antalgiques immédiats de la kétamine ont été confirmés et s’accompagnaient de l’amélioration des scores d’anxiété et de dépression, des aspects cognitifs et affectifs et du sommeil. Toutefois, par rapport au placebo, la mémantine et le dextrométhorphane n’ont pas permis de renforcer significativement l’antalgie induite par la kétamine. Chez les volontaires sains, le dextrométhorphane a révélé des effets anti-hyperalgiques suite à une sensibilisation périphérique et centrale. Cependant, aucun effet analgésique sur la douleur thermique aiguë n’a été observé. Ces deux approches clinique et mécanistique concernant l’effet curatif des antagonistes du récepteur NMDA ont permis d’une part de montrer : 1 - chez le patient, l’effet curatif prolongé de la kétamine et l’intérêt du dextrométhorphane et de la mémantine dans la prise en charge du retentissement négatif de la douleur neuropathique sur le statut cognitivo-émotionnel et la qualité de vie des patients; 2 - chez le volontaire sain, l’efficacité anti-hyperalgique du dextrométhorphane sur les phénomènes de sensibilisation périphérique et centrale ainsi que ses répercussions sédatives et cognitives. En complément de ces deux études et dans le but de confirmer en clinique les effets curatifs du dextrométhorphane sur le triptyque douleur-cognition-émotion, une étude clinique randomisée, en double aveugle, en groupes parallèles, contrôlée versus placebo est en cours de réalisation chez 40 patientes souffrant de douleur neuropathique chimio-induite subséquente au traitement du cancer du sein. En conclusion de ce travail de thèse, l’étude des effets du dextrométhorphane dans deux populations différentes souligne l’intérêt de la recherche translationnelle. Chez le sujet volontaire sain, le dextrométhorphane exerce un effet anti-hyperalgique marqué et provoque des effets centraux délétères. Chez le patient présentant une douleur neuropathique d’origine périphérique et étant répondeur à la kétamine, seule une tendance est observée en faveur de l’effet anti-nociceptif du dextrométhorphane donné en relais de la kétamine. En revanche l’administration de dextrométhorphane s’accompagne d’un certain bénéfice au niveau cognitif et sur la qualité de vie des patientsN-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine, dextromethorphan and memantine have gained an increasing interest in the management of neuropathic pain. In Pain Clinics, ketamine is widely used in the relief of neuropathic pain. However, its use in clinical practice is limited due to its numerous side effects. It is therefore necessary to propose to patients a drug relay with other NMDA receptor antagonists. This work is part of an academic program research dedicated to NMDA receptor antagonists in the management of neuropathic pain. Its first objective was to evaluate the antalgic effects of dextromethorphan and memantine. This randomized, single-blind, parallel-group, placebo-controlled study in 60 ketamine responder patients aimed also to assess the cognitive-emotional status of patients and their quality life. In parallel, a mechanistic study focusing on dextromethorphan was performed in 20 healthy volunteers in a randomized, double-blind, cross-over, placebo-controlled study. The objective was to investigate in a freeze-injury model the pharmacokinetic and mechanistic characteristics of the anti-nociceptive, central and cognitive effects of dextromethorphan as well as the genetic polymorphism involved in its response variability.In patients, the immediate analgesic effects of ketamine were confirmed with improved anxiety and depression scores, cognitive and affective aspects of pain, and different sleep parameters. However, memantine and dextromethorphan, compared to placebo, did not significantly increase the ketamine-induced analgesia. The analysis of the genetic polymorphism did not reveal any variability in the analgesic efficacy of these treatments. In healthy volunteers, dextromethorphan revealed anti-hyperalgesic effects following peripheral and central sensitization but no analgesic effect on acute heat pain. Moreover, the variability of the anti-nociceptive activity of dextromethorphan described in the literature seems to be more related to the genetic polymorphism of the CYP2D6 gene than to that of the CYP3A4,5 and ABCB1 genes. Finally, dextrorphan, the main active metabolite of dextromethorphan, appears to be responsible for the deleterious sedative and cognitive effects of the drug. These two clinical and mechanistic approaches concerning the curative effect of the NMDA receptor antagonists showed : 1 - in patients, the prolonged curative effect of ketamine and the interest of dextromethorphan and memantine in the management of the neuropathic pain-related cognitive-emotional and quality of life impairment; 2 - in healthy volunteers, the anti-hyperalgesic efficacy of dextromethorphan on peripheral and central sensitization and its sedative and cognitive side effects. In addition to these two studies, a randomized, double-blind, parallel-group, placebo-controlled clinical study is ongoing in 40 patients with chemotherapy-induced peripheral neuropathic pain subsequently to the treatment of breast cancer. In conclusion the assessment of the effects of dextromethorphan in two different populations led to discordant results. In the healthy volunteer, dextromethorphan exerts a marked anti-hyperalgesic effect and causes deleterious central effects. In the patient with peripheral neuropathic pain, only a trend is observed in favor of the anti-nociceptive effect of dextromethorphan given in ketamine responder patients. More studies with larger population are needed to determine the importance of the CYP2D6, CYP3A4,5 and ABCB1 genetic polymorphisms on the anti-nociceptive activity of dextromethorphan. The translational approach of this thesis does not allow a firm conclusion on the clinical use of dextromethorphan in the curative treatment of chronic peripheral neuropathic pain. The use of dextromethorphan as a preventive agent via other administration routes (i.e. local) or in combination with other drugs, all require further exploration in order to improve the benefit/risk ratio of this molecule
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Nakada, Hirohisa. "The effects of a non-competitive NMDA receptor antagonist FR115427 on LTP, spontaneous behaviour and performance in the water maze." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/21443.
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The effects of N-methyl-D-aspartate (NMDA) receptor antagonists on learning behaviour have been studied extensively as they block long-term potentiation (LTP), the surrogate neural model for memory storage mechanisms. However, NMDA receptor antagonists also induce prominent changes in motor behaviour and the role of this drug in learning impairment by blocking LTP or by inducing behavioural abnormality remains ambiguous. Thus competitive NMDA receptor antagonists are less than satisfactory pharmacological tools for resolving the above question since the doses required for both effects are indistinguishable. Furthermore, the non-competitive NMDA receptor antagonists like MK-801 (dizocilpine) induce pronounced behavioural effects at lower doses than those required to block LTP and severe ataxia inhibits the ability of animals to perform learning tasks involving motor ability. These features greatly reduce its usefulness as a pharmacological tool. In an attempt to resolve this issue, the novel non-competitive NMDA receptor antagonist, FR115427 ((+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride), was used in this thesis. Although its binding affinity to the NMDA receptors is about 10 times less than that of MK-801, it induces relatively mild ataxia which allows testing over a wider dose range. The faster kinetic profile of FR115427 has the additional advantage that it highlights the clear-cut time dependence of the drug's action. In conclusion, the action of FR115427 on LTP was temporally and dose dependently differentiated from that on spontaneous behaviour and learning. It is suggested that non-competitive NMDA receptor antagonists impair spatial learning by an unknown mechanism that need not be related to their action on LTP.
