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1
Daley, Emma. "The effect of mitochondrial membranolytic drugs on brain tumours in vitro." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272349.
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Gabriel, Kara Irene. "Effects of prenatal ethanol exposure and postnatal handling on cognition/behavior and hypothalamic-pituitary-adrenal stress responsiveness in Sprague-Dawley rats." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ56547.pdf.
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Li, Yuhong, and n/a. "Effect of alcohol exposure in early gestation on brain development." University of Otago. Department of Anatomy & Structural Biology, 2007. http://adt.otago.ac.nz./public/adt-NZDU20070502.100319.
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Fetal alcohol spectrum disorders (FASD), caused by maternal alcohol consumption during pregnancy, has been extensively studied in the human. Animal studies show that alcohol exposure during very early development may result in severe brain damage, often incompatible with a postnatal life. However, for surviving offspring it is unknown whether they suffer long term brain damage. The final assembly of the mature brain results from a controlled balance between proliferation of glial and neuronal precursors and programmed cell death. The overall aim of the current study was to use a physiologically relevant mouse model to assess the acute and long-term effects of binge alcohol exposure on the early embryo, to simulate human pregnancy at the third week of gestation when pregnancy may be undetected.
A number of paradigms were used to assess the acute dose-response effect, the blood alcohol concentration (BAC) profile and the extent of cell death following alcohol exposure on gestational day (G) 7.5. The exposure paradigms were single binge IG6.5, IG4.5, IP4.5, or an extended binge IG4.5+, IG3.0+. Two control groups were Con6.5 and Con4.5+. Acute cell death was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), activated caspase-3 staining, and transmission electron microscopy. Cell proliferation was investigated using S-phase immuno-labeling, bromodeoxyuridine (BrdU) birthdating and immuno-detection (BrdU/anti-BrdU). The long-term effects were investigated at G18.5 and postnatal day (PN) 60. Unbiased stereological methods were used to assess the effect of ethanol exposure at G7.5 on neocortical volume, cell number and density of neurons, glial cells, and capillary cells at PN60.
The first principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute apoptotic cell death in the ectoderm of the mouse embryo. Cell death was dependent on both peak BAC and the duration of elevated BAC. Significant increased cell death (TUNEL labeling) was observed in groups IG6.5 (9.43 � 2.08%) and IG4.5+ (8.97 � 2.12%) compared with control groups Con6.5 (2.14 � 0.09%) and Con4.5+ (2.81 � 0.36%). There was no significant increased cell death in ethanol exposed groups IG4.5 (3.43 � 0.45%), IP4.5 (3.68 � 0.67%), or IG3.0+ (1.72 � 0.24%). TEM analysis revealed that cell death exhibited characteristics of the apoptotic pathway.
The second principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute arrested proliferation in the ectoderm of the mouse embryo. The S-phase proliferation was significantly decreased within the whole ectoderm in the ethanol exposed group IG6.5 (45.58 � 2.34%) compared with control group Con6.5 (62.08 � 3.11%).
The third principal finding of the present study was that binge ethanol exposure during gastrulation induced the long term effect of laminate disorganization in the neocortex. The incidence of abnormal lamination was 87.5% in IG6.5 compared with 16.7% in IG3.0+ and 14.3% in Con6.5. Although ethanol exposure increased embryonic reabsorption, decreased litter size, and increased abnormal offspring, neocortical volume, and the total number of neurons, glial cells, and capillary cells was not affected. The total number (10⁶) of neurons, glial cells, and endothelial cells respectively was 12.221 � 0.436, 4.865 � 0.167, and 2.874 � 0.234 in IG6.5; 11.987 � 0.416, 4.942 � 0.133, and 2.922 � 0.130 in IG3.0+; and 11.806 � 0.368, 5.166 � 0.267, and 3.284 � 0.217 in controls, at PN60.
These results provide important information pertinent to fetal outcome for those women who drink heavily in early pregnancy. The results also demonstrate the importance of the pattern of ethanol exposure and blood alcohol concentration in determining the magnitude of ethanol�s teratogenic impact. Ethanol exposure on G7.5 that resulted in a high transient BAC, induced disorganized neocortical lamination, indicative of a permanent structural change. This disruption may result in altered neocortical function and requires further investigation.
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Heiberg, Ludvig. "An electrophoretic study of fetal mouse brain proteins after in vivo exposure to phenytoin and disulfiram." Master's thesis, University of Cape Town, 1990. http://hdl.handle.net/11427/27187.
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Although there have been two-dimensional electrophoretic studies on fetal brain tissue (for instance, Yoshida and Takahashi, 1980), the emphasis in most of this work has been on developmental changes in protein expression, and not on the effects that drugs have on fetal brain protein complement. Klose and co-workers (1977) did an early study using two-dimensional gel electrophoresis to determine the effects of various teratogens on whole embryos. No protein changes were found and that line of research was not continued. In this study two-dimensional gel electrophoresis is extensively used, in the belief that the usefulness of this technique to experimental teratology has not been fully evaluated. It is reasonable to suppose that a central nervous system teratogen administered during critical periods of susceptibility will led to perturbations of orderly brain development, and that these perturbations will be reflected as changes to the protein complement. The total brain protein complement of mice that have been exposed to drugs in utero will therefore be analysed, in the hope that any inductions or deletions of proteins as a result of drug exposure may provide a clue to the molecular events underlying drug injury to the fetus.
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Cader, Sarah. "Cognitive function in multiple sclerosis and its modulation by cholinergic drugs." Thesis, University of Oxford, 2005. http://ora.ox.ac.uk/objects/uuid:d07ad815-4fc6-43b7-96dc-97a2705d6c6a.