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Fritsch, Sébastien. "Synthèse de N-alkyl-a-amino-hydroxamates." Paris 5, 1993. http://www.theses.fr/1993PA05P161.
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Gibson, Cynthia J. "GABA-A Receptor Subunit Alterations Following Experimental Traumatic Brain Injury and the Effects of an NMDA Antagonist: A Western Blot Analysis." VCU Scholars Compass, 2001. http://scholarscompass.vcu.edu/etd/4707.
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Traumatic brain injury (TBI) produces an acute phase of neuronal excitation followed by a chronic phase of depressed neuronal function. Alterations in excitatory and inhibitory receptor interactions may be dynamically involved in subsequent long-term detriments in neuronal and cognitive functioning. TBI- induced elevations in intracellular calcium concentrations ([Ca2+]i) are mediated primarily by the NMDA receptor. Elevated [Ca2+]i may trigger intracellular mechanisms which drive changes in GABA-A receptor protein synthesis and expression, ultimately resulting in receptor dysfunction.
Western blot analysis was used to investigate alterations to GABA-A receptor subunits α1 and β33 in the hippocampus of rats 3 hours, 24 hours, or 7 days following TBI. No injury- induced alterations in protein expression were found for the β3 subunit, which in the hippocampus is primarily located on principal neurons (i.e., pyramidal and granule cells). No significant alterations to the α1 receptor were found 3 hours following TBl, but a significant increase in α1 protein was found 24 hours post- injury, and this increase persisted for at least 7 days. GABA-A receptors containing the α1 subunit are primarily located on interneurons, implying a potential strengthening of interneuron-mediated inhibitory tone during the chronic phase of TBI.
Study 2 used pre-injury injections of MK-801 (0.3 mg/kg) to block calcium influx through the NMDA receptor. This treatment normalized α1 protein expression 24 hours following injury (the time point of greatest change in study 1). NMDA-mediated calcium influx may, therefore, be responsible for triggering the cascade that results in increased GABA-A receptor α1 protein expression chronically following TBI.
These studies demonstrate that TBl produces an increase in GABA-A receptor α1, but not β3, subunits 24 hours and 7 days post-injury. The differential directions of the subunit changes may indicate a strengthening of inhibitory tone during the chronic phase of TBI, a period characterized by a depression of neuronal function. Although the exact mechanism of change to the α1 subunit is unknown, study 2 indicates that it is driven by NMDA-mediated elevations in [Ca2+]i. The functional consequences of increased inhibitory tone may contribute to long-term detriments in cognitive and behavioral outcome following injury.
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Broström, Jakob. "Ketamine for depression : The role of dissociative effects." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-18594.
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Several trials have reported rapid antidepressant response from the anesthetic drug ketamine although the mechanism behind this effect is not fully understood. Research has focused mainly on ketamine’s action in the brain, including its effects on chemical balance, connections between brain cells and networks, and cognition. Trials with psychedelic drugs have had similar antidepressant results as ketamine, and the quality of the subjective psychedelic experience seems to mediate antidepressant action. Ketamine causes similar alterations of consciousness, which have been viewed as side effects. This thesis examines whether ketamine works in a similar way as psychedelics, where the ketamine-induced dissociative-like experience has a relationship to antidepressant response. Leading theories of depression and ketamine’s action in the brain are presented, and eight studies examining the relationship between ketamine-induced subjective experience and antidepressant response are reviewed. Three included studies found a relationship between psychedelic- and dissociative-like symptoms and reduction in depression, while five did not. The supposed relationship between psychedelic- and dissociative-like symptoms and antidepressant action has not been adequately explored and needs further examination in clinical trials.
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Vergara, Padilla Andrea Paz. "Efecto antinociceptivo e interacción de un antagonista competitivo y uno no competitivo del receptor NMDA en un modelo de dolor crónico en rata." Tesis, Universidad de Chile, 2007. http://repositorio.uchile.cl/handle/2250/132166.
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Memoria para optar al Título Profesional de Médico VeterinarioEl receptor NMDA puede ser funcionalmente modulado por ligandos que actúan en diversos sitios del receptor. En el presente estudio se investigó la acción antinociceptiva de fármacos que actúan en distintos sitios de modulación del receptor: (±) CPP (bloqueador competitivo del sitio de glutamato), ketamina (bloqueador no competitivo del receptor), así como de combinaciones equianalgésicas de (±) CPP y ketamina, administrados por vía intratecal. Se utilizaron ratas Sprague-Dawley macho a las que se les indujo monoartritis mediante la administración intra-articular de adyuvante de Freund completo. La nocicepción fue evaluada electrofisiológicamente bajo anestesia, mediante el test de reflejo nociceptivo C y el wind-up espinal. Los resultados mostraron que en las ratas monoartríticas los fármacos y sus combinaciones indujeron efectos antinociceptivo dosis-dependiente de magnitud variable: (±) CPP fue más potente que ketamina; la combinación (±) CPP/ketamina mostró solo un efecto aditivo. Se concluye que la utilización de antagonistas competitivos y no competitivos del receptor NMDA o de sus combinaciones frente a dolor artrítico es actualmente no viable, porque aquellos fármacos más activos presentan efectos colaterales psicodislépticos a las dosis que producirían un efecto antinociceptivo substancial. La combinación de estos fármacos, por vía intratecal y en animales anestesiados, no representa una alternativa superior a los fármacos individuales
Proyecto FONDECYT 1040873
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LANNES, BEATRICE. "Interactions entre neurotransmissions dopaminergique et glutamatergique dans le striatum. Aspects neurobiologiques chez le rat traite chroniquement par antagonistes du recepteur nmda." Université Louis Pasteur (Strasbourg) (1971-2008), 1994. http://www.theses.fr/1994STR13018.
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L'objectif de ce travail etait d'etudier certaines consequences d'un traitement chronique par antagonistes nmda sur la neurotransmission dopaminergique chez le rat. Nous avons observe: une hypersensibilite pharmacologique a l'administration aigue d'agoniste (apomorphine) et d'antagoniste (haloperidol) dopaminergiques; l'absence de modification du taux, de la liberation et du taux de renouvellement de la dopamine dans le striatum; une augmentation de la synthese de recepteurs d2 (rd2) dans le striatum; la detection de l'arnm codant pour le rd2 dans des neurones dans lesquels il n'etait pas detecte chez les temoins. Ceci suggere que la neoexpression du gene du rd2 est une potentialite des neurones striataux. D'autre part, nous avons observe qu'une injection aigue et unique d'haloperidol entrainait une hypersensibilite pharmacologique a l'haloperidol, sans modification de la sensibilite a l'apomorphine. Au contraire, une administration chronique d'antagonistes d2 entraine une hypersensibilite vis-a-vis d'un agoniste d2 et une hyposensibilite vis-a-vis d'un antagoniste d2. Ceci suggere qu'in vivo, les recepteurs d2 peuvent presenter des etats fonctionnels differents. Ces differents etats sous-tendent des differences de reactivite aux agonistes et aux antagonistes. La neoexpression du gene du rd2 par certains neurones striataux pourrait participer au substrat neurobiologique d'un etat fonctionnel donne du rd2
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López, Gil Javier. "Efectos de los antagonistas NMDA sobre la neurotransmisión serotonérgica y glutamatérgica en la corteza prefrontal. Mecanismo de acción de los fármacos antipsicóticos." Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/922.
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La sintomatología esquizofrénica es múltiple y variada. En general, los síntomas se dividen en positivos o psicóticos (alucinaciones, pensamiento aberrante), negativos (falta de motivación, aislamiento social, depresión) y déficits cognitivos (problemas de atención y aprendizaje, de la memoria operativa). En el estudio de esta enfermedad se utilizan modelos farmacológicos como es el de los antagonistas del receptor NMDA. Estos compuestos, la ketamina, PCP y MK-801, provocan los tres tipos de síntomas en individuos sanos y los exacerban en pacientes de esquizofrenia. Administrados a animales de experimentación, provocan alteraciones del comportamiento así como de la neurotransmisión en la corteza prefrontal. Estos efectos pueden ser revertidos mediante la administración de fármacos antipsicóticos. En la presente tesis doctoral hemos estudiado las consecuencias de la administración de los antagonistas NMDA sobre la neurotransmisión serotonérgica y glutamatérgica en la corteza prefrontal, así como las posibles regiones del cerebro donde pueden estar actuando estos compuestos. Los resultados obtenidos muestran que la administración sistémica del antagonista NMDA, MK-801, provoca un incremento de la concentración extracelular de serotonina y glutamato en la corteza prefrontal, efecto que no se reproduce con su perfusión unilateral intracortical. Debido a esta falta de efecto local, se perfundió MK-801 en las posibles zonas candidatas donde podría estar actuando. Las principales entradas excitatorias a la corteza prefrontal provienen de la corteza prefrontal contralateral y, a nivel subcortical, del núcleo medio dorsal del tálamo y el hipocampo ventral. Mientras que la administración de MK-801 en el hipocampo, así como en el núcleo reticular o el pálido ventral (núcleos que ejercen el control inhibitorio sobre el tálamo en rata) no produjo ningún cambio en los niveles corticales de serotonina, la perfusión de MK-801 de forma bilateral en la corteza prefrontal izquierda y derecha sí aumentó la concentración de serotonina cortical. La perfusión unilateral de TTX en la corteza izquierda fue capaz de bloquear el incremento de serotonina en la corteza derecha tras la administración sistémica de MK-801, sugiriendo que, efectivamente, hace falta una acción bilateral para que el MK-801 provoque sus alteraciones sobre la neurotransmisión serotonérgica cortical. En este trabajo hemos estudiado también el mecanismo de acción de los fármacos antipsicóticos: el papel que tiene la corteza prefrontal en sus efectos y los principales receptores a través de los cuales actúan para revertir las alteraciones de los antagonistas NMDA. Comprobamos que, mientras que tanto los antipsicóticos clásicos como los atípicos fueron capaces de bloquear el incremento de glutamato cortical, solo los antipsicóticos atípicos fueron capaces de bloquear el incremento de serotonina tras la administración de MK-801. Esta capacidad se observó tanto con la administración sistémica de los fármacos como con su administración local, hecho que sugiere que los antipsicóticos están realizando parte de su acción de forma local en la corteza prefrontal. Con el fin de estudiar el mecanismo de acción de estos fármacos, se perfundieron compuestos específicos para los principales receptores a través de los cuales podrían estar actuando los antipsicóticos. Los resultados mostraron que, mientras que los compuestos que actuaban sobre los receptores dopaminérgicos no fueron capaces de bloquear el incremento de serotonina cortical (aunque sí el de glutamato) producido por el MK-801, los que actuaban en los receptores serotonérgicos o adrenérgico sí que fueron capaces de bloquear tanto el aumento de serotonina como de glutamato. Los resultados aquí presentados muestran la importancia de la corteza prefrontal en este modelo de esquizofrenia y en el tratamiento de la enfermedad, intentando así desvelar parte del sustrato anatómico de esta compleja patología.NMDA antagonists are used as a pharmacological model of schizophrenia because their administration to healthy individuals evokes psychotic and negative-cognitive symptoms. In experimental animals, the systemic administration of NMDA antagonists increases the extracellular concentration of dopamine, serotonin (5-HT) and glutamate in the medial prefrontal cortex (mPFC). In the present work, we have studied the effects of NMDA antagonists on the cortical transmission of serotonin and glutamate. The results show that the systemic administration of MK-801 increases mPFC levels of 5-HT and glutamate, alterations not reproduced after the unilateral perfusion of the drug in the mPFC. We then studied the brain regions where MK-801 could be exerting its actions, i.e. the hippocampus, the thalamus and the contralateral mPFC. The perfusion of MK-801 in the hippocampus, the ventral pallidum or the reticular nucleus (the latter areas are responsible for the inhibitory control of the thalamus) did not alter mPFC 5-HT. However, the bilateral perfusion of MK-801 in both mPFC (left and right) elicited an increase in 5-HT levels. The unilateral perfusion of TTX through the left probe was able to block the increase of serotonin in the right mPFC caused by the systemic administration of MK-801, thus suggesting that a bilateral perfusion is needed to induce the alterations on 5-HT neurotransmission. We also studied the mechanism of action of antipsychotic drugs. While both classical and atypical antipsychotics were able to block the MK-801-induced increase in glutamate levels, only the atypical antipsychotics were able to block cortical 5-HT. The local perfusion of antipsychotics reproduce the same effects than their systemic administration, which suggests that part of their actions are done locally in the mPFC. We also show that compounds that act on dopaminergic receptors where able to block the increase of cortical glutamate but not that of 5-HT following systemic MK-801. In contrast, compounds that act over the serotonergic or adrenergic receptors were able to block both the 5-HT and glutamate increases. The present results underscore the importance of the mPFC in this model of schizophrenia and in the pharmacological treatment of the illness.