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In order to assess cognitive function in multiple sclerosis (MS) and the effect of cholinergic modulation, experiments were conducted using functional magnetic resonance imaging (fMRI) to assess the brain activation during cognitive tasks. A study comparing the processing of verbal working memory with an N-back task found that patients showed smaller increase in activation than healthy controls with greater task difficulty, suggesting a reduced functional reserve. Controls and patients showed differences of correlations between brain regions activated. Interactions between prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. The effect of Rivastigmine on the cognitive processing in MS patients was tested in a longitudinal study, involving serial fMRI scans. Changes in the brain activation patterns were demonstrated with drug administration, without any changes in behavioural measures. Rivastigmine may act to increase the functioning of the normal neural network reducing the need for previously recruited compensatory mechanisms in MS patients. A study on healthy subjects examined the effect of cholinergic inhibition on cognitive processing and brain activation. Changes in functional activation due to Hyoscine during verbal working memory were found analogous to that in MS patients without any changes in behavioural measures. Processes that potentially impair brain cognitive function may recruit similar compensatory functional adaptive mechanisms. Studies on rats and MS patients explored the effect of Rivastigmine on the relationship of the BOLD fMRI signal with the underlying neural activity. Rivastigmine may be influencing the cortical excitability after direct cortical stimulation but showed only a small effect on the BOLD signal under more physiological neural activity. The neural activity in response to visual stimulation is slightly increased with Rivastigmine in MS patients, a change not detected with functional imaging. These studies suggest that changes in BOLD signal do represent sufficiently large changes of underlying neural activity in the presence of Rivastigmine. The relationship of damage in MS to measures of connectivity was studied using diffusion tensor imaging (DTI). Correlation was found between measures of connectivity and callosal size, a measure of fibre loss. The distribution of lesions was spatially correlated with changes in connectivity due to MS. Thus DTI could be utilized to explore the connectivity changes associated with MS, and the relationship with changes in functional activation.
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Sharpley, Ann Louise. "The effect of drugs altering brain 5-hydroxytryptamine function on slow wave sleep in humans." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293567.
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Husum, Bak-Jensen Henriette. "Maternal deprivation and mood stabilizing drugs : effects on rat brain NPY /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-348-1/.
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Gruber, Susanne H. M. "Novel mechanism of action of antipsychotic drugs : effects on neuropeptides in rat brain /." Stockholm : [Karolinska institutets bibliotek], 2002. http://diss.kib.ki.se/2002/91-7349-229-9.
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Muhammad, Arif, and University of Lethbridge Faculty of Arts and Science. "Metaplasticity : how experience during brain development influences the subsequent exposure to a drug of abuse." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Neuroscience, c2011, 2011. http://hdl.handle.net/10133/2623.
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The influence of experience during brain development was investigated on juvenile behavior, adult amphetamine sensitization, and neuronal structural plasticity in rats. Two experiential factors (i.e., tactile stimulation and stress) were studied either before or soon after birth. Early experience feminized social behavior in males; however, only stress enhanced anxiety-like behavior in males. Repeated amphetamine administration resulted in the development and persistence of behavioral sensitization. However, tactile stimulation attenuated the drug-induced behavioral sensitization whereas stress failed to influence the degree of sensitization. Neuroanatomical findings revealed that early experience altered the cortical and subcortical structures. Furthermore, drug exposure reorganized the brain structures involved in addiction but early experience prevented the drug-associated changes. Early adverse experience influences the subsequent exposure to a drug of abuse at anatomical level whereas a favorable experience has an effect both at behavioral and anatomical levels and thus may play a protective role against drug-induced sensitization and addiction.xii, 263 leaves : ill. ; 29 cm
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Benjamin, Daniel E. (Daniel Ernest). "The effects of sustained gepirone administration on rodent brain 5-HT receptors and behavioral analogues of anxiety." Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc798440/.
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Clinical evidence has demonstrated that the anxiolytic effects produced by the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist, gepirone, increase progressively over one to three weeks of treatment.
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Kaelen, Mendel. "The psychological and human brain effects of music in combination with psychedelic drugs." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/55900.
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This research investigated how psychedelics and music work together in the brain and modulate subjective experience. Chapter 1 highlighted the prominent role of music in psychedelic therapy in the 1950s and 1960s, and how music continues to be used in modern psychotherapeutic trials with psychedelics. Although ‘psychedelic therapy’ shows promising findings for mental health care, little is known empirically about the therapeutic functions of music. The primary objective of this thesis was to address this knowledge gap, via studying the effects of psychedelics and music on human brain function in healthy volunteers, and via studying the subjective experience of music, both in healthy volunteers and in patients undergoing psychedelic therapy. Study 1 (Chapter 3) demonstrated intensified music-evoked emotions under the classic psychedelic LSD, including emotions of ‘wonder’ and ‘transcendence’. In subsequent work (study 2, Chapter 4), increased activation in the inferior frontal gyrus and the precuneus to the timbre features in the music, was associated with increased music-evoked emotions of wonder. Study 3 (Chapter 5) demonstrated that LSD and music interact to enhance information flow from the parahippocampus to the visual cortex, and that this effect correlated with increased complex mental imagery and autobiographical memories. Study 4 (Chapter 6), showed that music has a substantial influence on the therapeutic experience with psilocybin in patients with depression, and the quality of the music-experience predicted peak experiences and insightfulness during sessions, and reductions in depression after sessions. These findings support the hypothesis that the music-experience is intensified under psychedelics, and the widely-held view that this effect may be therapeutically significant. Possible brain mechanisms and therapeutic mechanisms are discussed in Chapter 7, but further research is warranted to better understand these mechanisms, and to learn how music can be best used in psychedelic therapy.
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黑明燕 and Mingyan Hei. "Neuroprotection of tanshinone IIA to hypoxic-ischemic brain damage in neonatal SD rat." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29797809.
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Balaños, Guzman Carlos Alberto. "The effects of the kappa agonist U-50,488 on morphine-induced place preference conditioning and Fos immunoreactivity in the preweanling and periadolescent rat." CSUSB ScholarWorks, 1995. https://scholarworks.lib.csusb.edu/etd-project/1074.