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Espinosa, Aravena Jeannette Emilia. "Efecto antinociceptivo e interacción sinérgica de un antagonista competitivo y uno no competitivo del receptor NMDA en un modelo de dolor crónico en rata." Tesis, Universidad de Chile, 2006. http://repositorio.uchile.cl/handle/2250/140982.
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Trabajo de Investigación Requisito para optar al Título de Cirujano DentistaEl receptor NMDA puede ser funcionalmente modulado por Iigandos que actúan en diversos sitios del receptor. En el presente estudio se investigó si la asociacion de ketamina (bloqueador no competitivo del receptor) con (±) CPP (bloqueador competitivo del sitio de glutamato) administrados por via intratecal produce sinergia en ratas normales y monoartrlticas frente a nocicepcion química. Se utilizaron ratas Sprague- Dawley macho adultas a las que se les indujo rnonoartritis mediante la administración mira-articular de adyuvante de Freund eompleto, y la nocieepción quimica fue evaluada mediante el test de administración intraplanlar de capsaicina ( 1.5 ug/25 uL). Como controles se utilizaron ratas normales. Los resultados mostraron que tanto en las ratas normales como monoartriticas los fármacos indujeron un efecto am-inociceptivo dosis- dependiente: ketamina (DE50 = 4.37 ug/rata normal: DE50= 0.93 ug/rata monoartrítica), (±)CPP (DE50= 11.05 ug/rata normal; DE50 = 0.73 ug/rata monoartrítica›. igualmente, la asociación ketamina/(±ìCPP mostró un efecto supra-aditivo tanto en las ratas normales como monoartríticas (DE50 = 0.04 ug/rata normal; DE = 0.01 ug/rata monoartritica). Se concluye que la asociación estudiada es supra-aditiva en dolor de tipo químico, lo que podria deberse a que el receptor vaniloide VR-l está presente esencialmente en nociceprores tipo C, fundamentales en este tipo de dolor.
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Cunha, Aline Andrea da. "Avaliação do uso do antagonista dos receptores NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de lesão pulmonar aguda." Pontifícia Universidade Católica do Rio Grande do Sul, 2007. http://hdl.handle.net/10923/1383.
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Previous issue date: 2007Acute Lung Injury (ALI) is a syndrome of acute respiratory failure that results from pulmonary inflammation and acute pulmonary edema caused by the increased permeability of the alveolar-capillary barrier. In ALI, capillary endothelium and alveolar epithelium damage occurs resulting from the release of proinflammatory molecules, mainly cytokines, as a response to systemic insults. Free radical production is another important pathologic mechanism mediated by neurophils, which are capable of developing several clinical disorders found in ALI. It is well known that endogenous glutamate production stimulates the release of many inflammatory mediators, including aracdonic acid metabolites, free radicals and nitric oxide (NO). The first report describing a possible involvement of NMDA receptors in pulmonary physiophatology was based on a treatment with a selective inhibitor to this receptor (MK-801) used for the prevention of pulmonary edema caused by the increase of NMDA instilled intratracheally in rats under mechanic ventilation. The aim of this study was to evaluate the use of NMDA receptor antagonist (MK-801) as a protection against the oxidative injury in experimental model of ALI. Adult male Wistar rats were used. The animals were randomly divided into four groups: (1) intratracheal instillation (I. T. ) of 1 mL isotonic saline (n=6); (2) ALI induction with intratracheal LPS (100 \g/100 g of body weight) plus treatment with saline administered intraperitoneally (I. P. ) after ALI (n=6); (3) ALI induction plus MK- 801 (0. 3 mg/kg administered I. P. ) after ALI (n=6); and (4) ALI induction plus MK-801 (0. 3 mg/kg administered I. T. ) after ALI (n=6). Twelve hours after the treatment, the animals were anesthetized for blood collection using retroorbital puncture and bronchoalveolar lavage (BAL) was collected as well. After that, the animals were killed by decapitation and lung tissue was colleted. The treatment with MK-801 promoted a decrease in the total protein concentration, LDH activity and in the total cell number in BAL. In the lung tissue we verified a decrease of the oxidative injury measured by TBARS and NO levels and an improvement in antioxidant levels such as CAT, SOD, GSH and SH. We also verified an improvement in the inflammatory process as observed by the histopathology analysis of lung tissue. The results obtained in this study let us to conclude that treatment with MK-801 promoted an improvement in the inflammatory process and antioxidant levels, as well as a decrease of the oxidative injury in rats with intratracheal LPS-induced ALI.
A lesão pulmonar aguda (LPA) é uma síndrome caracterizada por inflamação pulmonar aguda e persistente, com edema pulmonar devido ao aumento da permeabilidade vascular. Na LPA ocorre uma lesão do epitélio alveolar e do endotélio capilar por diferentes mediadores pró-inflamatórios, principalmente, pelas citocinas liberadas em resposta à grande variedade de insultos. A geração de radicais livres (RLs) é outro importante mecanismo de lesão utilizado pelos neutrófilos, que são capazes de gerar muitas das alterações encontradas na LPA. Sabe-se que a produção endógena de glutamato estimula uma variedade de mediadores inflamatórios, incluindo metabólitos do ácido araquidônico, RLs e óxido nítrico (NO). O primeiro relato de que os receptores NMDA poderiam estar envolvidos na fisiopatologia pulmonar ocorreu através da demonstração que o tratamento com um inibidor seletivo desse receptor (MK-801) prevenia o edema pulmonar provocado pelo aumento de NMDA instilado na traquéia de ratos sob ventilação mecânica.O objetivo deste trabalho foi avaliar o uso do antagonista de receptor NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de LPA. Foram utilizados ratos Wistar, machos. Os animais foram divididos em 4 grupos experimentais: Grupo 1: Injeção intratraqueal (I. T. ) de 1 mL de solução salina (n=6); grupo 2: Indução da LPA através da injeção de LPS intratraqueal (100 \g/100 g de peso corporal) e tratamento com solução salina intraperitoneal (I. P. ) após indução da LPA (n=6); grupo 3: Indução da LPA e tratamento com MK-801 (0. 3 mg/kg I. P. ) após indução da LPA (n=6) e grupo 4: Indução da LPA e tratamento com MK-801 (0. 3 mg/kg I. T. ) após indução da LPA (n=6). Doze horas após o tratamento, os animais foram anestesiados para a retirada do sangue por punção retro-orbital, coleta do lavado broncoalveolar (LBA) e posteriormente, submetidos à eutanásia por decapitação para coleta do tecido pulmonar.O tratamento com MK-801 promoveu uma diminuição na concentração de proteínas totais, uma diminuição na atividade da lactato desidrogenase (LDH), além de diminuir o número de células inflamatórias no LBA. No tecido pulmonar ocorreu uma diminuição do dano oxidativo avaliado através dos níveis de TBARS e NO, e um aumento nos níveis de antioxidantes como a CAT, SOD, GSH e SH. Também observamos uma melhora do processo inflamatório através da análise histopatológica do tecido pulmonar. Podemos concluir através de nossos resultados que o tratamento com MK-801 promoveu uma melhora do processo inflamatório, uma melhora nos níveis de antioxidantes e uma diminuição do dano oxidativo em ratos com LPA induzida através da injeção intratraqueal de LPS.
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Bender, Kelly Juliana Seibt. "Avaliação do potencial neuroprotetor de fármacos antipsicóticos em alterações bioquímicas, moleculares e comportamentais induzidas por antagonista de receptor NMDA (MK-801) em peixe zebra (Danio rerio)." Pontifícia Universidade Católica do Rio Grande do Sul, 2011. http://hdl.handle.net/10923/1418.
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Previous issue date: 2011Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. This pathology is still poorly understood. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics disease symptoms. Many animal models have shown their importance in the study of this disease and the zebrafish has been proposed as a promissor model to study the in vivo effects of several drugs and to discover new pharmacological targets. In this study we characterized the behavioral syndrome produced by the NMDA receptor antagonist, MK-801, exposure in zebrafish and investigated the ability of antipsychotic drugs to reverse the schizophrenia-like symptoms. MK-801 (20 μM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60 min of exposure. The antipsychotics sulpiride, olanzapine, and haloperidol counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Results showed that MK-801 (5 μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250 μM) and olanzapine (50 μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9 μM) was ineffective to reverse those behavioral deficits. Some evidence suggests that changes in the purinergic system, more specifically in adenosinergic activity, could be involved in the physiopathology of schizophrenia. In this study, we demonstrated that haloperidol treatment (9 μM) was able to decrease ATP hydrolysis (35%), whereas there were no significant changes in ADP and AMP hydrolysis in brain membranes. Adenosine deaminase activity in membrane fractions was significantly inhibited (38%) after haloperidol treatment when compared to the control group. Furthermore, haloperidol exposure also led to a decrease in NTPDase gene expression (entpd2_mq and entpd3), and adenosine deaminase (adal). Considering that the enzyme Na+,K+-ATPase is essencial to brain normal function, we evaluated the effect of MK-801 and antipsychotic drugs on activity this enzyme. Our results showed that MK-801 treatment significantly decreased Na+,K+-ATPase activity, and all antipsychotics tested prevented such effects. Moreover, it is known that oxidative stress may be associated with the physiopathology of schizophrenia and the Na+,K+-ATPase is particularly susceptible to free radical attack. We showed that MK-801 treatment did not alter reactive oxygen/nitrogen species by 2′7′-dichlorofluorscein (DCF) oxidation assay, but increased the levels of thiobarbituric acid reactive substances (TBARS), when compared to controls. The antipsychotics sulpiride, olanzapine, and haloperidol prevented the increase of TBARS caused by MK-801. Therefore, we demonstrated that zebrafish might present some behavioral and biochemical features observed in schizophrenia, being considered a promising animal model able to contribute for providing information on potential treatments and disease characteristics.
A esquizofrenia é uma doença mental grave caracterizada por sintomas positivos, negativos e déficits cognitivos que ainda é pouco compreendida. A redução da neurotransmissão glutamatérgica por antagonistas dos receptores NMDA mimetiza os sintomas da esquizofrenia. Muitos modelos animais têm mostrado sua importância para o estudo dessa doença, e o peixe-zebra tem sido proposto como um modelo promissor para estudar os efeitos in vivo de várias drogas e descobrir novos alvos farmacológicos. Neste estudo caracterizamos a síndrome comportamental produzida pela exposição ao antagonista do receptor NMDA, MK-801, no peixe zebra, e investigamos a capacidade dos fármacos antipsicóticos em reverter estes sintomas. MK-801 (20 μM) aumentou o comportamento locomotor que foi medido pelo número de linhas cruzadas, a distância percorrida e a velocidade média no aquário teste, após 15, 30 e 60 min de exposição. Os antipsicóticos sulpirida, olanzapina e haloperidol reverteram as alterações locomotoras induzidas pelo MK-801 em todos os parâmetros testados, e em doses que administrado isoladamente não tiveram efeito sobre a atividade locomotora. Modelos de interação social e déficits cognitivos em animais pode ser de grande utilidade para o desenvolvimento de novos tratamentos para os sintomas negativos e cognitivos da esquizofrenia. Os resultados mostraram que o MK-801 (5 μM) administrado antes do treino impediu a formação da memória, enquanto ambos os antipsicóticos atípicos sulpirida (250 μM) e olanzapina (50 μM) melhoraram a amnésia.A mesma alteração foi observada na tarefa de interação social, onde os antipsicóticos atípicos reverteram o déficit de interação social induzida pelo MK-801, enquanto o antipsicótico tipico testado, o haloperidol (9 μM), não foi capaz de reverter esse déficit comportamental. Algumas evidências sugerem que mudanças no sistema purinérgico, mais especificamente na atividade adenosinérgica, poderiam estar envolvidos na fisiopatologia da esquizofrenia. Nesse estudo, mostramos que o tratamento com haloperidol (9 μM) foi capaz de diminuir a hidrólise de ATP (35%), enquanto que não houve mudanças significativas na hidrólise de ADP e AMP em membranas cerebrais. A atividade da ADA em frações de membrana também foi inibida significativamente (38%) após o tratamento com haloperidol, quando comparado ao grupo controle. Além disso, a exposição ao haloperidol também promoveu uma diminuição na expressão gênica das NTPDases (entpd2_mq e entpd3) e adenosina desaminase (adal). Considerando que a enzima Na+, K+- ATPase é essencial para a função cerebral normal, avaliamos os efeitos do MK-801 e farmacos antipsicóticos na atividade desta enzima. Nossos resultados mostraram que o tratamento com MK-801 diminuiu significativamente a atividade da Na+, K+-ATPase, e todos os antipsicóticos testados impediram tais efeitos. Sabe-se que o estresse oxidativo pode estar associado com a fisiopatologia da esquizofrenia e que a Na+,K+-ATPase é particularmente suscetível ao ataque de radicais livres. Mostramos que o tratamento com MK-801 não alterou as espécies reativas de oxigênio/nitrogênio pelo ensaio de oxidação 2'7'-diclorofluorosceína (DCF), mas aumentou os níveis de substâncias reativas ao ácido tiobarbitúrico (TBARS).Os antipsicóticos haloperidol, sulpirida e olanzapina preveniram o aumento nos níveis de TBARS induzidos pelo MK-801. Portanto, demonstramos que o peixe zebra pode apresentar algumas características comportamentais e bioquímicas observadas na esquizofrenia, sendo considerado um promissor modelo animal capaz de contribuir na obtenção de informações sobre potenciais tratamentos e características da doença.