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The effects of the kappa opioid agonist U-50,488 on morphine-induced condtioned place preference (CPP), locomotor activity and Fos immunoreactivity and assessed in 10-, 17- and 35-day old rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by morhine (a mu opioid receptor agonist).
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Dalton, George D. "The Study of the Effect of Drugs of Abuse on Protein Kinase A Activity in Mouse Brain and Spinal Cord." VCU Scholars Compass, 2005. http://scholarscompass.vcu.edu/etd/1527.
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Morphine and Δ9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and Δ9-THC produces problematic side-effects including tolerance and physical dependence. The cellular mechanisms underlying opioid and cannabinoid antinociceptive tolerance have been studied for years. Research has demonstrated that the expression of morphine and Δ9-THC antinociceptive tolerance may be mediated through intracellular signaling pathways, such as the adenylyl cyclase /Protein Kinase A (PKA) cascade. The present study investigated the role of PKA in the expression of morphine and Δ9-THC antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or Δ9-THC and the warm-water tail-flick test was used to assess antinociception. These studies revealed that the level and the duration of morphine antinociceptive tolerance both influenced whether PKA activity was increased in mouse brain and spinal cord. Cytosolic PKA activity was increased in the thalamus of 3-day morphine-tolerant mice expressing a 45-fold level of tolerance, but not in mice that expressed a 10-fold level of tolerance. In addition, cytosolic PKA activity was increased in the lumbar spinal cord (LSC) of 15-day morphine-tolerant mice. However, chronic treatment with A9-THC had no effect on neuronal PKA activity even in mice that expressed a high level of antinociceptive tolerance. The absence of an effect of chronic treatment with A9-THC on neuronal PKA activity was supported by the development of a positive control in which the PKA activator Sp-8-Br-cAMPS was administered intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in drug-naYve mice and increases in PKA activity were observed in several brain regions and LSC. Finally, the i.c.v. injection of two peptide fragments of native Protein Kinase A inhibitor (PKI) peptide, PKI-(6-22)-amide and PKI-(Myr- 14-22)- amide, significantly reversed antinociceptive tolerance in mice treated chronically with morphine. PKI-(6-22)-amide (i.c.v.) also inhibited PKA activity in brain regions (thalamus, periaqueductal gray (PAG), and medulla) and LSC, which studies have shown play a role in morphine-induced analgesia. Moreover, PKI-(6-22)-amide reduced the increase in PKA activity in thalamus and LSC observed with chronic morphine treatment. Overall, these studies provide evidence that PKA plays a role in morphine tolerance, but not Δ9-THC tolerance at the doses and times tested.
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Kedzior, Karina Karolina. "Chronic cannabis use and attention-modulated prepulse inhibition of the startle reflex in humans." University of Western Australia. School of Medicine and Pharmacology, 2004. http://theses.library.uwa.edu.au/adt-WU2004.0027.
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Background. Various studies show that cannabis use alters attention and cognitive functioning in healthy humans and may contribute to development of schizophrenia or worsening of pre-existing psychosis. However, the impact of cannabis use on brain function in humans is not well understood. Schizophrenia is associated with a deficit in prepulse inhibition (PPI), the normal inhibition of the startle reflex by a non-startling stimulus (prepulse), presented before the startle stimulus at short time intervals (lead-time intervals). Such PPI deficit is thought to reflect a sensorimotor gating dysfunction in schizophrenia. PPI is also modulated by attention and PPI reduction in schizophrenia is observed when patients are asked to attend to, not ignore, the stimuli producing PPI. The aim of the current study was to investigate the association between self-reported chronic cannabis use and attentional modulation of PPI in healthy controls and in patients with schizophrenia. Furthermore, the association between cannabis use and other startle reflex modulators, including prepulse facilitation (PPF) of the startle reflex magnitude at long lead-time intervals, prepulse facilitation of the startle reflex onset latency and habituation of the startle reflex magnitude, were examined. Method. Auditory-evoked electromyographic signals were recorded from orbicularis oculi muscles in chronic cannabis users (29 healthy controls and 5 schizophrenia patients) and non-users (22 controls and 14 patients). The data for 36 participants (12 non-user controls, 16 healthy cannabis users, and eight non-user patients) were used in the final analyses and the patient data were used as a pilot study, because relatively few participants met the rigorous exclusionary criteria. Participants were instructed to attend to or to ignore either the startle stimuli alone (70 100 dB) or prepulse (70 dB) and startle stimuli (100 dB) separated by short lead-time intervals (20 200 ms) and long lead-time intervals (1600 ms). In order to ignore the auditory stimuli the participants played a visually guided hand-held computer game. A pilot study showed that the response component of playing the game had no effects on attentional modulation of the startle reflex magnitude and onset latency. Results. Relative to controls, cannabis use in healthy humans was associated with a reduction in PPI similar to that observed in schizophrenia while attending to stimuli, and with an attention-dependent dysfunction in the startle reflex magnitude habituation. While ignoring the stimuli there were no statistical differences in PPI between cannabis users and controls, although PPI in cannabis users tended to differ from that of the patients. The reduction in PPI in cannabis users was correlated with the increased duration of cannabis use, in years, but not with the concentration of cannabinoid metabolites in urine or with the recency of cannabis use in the preceding 24 hours. Furthermore, cannabis use was not associated with any differences in PPF, onset latency facilitation, and startle reflex magnitude in the absence of prepulses. The accuracy of self-reports of substance use was also investigated in this study and was found to be excellent. In addition, the study examined the validity of the substance use module of the diagnostic interview, CIDI-Auto 2.1, which was found to be acceptable for cannabis misuse diagnoses (abuse and/or dependence). Finally, cannabis dependence was found to be associated with more diagnoses of mental illness other than schizophrenia (mainly depression). Conclusions. The results of the current study suggest that chronic cannabis use is associated with schizophrenia-like deficit in PPI in otherwise healthy humans. This PPI reduction is associated with attentional impairment rather than a global sensorimotor gating deficit in healthy cannabis users.