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Cunha, Aline Andrea da. "Avalia??o do uso do antagonista dos receptores NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de les?o pulmonar aguda." Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2008. http://tede2.pucrs.br/tede2/handle/tede/5529.
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Previous issue date: 2008-12-18A les?o pulmonar aguda (LPA) ? uma s?ndrome caracterizada por inflama??o pulmonar aguda e persistente, com edema pulmonar devido ao aumento da permeabilidade vascular. Na LPA ocorre uma les?o do epit?lio alveolar e do endot?lio capilar por diferentes mediadores pr?-inflamat?rios, principalmente, pelas citocinas liberadas em resposta ? grande variedade de insultos. A gera??o de radicais livres (RLs) ? outro importante mecanismo de les?o utilizado pelos neutr?filos, que s?o capazes de gerar muitas das altera??es encontradas na LPA. Sabe-se que a produ??o end?gena de glutamato estimula uma variedade de mediadores inflamat?rios, incluindo metab?litos do ?cido araquid?nico, RLs e ?xido n?trico (NO). O primeiro relato de que os receptores NMDA poderiam estar envolvidos na fisiopatologia pulmonar ocorreu atrav?s da demonstra??o que o tratamento com um inibidor seletivo desse receptor (MK-801) prevenia o edema pulmonar provocado pelo aumento de NMDA instilado na traqu?ia de ratos sob ventila??o mec?nica. O objetivo deste trabalho foi avaliar o uso do antagonista de receptor NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de LPA. Foram utilizados ratos Wistar, machos. Os animais foram divididos em 4 grupos experimentais: Grupo 1: Inje??o intratraqueal (I.T.) de 1 mL de solu??o salina (n=6); grupo 2: Indu??o da LPA atrav?s da inje??o de LPS intratraqueal (100 \g/100 g de peso corporal) e tratamento com solu??o salina intraperitoneal (I.P.) ap?s indu??o da LPA (n=6); grupo 3: Indu??o da LPA e tratamento com MK-801 (0.3 mg/kg I.P.) ap?s indu??o da LPA (n=6) e grupo 4: Indu??o da LPA e tratamento com MK-801 (0.3 mg/kg I.T.) ap?s indu??o da LPA (n=6). Doze horas ap?s o tratamento, os animais foram anestesiados para a retirada do sangue por pun??o retro-orbital, coleta do lavado broncoalveolar (LBA) e posteriormente, submetidos ? eutan?sia por decapita??o para coleta do tecido pulmonar. O tratamento com MK-801 promoveu uma diminui??o na concentra??o de prote?nas totais, uma diminui??o na atividade da lactato desidrogenase (LDH), al?m de diminuir o n?mero de c?lulas inflamat?rias no LBA. No tecido pulmonar ocorreu uma diminui??o do dano oxidativo avaliado atrav?s dos n?veis de TBARS e NO, e um aumento nos n?veis de antioxidantes como a CAT, SOD, GSH e SH. Tamb?m observamos uma melhora do processo inflamat?rio atrav?s da an?lise histopatol?gica do tecido pulmonar. Podemos concluir atrav?s de nossos resultados que o tratamento com MK-801 promoveu uma melhora do processo inflamat?rio, uma melhora nos n?veis de antioxidantes e uma diminui??o do dano oxidativo em ratos com LPA induzida atrav?s da inje??o intratraqueal de LPS.
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Silva, Naielly Rodrigues da. "Tratamento repetido com canabidiol reverte alterações comportamentais observadas em um modelo de esquizofrenia baseado no antagonismo dos receptores NMDA: possível envolvimento dos receptores 5-HT1A e CB1." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-22082017-144713/.
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Dados pré-clínicos e clínicos indicam que o canabidiol (CBD), um composto não-psicotomimético presente na planta Cannabis sativa, induz efeitos tipoantipsicóticos sem produzir efeitos extrapiramidais. Estudos realizados pelo nosso grupo mostram que o tratamento repetido com CBD atenuou as alterações comportamentais induzidas pelo tratamento repetido com MK-801, uma antagonista dos receptores NMDA, nos testes de reconhecimento de objeto (RO), utilizado no estudo de funções cognitivas, e teste de interação social (IS), utilizado para o estudo dos sintomas negativos da esquizofrenia quando ambas as drogas foram administradas concomitantemente. Estudos mostram que as alterações induzidas por antagonistas NMDA foram observadas até 6 semanas após o tratamento, sendo essas alterações revertidas por antipsicóticos atípicos como clozapina e aripripazol, mas não pelo haloperidol, um antipsicótico típico. Apesar das evidências indicarem o possível efeito tipo-antipsicótico do CBD o mecanismo de ação pelo qual ele exerce este efeito ainda não está elucidado, acredita-se que o sistema endocanabinoide e/ou o sistema serotoninérgico possam estar evolvidos. Assim, no presente estudo, nós avaliamos se o tratamento repetido por 7 dias com CBD seria capaz de reverter as alterações nos testes de IS e RO após o fim do tratamento com MK-801 por 14 dias. Além disso, foi avaliado se o efeito do canabidiol em reverter os prejuízos nos testes de IS e RO seria bloqueado pelo tratamento com AM251, um antagonista dos receptores CB1, e/ou WAY100635, um antagonista dos receptores 5-HT1A. Foi observado que o CBD (15 e 30 mg/kg) atenuou os prejuízos nos testes de IS e RO induzidos por MK- 801 e este efeito foi bloqueado pelo WAY100635 mas não pelo AM251. Estes dados reforçam a proposta de que o CBD tem propriedades antipsicóticas e indicam que o CBD poderia ser uma interessante alternativa para o tratamento de sintomas negativos e cognitivos de pacientes com esquizofrenia.Preclinical and clinical data indicate that cannabidiol (CBD), a nonpsychotomimetic compound in the Cannabis sativa plant, induces antipsychoticlike effects without producing extrapyramidal effects. Studies conducted by our group show that repeated treatment with CBD attenuated the behavioral changes induced by repeated treatment with MK-801, an NMDA receptor antagonist, in the object recognition (RO) test, used in the study of cognitive functions, and social interaction test (IS), used to study the negative symptoms of schizophrenia when both drugs were administered concomitantly. Studies show that changes induced by NMDA antagonists have been observed up to 6 weeks after treatment, and these changes are reversed by atypical antipsychotics such as clozapine and aripiprazole, but not by haloperidol, a typical antipsychotic. Although the evidence indicates the possible antipsychotic-like effect of CBD, the mechanism of action by which it exerts this effect has not yet been elucidated, it is believed that the endocannabinoid system and / or the serotoninergic system may be involved. Thus, in the present study, we evaluated whether repeated 7-day treatment with CBD would be able to reverse changes in IS and RO tests after the end of MK-801 treatment for 14 days. In addition, it was assessed whether the effect of cannabidiol on reversing impairments in the IS and RO tests would be blocked by treatment with AM251, a CB1 receptor antagonist, and / or WAY100635, a 5-HT1A receptor antagonist. CBD (15 and 30 mg / kg) was observed to attenuate the impairments in the IS and RO tests induced by MK-801 and this effect was blocked by WAY100635 but not by AM251. These data reinforce the proposal that CBD has antipsychotic properties and indicate that CBD could be an interesting alternative for the treatment of negative and cognitive symptoms of patients with schizophrenia.