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Belanger, Annie. "Brain Basis of the Placebo Effect: A Proposed Integrative Model Implicating the Rostral Anterior Cingulate." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/scripps_theses/272.
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How is the brain capable of mediating pain relief via the mind alone? Placebo analgesia is just such a case, wherein an inert substance yields relief from a number of pain inducing stimuli. Scholars typically separate several factors thought to contribute to the placebo effect into psychological and neurobiological influences. Psychological mechanisms include expectation and conditioning of analgesic effects, while neurobiological mechanisms implicate the opioidergic descending pain system. The current paper proposes an integrative model in which the rostral anterior cingulate cortex (rACC), implicated in cognitive-affective modulation, receives goal-directed input (i.e., expected pain relief) from the prefrontal cortex. As the rACC processes the cognitive difference between expected and actual pain, it recruits a critical descending pain pathway by means of modulating the periaqueductal gray area (PAG). The PAG is a key relay station that connects to other endogenous subsystems of opioidergic pain relief. Whether the rACC and its connection to the PAG are necessary for the placebo effect is a question future research will have to address.
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Silber, Yvonne Beata. "The acute side effects of d-amphetamine and methamphetamine on simulated driving performance, cognitive functioning, brain activity, and the standardised field sobriety tests." Australasian Digital Theses Program, 2006. http://adt.lib.swin.edu.au/public/adt-VSWT20070319.105603/index.html.
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Thesis (PhD) - Swinburne University of Technology, 2006.Typescript. [Submitted for the degree of] Doctor of Philosophy, Swinburne University of Technology - 2006. Includes bibliographical references (p. 253-290).
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Virmani, M. A. "The effects of ions and drugs on amine and #gamma#-aminobutyric acid release from rat brain." Thesis, University of Newcastle Upon Tyne, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375163.
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Pike, Andrew. "Effects of P-glycoprotein on brain penetration of drugs in the CF-1 mdrla -/- mouse model." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414744.
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Schmiegelow, Marianne. "Endocrinological late effects following radiotherapy and chemotherapy of childhood brain tumours. /." København : Lægeforeningens Forlag, 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014566238&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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許瑰蓮 and Guilian Xu. "Some studies on the cholinergic and somatostatinergic systems in the brain of mouse alzheimer models with transgenes for amyloid precursorprotein (APP) and presenilin." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31242534.
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Fraser, Caroline Margaret. "Effects of antiepileptic drugs in rodent and human astrocyte cultures, rodent brain and pentylenetetrazol-induced seizures in mice." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301809.
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Kankaanpää, Aino. "The effects of psychostimulant drugs on brain dopaminergic and serotonergic neuronal systems : the role of 5-HT3 receptors." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/farma/vk/kankaanpaa/.
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Glock, Mareike Carola [Verfasser]. "Effects of lysosomotropic drugs on drug-induced phospholipidosis and the blood-brain barrier in vitro in connection with the acid sphingomyelinase / Mareike Carola Glock." München : Verlag Dr. Hut, 2020. http://d-nb.info/1219475580/34.
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Sun, Jingjing. "Exploring the effect of alpha2 receptor on brain 5-HT via a mechanism-based pharmacodynamic model." Scholarly Commons, 2012. https://scholarlycommons.pacific.edu/uop_etds/154.
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Purpose: 5-hydroxytryptamine (5-HT) is an important neurotransmitter in depression. It is believed that α 1 and α 2 adrenoceptors mediate the 5-HT level in the brain. The mechanism is complex and not well explored. Especially in different combination treatments, the receptor systems may show varied modulation capability. Additionally, some research has suggested that α 2 heteroceptors may contribute to the time delay problem in dual depression treatment which is thought as the time needed for certain inhibition receptor to get desensitized. We hypothesized that the α 2 adrenoceptors had inhibition effect on 5-HT level in dorsal raphé nucleus (DRN), Prefrontal cortex (PFC) and Hippocampus (HP) with the dual reuptake inhibition. The present study was undertaken to explore the effect of BRL44408 (α 2 receptor antagonist) on 5-HT level in rat PFC, DRN and HP under dual antidepressant with blocking the α 1 receptor. Method: Serotonin reuptake inhibitor and norepinephrine reuptake inhibitor were used to mimic the dual reuptake inhibition antidepressant. To differentiate the α 2 adrenoceptors effect from al adrenoceptors effect, prazosin, an antagonist of α 1 adrenoceptors, was added to block α 1 adrenoceptors. Using the microdialysis method, the drug combination was examined in HP area and then DRN area to explore the drug effect on time course of 5-HT release in DRN and PFC. Based on the experiment results from DRN and PFC, a mechanism-based pharmacodynamic model was developed. Result: BRL44408 increased the serotonin (5-HT) level in rat PFC, DRN and HP to different degrees with the dual reuptake inhibition (p < 0.05). The overall model reasonably captured the time course of 5-HT in both DRN and PFC with different dose schemes of BRL44408. The model predicted EC50 of BRL44408 (0.0075 µM) for the α 2 heteroreceptor which control PFC 5-HT is close to the reported value of BRL44408 for α 2 adrenorceptor (0.008 µM). However, the model predicted EC50 of BRL44408 on the α 2 heteroreceptor which control DRN 5-HT need to be explained. Simulation result from this model suggested varied modulation capability of α 2 adrenoceptors on the 5-HT in DRN and the 5-HT in PFC. Conclusion: α 2 heteroceptor play a role in regulation 5-HT level under dual reuptake inhibition. Further exploration may bring a potential target for depression treatment. The mechanism model was developed to characterize and better understand the neurotransmitter mechanisms, providing estimations of various parameters of the disease related receptor system.