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Bender, Kelly Juliana Seibt. "Avalia??o do potencial neuroprotetor de f?rmacos antipsic?ticos em altera??es bioqu?micas, moleculares e comportamentais induzidas por antagonista de receptor NMDA (MK-801) em peixe zebra (Danio rerio)." Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2011. http://tede2.pucrs.br/tede2/handle/tede/5421.
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Previous issue date: 2011-11-29Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. This pathology is still poorly understood. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics disease symptoms. Many animal models have shown their importance in the study of this disease and the zebrafish has been proposed as a promissor model to study the in vivo effects of several drugs and to discover new pharmacological targets. In this study we characterized the behavioral syndrome produced by the NMDA receptor antagonist, MK-801, exposure in zebrafish and investigated the ability of antipsychotic drugs to reverse the schizophrenia-like symptoms. MK-801 (20 μM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60 min of exposure. The antipsychotics sulpiride, olanzapine, and haloperidol counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Results showed that MK-801 (5 μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250 μM) and olanzapine (50 μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9 μM) was ineffective to reverse those behavioral deficits. Some evidence suggests that changes in the purinergic system, more specifically in adenosinergic activity, could be involved in the physiopathology of schizophrenia. In this study, we demonstrated that haloperidol treatment (9 μM) was able to decrease ATP hydrolysis (35%), whereas there were no significant changes in ADP and AMP hydrolysis in brain membranes. Adenosine deaminase activity in membrane fractions was significantly inhibited (38%) after haloperidol treatment when compared to the control group. Furthermore, haloperidol exposure also led to a decrease in NTPDase gene expression (entpd2_mq and entpd3), and adenosine deaminase (adal). Considering that the enzyme Na+,K+-ATPase is essencial to brain normal function, we evaluated the effect of MK-801 and antipsychotic drugs on activity this enzyme. Our results showed that MK-801 treatment significantly decreased Na+,K+-ATPase activity, and all antipsychotics tested prevented such effects. Moreover, it is known that oxidative stress may be associated with the physiopathology of schizophrenia and the Na+,K+-ATPase is particularly susceptible to free radical attack. We showed that MK-801 treatment did not alter reactive oxygen/nitrogen species by 2′7′-dichlorofluorscein (DCF) oxidation assay, but increased the levels of thiobarbituric acid reactive substances (TBARS), when compared to controls. The antipsychotics sulpiride, olanzapine, and haloperidol prevented the increase of TBARS caused by MK-801. Therefore, we demonstrated that zebrafish might present some behavioral and biochemical features observed in schizophrenia, being considered a promising animal model able to contribute for providing information on potential treatments and disease characteristics.
A esquizofrenia ? uma doen?a mental grave caracterizada por sintomas positivos, negativos e d?ficits cognitivos que ainda ? pouco compreendida. A redu??o da neurotransmiss?o glutamat?rgica por antagonistas dos receptores NMDA mimetiza os sintomas da esquizofrenia. Muitos modelos animais t?m mostrado sua import?ncia para o estudo dessa doen?a, e o peixe-zebra tem sido proposto como um modelo promissor para estudar os efeitos in vivo de v?rias drogas e descobrir novos alvos farmacol?gicos. Neste estudo caracterizamos a s?ndrome comportamental produzida pela exposi??o ao antagonista do receptor NMDA, MK-801, no peixe zebra, e investigamos a capacidade dos f?rmacos antipsic?ticos em reverter estes sintomas. MK-801 (20 μM) aumentou o comportamento locomotor que foi medido pelo n?mero de linhas cruzadas, a dist?ncia percorrida e a velocidade m?dia no aqu?rio teste, ap?s 15, 30 e 60 min de exposi??o. Os antipsic?ticos sulpirida, olanzapina e haloperidol reverteram as altera??es locomotoras induzidas pelo MK-801 em todos os par?metros testados, e em doses que administrado isoladamente n?o tiveram efeito sobre a atividade locomotora. Modelos de intera??o social e d?ficits cognitivos em animais pode ser de grande utilidade para o desenvolvimento de novos tratamentos para os sintomas negativos e cognitivos da esquizofrenia. Os resultados mostraram que o MK-801 (5 μM) administrado antes do treino impediu a forma??o da mem?ria, enquanto ambos os antipsic?ticos at?picos sulpirida (250 μM) e olanzapina (50 μM) melhoraram a amn?sia. A mesma altera??o foi observada na tarefa de intera??o social, onde os antipsic?ticos at?picos reverteram o d?ficit de intera??o social induzida pelo MK-801, enquanto o antipsic?tico tipico testado, o haloperidol (9 μM), n?o foi capaz de reverter esse d?ficit comportamental. Algumas evid?ncias sugerem que mudan?as no sistema purin?rgico, mais especificamente na atividade adenosin?rgica, poderiam estar envolvidos na fisiopatologia da esquizofrenia. Nesse estudo, mostramos que o tratamento com haloperidol (9 μM) foi capaz de diminuir a hidr?lise de ATP (35%), enquanto que n?o houve mudan?as significativas na hidr?lise de ADP e AMP em membranas cerebrais. A atividade da ADA em fra??es de membrana tamb?m foi inibida significativamente (38%) ap?s o tratamento com haloperidol, quando comparado ao grupo controle. Al?m disso, a exposi??o ao haloperidol tamb?m promoveu uma diminui??o na express?o g?nica das NTPDases (entpd2_mq e entpd3) e adenosina desaminase (adal). Considerando que a enzima Na+, K+- ATPase ? essencial para a fun??o cerebral normal, avaliamos os efeitos do MK-801 e farmacos antipsic?ticos na atividade desta enzima. Nossos resultados mostraram que o tratamento com MK-801 diminuiu significativamente a atividade da Na+, K+-ATPase, e todos os antipsic?ticos testados impediram tais efeitos. Sabe-se que o estresse oxidativo pode estar associado com a fisiopatologia da esquizofrenia e que a Na+,K+-ATPase ? particularmente suscet?vel ao ataque de radicais livres. Mostramos que o tratamento com MK-801 n?o alterou as esp?cies reativas de oxig?nio/nitrog?nio pelo ensaio de oxida??o 2'7'-diclorofluorosce?na (DCF), mas aumentou os n?veis de subst?ncias reativas ao ?cido tiobarbit?rico (TBARS). Os antipsic?ticos haloperidol, sulpirida e olanzapina preveniram o aumento nos n?veis de TBARS induzidos pelo MK-801. Portanto, demonstramos que o peixe zebra pode apresentar algumas caracter?sticas comportamentais e bioqu?micas observadas na esquizofrenia, sendo considerado um promissor modelo animal capaz de contribuir na obten??o de informa??es sobre potenciais tratamentos e caracter?sticas da doen?a.