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van, Waes Linda T. A., and University of Lethbridge Faculty of Arts and Science. "Does one plus one make two? Investigation of pharmacological effects and cortical injury on the developing brain." Thesis, Lethbridge, Alta. : University of Lethbridge, Deptartment of Neuroscience, 2008, 2009. http://hdl.handle.net/10133/782.
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This thesis examined how pharmacological treatment and cortical injury during development affects brain plasticity. Rats were given either a low dose of perinatal fluoxetine or a mild postnatal day 7 Hypoxic‐Ischemic (HI) injury, both, or neither. The functional outcome was assessed using a series of behavioral tasks and anatomical measures. To assess how HI affects the development of
motor maps, forelimb motor maps were evoked at P19. The findings indicate that fluoxetine treatment or HI injury mostly negatively affected functional outcome. The combined treatment with fluoxetine and HI injury only interacted on a limited number of measures. There was no delay in the emergence of evoked motor movements, or change in map location in the HI animals. These results suggest that the pharmacological treatment and cortical injury described in this thesis may have different mechanisms whereby plastic changes are induced and the interaction between these two mechanisms is limited.xii, 169 leaves : ill. ; 29 cm.
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Englund, Marita. "Effects of hypoxia and antiepileptic drugs on electrophysiological properties of CA1 neurons in hippocampus /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-237-8/.
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Fisher, Kim Noël. "Behavioural and physiological effects of two aniracetam analogues." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22585.
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The behavioural and electrophysiological consequences of two newly developed aniracetam analogues were investigated in male Long-Evans rats. Results indicate that an intraperitoneal (i.p.) injection of LD38.2 significantly improved retention in a two odour olfactory discrimination task. However, three different dosages of LN1 did not facilitate memory in the task. In rats with chronically implanted electrodes, both compounds rapidly crossed the blood brain barrier (BBB) after an i.p. injection and influenced several parameters of the field excitatory postsynaptic potential (EPSP) in the CA1 and dentate gyrus regions of the hippocampus. The enhancement of the field EPSP following LD38.2 administration may be related to the drug's ability to facilitate memory in the olfactory discrimination task. Compounds, like LD38.2, that enhance both hippocampal transmission and performance in learning/memory tasks in laboratory rodents may have implications for the treatment of clinical memory disorders.
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Wright, Nicola Anne. "Central effects of antihypertensive drugs in man : pharmacological modification of the electrical activity of the brain and changes in alertness." Thesis, Open University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336975.
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Patel, Sulay H. "Effects of HIV-1 Tat and drugs of abuse on antiretroviral penetration inside different CNS cell types." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5685.
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Human immunodeficiency (HIV) infection can result in neurocognitive deficits in about one-half of infected individuals. Despite excellent systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting HIV infection within the central nervous system (CNS). Drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV-infected individuals. This work investigates the effects of the HIV-1 protein, Tat, and drugs of abuse on factors affecting drug penetration into the brain.
Firstly, an in vitro model of the blood-brain barrier was built to study effects of HIV-1 Tat and methamphetamine (Meth) on integrity and function of the BBB, in turn how HIV-1 Tat and meth will affect antiretroviral penetration into the brain. We found that co-exposure HIV-1 Tat and Meth results in inhibition or impairment of P-glycoprotein activity at the BBB. Also, simultaneous inhibition of P-glycoprotein (P-gp) and Multidrug Resistant Protein -1 (MRP-1), by verapamil and MK-571 causes an increase in accumulation of atazanavir inside the primary human brain endothelial cells.
Secondly, we developed and validated the method for simultaneous determination of tenofovir, emtricitabine, and dolutegravir in cell extracts of CNS cells. This method was used to study how HIV-1 Tat and/or morphine affects antiretroviral penetration in CNS cells like human brain microvascular endothelial cells, human astrocytes, human microglia, and human pericytes. We found that in untreated cells, accumulation of antiretroviral drugs was higher in hCMEC/D3 cells compared to other CNS cell types. Also, HIV-1 Tat and/or morphine had no significant effect on antiretroviral penetration amongst these cell types. Overall, the rank order of intracellular accumulation observed in treated and untreated cells was dolutegravir > emtricitabine > tenofovir.
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Perna, Marla K. "The Effects of Nicotine Administration on Behavior and Markers of Brain Plasticity in a Rodent Model of Psychosis." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etd/1432.
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Schizophrenia affects about 1% of the population. A hallmark of the disorder is increased dopamine D2 receptor sensitivity in the brain. Studies have shown that schizophrenics smoke cigarettes at approximately 4 times the rate of the general population. It has been suggested that nicotine use is a form of self-medication for symptoms in schizophrenia. Smoking behaviors typically begin in adolescence. We assessed effects of nicotine on behavior and brain plasticity in an adolescent rodent model of schizophrenia with the goal of identifying targets for smoking cessation. Methods: Rats were neonatally treated with quinpirole (a D2/D3 agonist) or saline and sensitized to 0.3, 0.5, or 0.7 mg/kg (free base) nicotine or saline, every other day for 9 days, and locomotor activity was recorded. After behavioral testing, animals demonstrating sensitization to 0.5mg/kg nicotine were surgically implanted with a guide cannula, aimed at the nucleus accumbens core. After recovery, animals underwent microdialysis and in vivo samples were collected every 20 minutes for 300 minutes. Postmortem brains from animals exposed to 0.5mg/kg nicotine or saline were dissected and the nucleus accumbens and dorsal striatum were analyzed for brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding protein (pCREB), and glial-cell derived neurotrophic factor (GDNF), all proteins involved in neuronal plasticity. Results: Animals neonatally treated with quinpirole and administered nicotine showed robust increases in locomotor sensitization and a 400% increase in dopamine overflow from the accumbens core, which was greater than all other groups. Nicotine administration led to increased accumbal BDNF levels, which was enhanced by neonatal quinpirole pretreatment. GDNF levels were also increased in control animals given nicotine, which was attenuated to control levels by neonatal quinpirole. Finally, pCREB levels were robustly increased in animals neonatally treated with quinpirole, an effect that was partially attenuated by adolescent nicotine treatment. These data on pCREB suggest a possible biological marker of anhedonia. In conclusion, it is apparent that nicotine results in a robust increase in behavioral activity and changes in neural proteins of brain plasticity that may serve as possible pharmaceutical targets for smoking cessation in schizophrenia.
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Brandmann, Maria [Verfasser], Ralf [Akademischer Betreuer] Dringen, and Johannes [Akademischer Betreuer] Hirrlinger. "Effects of Antiretroviral Drugs on the Glutathione and Glucose Metabolism of Cultured Brain Cells / Maria Brandmann. Gutachter: Ralf Dringen ; Johannes Hirrlinger. Betreuer: Ralf Dringen." Bremen : Staats- und Universitätsbibliothek Bremen, 2014. http://d-nb.info/1072226081/34.
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Africa, Luan Dane. "HIV-1 associated neuroinflammation : effects of two complimentary medicines illustrated in an in vitro model of the blood-brain barrier." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95869.
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Thesis (MSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Background: Neuroinflammation is central to the aetiology of HIV-associated neurocognitive disorders (HAND) that are prevalent in late stage AIDS. ARV treatments are rolled out relatively late in the context of neuroinflammatory changes, so that their usefulness in directly preventing HAND is probably limited. It is common practice for HIV+ individuals in developing countries to make use of traditional/complimentary medicines. One such medicine is Sutherlandia frutescens - commonly consumed as a water infusion. We have also identified a new candidate complimentary medicine for use in this context - grape seed-derived proanthocyanidolic oligomers (PCO) have significant anti-inflammatory action in the peripheral compartment in the context of e.g. skeletal muscle injury, but have not been investigated in the context of either neuroinflammation or HIV/AIDS. Here the efficacy of these two substances as an anti-inflammatory modality in this context was investigated in an in vitro co-culture model of the blood-brain barrier (BBB). Methods: Single cultures of human astrocytes, HUVECs and primary human monocytes, as well as co-cultures (BBB), were stimulated with HIV-1 subtype B & C Tat protein and/or HL2/3 cell secretory proteins after pre-treatment with S. frutescens or PCO extracts. Effects of this pre-treatment on pro-inflammatory mediator expression and monocyte migration across the BBB were assessed. Results: In accordance with others, B Tat was more pro-inflammatory than C Tat, validating our model. S. frutescens decreased IL-1β secretion significantly (P<0.0001), but exacerbated both monocyte chemoattractant protein-1 (P<0001) – a major role player in HIV-associated neuroinflammation – and CD14+ monocyte infiltration across the BBB (P<0.01). PCO pre-treatment resulted in a significantly dampened IL-1β (P<0.0001) response to stimulation with HIV-associated proteins. In contrast to S. frutescens, PCO modulated monocyte chemoattractant protein-1 (P<0001) response and decreased capacity for CD14+ monocytes to migrate across the simulated BBB (P<0.0001). Additionally, PCO pre-treatment decreased both GFAP (P<0.001) and HSP-27 (P<0.001) expression in the astrocytes of the BBB. Conclusions: Current data illustrates that the combined use of HL2/3 cells and the simulated BBB presents an accurate, disease relevant in vitro model with which to study neuroinflammation in the context of HIV/AIDS. In addition, our results caution against the use of S. frutescens as anti-inflammatory modality at any stage post-HIV infection. Novel data presented here illustrate that PCO is able to blunt the MCP-1 and IL-1β response to HIV-1 proteins in single cultures of human astrocytes and HUVECs, as well as in an in vitro simulation of the BBB. In addition, PCO was able to limit monocyte transmigration across the simulated BBB in response to HIV-1 proteins generated by HL2/3 cells. This suggests that grape seed-derived PCO could be considered as complimentary anti-neuroinflammatory drug in the context of HIV/AIDS.