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Miksa, Michael. "N-Methyl-D-Aspartat-Antagonisten induzierten apoptotische Zelluntergänge im Gehirn junger Ratten." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2004. http://dx.doi.org/10.18452/15030.
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Der wichtigste exzitatorische Neurotransmitter Glutamat spielt eine grosse Rolle in der Gehirnentwicklung, wie neuronale Migration und Synaptogenese. Ob glutamaterge Stimulation für das Überleben entwickelnder Neuronen notwendig ist, war bislang jedoch unbekannt. Um zu untersuchen, ob eine Hemmung von Glutamatrezeptoren im unreifen Gehirn zu Neurodegeneration führt, wurden Ratten im Alter von 1 bis 31 Tagen für 24 Stunden mit dem N-Methyl-D-Aspartat-(NMDA) Glutamatrezeptorantagonisten Dizocilpin (MK801) behandelt. Die Dichte neuronaler Degeneration wurde mikroskopisch in Kupfer-Silber- und TUNEL- gefärbten Hirnschnittpräparaten ermittelt und Unterschiede mittels ANOVA analysiert (Signifikanzniveau pThe predominant excitatory neurotransmitter glutamate plays a major role in certain aspects of neural development. However, whether developing neurons depend on glutamate for survival remains unknown. To investigate if deprivation of glutamate stimulation in the immature mammalian brain causes neuronal cell death (apoptosis), rat pups aged 0 to 30 days were treated for 24 hours with dizocilpine maleate (MK801), an N-methyl-D-aspartate-(NMDA) glutamate receptor antagonist. Density of neural degeneration was evaluated by a stereological dissector method in cupric-silver and TUNEL-stained brain slices. Groups were compared by ANOVA and significance considered at p
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Keng, Nien-Tzu, and 耿念慈. "Regulation by ethanol of the effects of NMDA receptor antagonists on spinal NMDA-induced pressor responses in rats." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/00892096108945356940.
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博士慈濟大學
醫學科學研究所
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NMDA (N-methyl-D-aspartate) receptor has been shown to be a pivotal target for ethanol. Acute exposure of ethanol inhibits NMDA receptor function. Our previous study showed that acute ethanol inhibited the pressor responses induced by NMDA applied intrathecally; however, prolonged ethanol exposure may increase the levels of phosphorylated NMDA receptor subunits leading to changes in ethanol inhibitory potency on NMDA-induced responses. The present study was carried out to examine whether acute ethanol exposure influences the effects of several NMDA receptor antagonists on spinal NMDA-induced pressor responses；ketamine and memantine are uncompetitive, open channel blocker; ifenprodil has a high selectivity for the NR2B-containing subtype of NMDA receptor. Repeated intrathecal injections of NMDA (2 nmol) into T7-T9 segment of spinal cord every 30 min caused reproducible increases in blood pressure in urethane-anesthetized rats weighing 250-270g. Intravenous injection of ethanol (0.16 g), ketamine (2, 4 mg/kg) or memantine (2, 4 mg/kg) or intrathecal injection of ifenprodil (20, 40 nmol) inhibited NMDA-induced pressor effects in a reversible manner. Co-administration of ethanol with ketamine or ifenprodil, but not with memantine, produced synergetic effects on the inhibition of NMDA-induced pressor effects. However, the above inhibition effects were not observed while NMDA receptor antagonists were applied at 10 min after intravenous ethanol. Western blot analysis showed that intravenous ethanol increased the levels of phosphoserine 897 on GluN1 subunits (pGluN1-serine 897), selectively hosphorylated by protein kinase A (PKA), in the lateral horn regions of spinal cord at 10 min after administration. Intrathecal administration of cAMPS-Sp, a PKA activator, at doses elevating the levels of pGluN1-serine 897, significantly blocked ketamine or ifenprodil inhibition of spinal NMDA-induced responses. The results suggest that ethanol may differentially regulate ketamine, memantine and ifenprodil inhibition of spinal NMDA receptor function depending on ethanol exposure time and the resulting changes in the levels of pGluN1-serine 897.
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Thurgur, Claire Helen. "The anticonvulsant actions of novel ’broad-spectrum’ Ca2+ channel blockers and low affinity, uncompetitive NMDA receptor antagonists." Thesis, 1996. http://hdl.handle.net/2429/5731.
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Epilepsy is a prominent neurological disorder. Presently available anticonvulsant drugs
however fail to alleviate seizures in approximately 25% of individuals, and are often
accompanied by serious side effects. More efficacious and less toxic agents are required. In
this study, the effects of a range of structurally dissimilar a site ligands were examined against
evoked and spontaneous epileptiform activity induced in rat hippocampal slices by perfusion
with Mg2+-free medium. Extracellular recordings were made in the CA1 hippocampal region
of epileptiform activity evoked by stimulation of the Schaffer collateral (SC) pathway, and of
spontaneous epileptiform activity originating from the CA3 hippocampal region. Evoked and
spontaneous epileptiform activity was inhibited by all compounds tested with the rank order
(IC5 0 values against evoked epileptiform activity in uM): dextrorphan (2) > ifenprodil (6) >
dextromethorphan (10) > l,3-di(2-tolyl)guanidine (15) > loperamide (28) > carbetapentane
(38) > caramiphen (46) > opipramol (52). Ifenprodil, loperamide, caramiphen and dextrorphan
were also examined for their effects on the input/output (I/O) functions along the SC pathway
and on the paired pulse facilitation (PPF) ratio. An effect was observed only in the presence of
caramiphen, which showed a decrease in the synaptic transmission I/O function and reduced
markedly the PPF ratio. The (micromolar) concentrations required for the anticonvulsant
activity of the CT ligands tested suggests that their anticonvulsant actions are not mediated by
high affinity (nanomolar) binding to rj binding sites, but rather to blockade of high voltage
activated Ca2 + channels and/or NMD A receptors, actions which occur at micromolar
concentrations.