AFRIKAANSE OPSOMMING: Agtergrond: Neuroinflammasie staan sentraal in die ontwikkeling van MIV-verwante toestande wat gekenmerk word deur neurokognitiewe afteruitgang, veral in die later stadia van die siekte. Aangesien anti-virale middels relatief laat toegedien word in die konteks van neuroinflammasie, is hul rol in die voorkoming van neuroinflammatoriese veranderinge heel moontlik weglaatbaar. MIV+ individue, veral in ontwikkelende lande, gebruik algemeen natuurlike medisinale preparate. Sutherlandia frutescens is een so „n middel wat as „n tee ingeneem word. Verder het ons ook „n nuwe kandidaat komplimentêre medisyne identifiseer – druiwepitekstrak wat polifenole bevat (PCO) het aansienlike anti-inflammatoriese eienskappe in die periferie, bv. in die konteks van skeletspierskade, maar die middel is nog nie voorheen in die konteks van neuroinflammasie of MIV/VIGS ondersoek nie. Hier word die anti-inflammatoriese effektiwiteit van beide middels in hierdie konteks ondersoek deur gebruik te maak van „n in vitro simulasie van die bloedbreinskans (BBS). Metodes: Kulture van menslike astrosiete, menslike naelstring endoteelselle (HUVECs) en primêre menslike monosiete, sowel as gesamentlike kulture (BBS) is met MIV-1 subtipe B en C Tat proteïen en/of HL2/3 selprodukte gestimuleer na voorafbehandeling met S. frutescens of PCO ekstrakte. Effekte op pro-inflammatoriese mediator uitdrukking sowel as monosiet migrasie oor die BBS is ondersoek. Resultate: In ooreenstemming met die literatuur was B Tat meer inflammatories as C Tat, wat die akkuraatheid en gepastheid van ons model bevestig. . S. frutescens het afskeiding van IL-1β betekenisvol verminder (P<0.0001), maar het afskeiding van beide monosiet chemoaantrekkingsproteïen-1 – „n groot rolspeler in MIV-verwante neuroinflammasie – en CD14+ monosiet migrasie oor die BBS vererger (P<0.0001 en P<0.01 onderskeidelik). PCO behandeling het „n betekenisvolle demping van die IL-1β reaksie (P<0.0001) op stimulasie met MIV-geassosieerde proteïene tot gevolg gehad. Anders as S. frutescens het PCO die MCP-1 reaksie, asook CD14+ monosiet migrasie betekenisvol inhibeer. Verder het PCO ook beide GFAP en HSP-27 uitdrukking in astrosiete van die BBS verminder (beide P<0.001). Gevolgtrekkings: Huidige data wys dat die gekombineerde gebruik van HL2/3 selle en die gesimuleerde BBS „n akkurate en fisiologies relevante in vitro model daarstel, waarmee neuroinflammasie in die konteks van MIV/VIGS bestudeer kan word. Ons resultate waarsku verder teen die gebruik van S. frutescens as anti-inflammatoriese middel in selfs die vroeë stadium na MIV infeksie. Oorspronklike data wat hier aangebied word illustreer dat PCO die pro-inflammatoriese reaksie op MIV-proteïene in kulture van astrosiete en HUVECs, asook die in vitro simulasie van die BBS, effektief demp. Verder het PCO die vermoë getoon om monosiet migrasie oor die BBS, in reaksie op MIV-1 proteïene wat hul oorsprong uit HL2/3 selle het, te beperk. Hierdie bevindings beteken dat PCO dus eerder as S. frutescens oorweeg moet word as komplimentêre anti-inflammatoriese medisyne in die konteks van MIV/VIGS.
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Zhou, Zhu. "Exploring the effects of 5-HT2A and AMPA receptors on brain 5-HT via a mechanism-based pharmacodynamic model." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/143.
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Depression is a common mood disorder. Although major ethical challenges make it nearly impossible to invasively and directly measure serotonin (5-hydroxytryptamine, 5-HT) levels in human brains, neuroimaging technologies have shown macroscopic structural and functional abnormalities in the prefrontal cortex (PFC) of depressed patients. The monoamine hypothesis of depression is based on the neurotransmitter imbalance, such as deceased serotonin brain levels are implicated in the cause of depression. Research has focused on the control mechanisms involved in the dorsal raphé nucleus (DRN) which is the serotonergic control center located in the midbrain. We hypothesized that activation 5-HT 2A receptor in PFC would increase serotonin levels by an AMPA-dependent mechanism in both DRN and PFC. Enhancement of the 5-HT in DRN may inhibit 5-HT level in PFC by 5-HT 1A receptor. This becomes the full feedback loop system. While 5-HT levels in the PFC have been well studied, pathway that modulate this DRN pool through upstream cascade interactions leading to a downstream feedback loop have been difficult to elucidate. Developing a mechanism-based pharmacokinetics (PK) and pharmacodynamics (PD) model to quantitatively describe the effect of 5-HT 2A receptors regulation to serotonin in the DRN and PFC would help us to better understand the complex brain. 5-HT 2A receptor agonist and AMPA receptor agonist and antagonist were used to activate or block the related receptor. Male Wistar rats underwent neurosurgery for implantation of microdialysis (MD) probes. Three to five rats were randomly assigned to experimental arms. Using the MD method, the drug combination was examined to explore the drug effect on time course of 5-HT release in DRN and PFC. Based on the experiment results, a mechanism-based PD model was developed. Phoenix WinNonlin ® and Berkeley Madonna™ were used for model estimation, external validation with secondary data set, and simulation. The result supports the possibility of a 5-HT 2A /AMPA feedback control circuit that originates in the PFC and modulates DRN and PFC 5-HT levels through feedback coupling of 5-HT. The time-course profiles of 5-HT in both DRN and PFC was well modeled and model parameters were estimated with good precision (CV% ranged from 1.37% to 35.03%). The mechanism model was developed to characterize and better understand the neurotransmitter mechanisms, providing estimations of various parameters of the disease related receptor system.
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Patel, Ankita Anil. "Examination Of A Post-Stroke Drug Treatment For Its Effect On Blood Brain Barrier Permeability, And Gene Expression Changes In The Peri-Infarct Region." Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1472131819.
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Lafaille, Francine. "Characterization of [125I]7-amino-8-iodo-ketanserin binding and comparative effects of long-term treatment with anxiolytic and antidepressant drugs on serotonin type 2 and beta-adrenergic receptors in rat brain." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60548.
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Changes to 5-HT$ sb2$ receptors in rat brain following antidepressant and anxiolytic treatment were investigated. The B$ sb{ rm max}$ of ($ sp{125}$I) AMIK was found to be decreased significantly in rat fronto-parietal cortex after 21 days administration of antidepressant drugs including desmethylimipramine (30%), buspirone (47%) and adinazolam (17%). The anxiolytic drug, diazepam, which is devoid of intrinsic antidepressant action, did not significantly change the binding parameters. In comparison to 5-HT$ sb2$ receptors, the beta-adrenoceptors labelled by ($ sp{125}$I) cyanopindolol in membrane binding were decreased only by desmethylimipramine, with a 17% reduction in B$ sb{ rm max}$. Data from in-vitro quantitative autoradiography suggests that ($ sp{125}$I) AMIK binding to 5-HT$ sb2$ receptors is decreased in frontal and parietal cortices following 21 days administration of DMI, amitryptiline, gepirone and adinazolam. The results from the present study strongly suggest that the 5-HT$ sb2$ receptor is involved in depressive disorders. Since some of the antidepressant drugs tested possess anxiolytic activity after prolonged administration, 5-HT$ sb2$ receptors may also be important in anxiety disorders.
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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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Mantovani, Michela [Verfasser], and Rolf [Akademischer Betreuer] Schubert. "Modulation of neocortical neurotransmissions by antidepressants and neuromodulatory drugs in human and rodent brain tissue and effect of electrical high-frequency stimulation in human neocortex = Modulation der Neokortikalen Neurotransmissionen durch Antidepressiva und Neuromodulatorische Substanzen im Hirngewebe von Menschen und Nagetieren und Wirkung der elektrischen Hochfrequenzstimulation im menschlichen Neokortex." Freiburg : Universität, 2012. http://d-nb.info/1123472971/34.
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Salam, Al-Maliki Shanta Taher. "Nose to Brain Delivery of Antiepileptic Drugs Using Nanoemulsions." University of Toledo Health Science Campus / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1449771501.
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Dimova, Neviana G. "Brain protein kinase activity following chronic exposure to antidepressant drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ40040.pdf.
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Wood, David. "Impact of Alcohol and Drugs on the Developing Adolescent Brain." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/7679.
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Cerqueira, Carlos Toledo. "Estudo de ressonância magnética funcional das mudanças da atividade cerebral durante recordações afetivas autobiográficas decorrentes da administração prolongada de clomipramina a sujeitos saudáveis." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-12022014-141907/.
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INTRODUÇÃO: Apesar da importância dos medicamentos antidepressivos no tratamento dos transtornos de humor e de ansiedade, sua ação sobre sistemas cerebrais responsáveis pela expressão emocional ainda não foram claramente estabelecidos. Estudos recentes têm examinando o sinal dependente de nível de oxigenação sanguínea (do inglês, \"BOLD\") durante estímulos emocionais em indivíduos saudáveis sob uso de antidepressivos. Nesse estudo, pretendemos estender essa avaliação às alterações do humor e comportamento emocional devido ao uso prolongado de um antidepressivo bloqueador de serotonina e noradrenalina em pessoas saudáveis. MÉTODOS: foram selecionados dezesseis voluntários, sem antecedentes psiquiátricos pessoais ou familiares, que participaram de um ensaio farmacológico simples-cego de quatro semanas de doses baixas de clomipramina (até 40 mg/dia). Ao final desse período, dez sujeitos foram selecionados como não responsivos, e os restantes seis sujeitos foram selecionados como responsivos por apresentarem claras mudanças em três dos quatro seguintes critérios: tolerância interpessoal, eficiência, bem estar, e mudança substancial em sua auto percepção. O grupo de sujeitos classificados como responsivos foram submetidos a um ensaio controlado duplo-cego confirmatório. A aquisição de imagens cerebrais ocorreu após quatro semanas de uso de medicação (simples cego) e quatro semanas após a sua suspensão, ao final da participação no ensaio farmacológico. O imageamento cerebral foi realizado durante a indução de estados afetivos de felicidade, irritabilidade e neutros por relatos autobiográficos. A resposta emocional desses estados foi obtida por escalas de auto avaliação de ansiedade, irritabilidade e felicidade. As diferenças de sinal entre os estados afetivos foram utilizadas para a análise estatística da interação dos efeitos estado medicamentoso e grupo por testes ANOVA. RESULTADOS: Foi encontrada uma interação significativa entre o efeito de grupo e o estado medicamentoso sobre os estados afetivos de irritabilidade, mas não sobre os de felicidade. Se observou redução na auto avaliação de ansiedade no grupo responsivo com o uso de medicação na diferença entre os estados induzidos de irritabilidade e felicidade, em comparação com o efeito no grupo não responsivo; e também, redução na auto avaliação de felicidade com o uso de clomipramina na totalidade da amostra, na diferença entre o estados induzidos de irritabilidade e neutro. A alteração sobre o efeito BOLD (p < 0,005) foi localizada em regiões adjacentes à junção frontoparietal para a indução de irritabilidade em relação à felicidade e em relação aos estados neutros, no grupo responsivo em relação ao não responsivo, durante o período em uso relativo àquele sem uso de clomipramina, e na junção têmporo-paríeto-occipital, exclusivamente para a diferença irritabilidade-felicidade. CONCLUSÕES: a modificação favorável que sujeitos saudáveis apresentaram ao uso prolongado de um antidepressivo bloqueador da serotonina e noradrenalina, pode estar relacionada à modificação no processamento cerebral da memória autobiográfica de emoções negativasINTRODUCTION: despite the importance of antidepressant agents to the treatment of anxiety and depressive disorders, there is not yet a clear understanding of their actions upon specific brain systems relevant to emotional processing. Recent studies have examined blood oxygen level dependent (BOLD) signal during emotion stimuli in healthy individuals in antidepressant use. The study intends to extend these measures to the changes over mood and emotional behavior by prolonged use of a serotonin and noradrenaline blocker antidepressant. METHODS: we selected sixteen subjects, with no personal or family history of psychiatric disorders, which participated of a four-week single-blind trial with low doses of clomipramine (up to 40mg/day). After this period, ten subjects were classified as non responsives, the remaining six subjects being classified as responsives because clomipramine provided positive changes in three of four of the following criteria: interpersonal tolerance, self-efficacy, mood and self-perception of a substantial change. Responsives were included in a placebo-controlled confirmatory trial. Imaging sessions occurred at the end of the four-week course of clomipramine and again after a four-week clomipramine washout period, at the end of pharmacological trial. Subjects were scanned during the induction of irritability, happiness and neutral affective states by autobiographical recall. Self-report assessment was performed for each induction by anxiety, irritability and happiness scales. Inter-condition differences (affective induction) were used in the analysis of interaction of medication status and group effects by ANOVA tests. RESULTS: A significant interaction was found between group and treatment during irritability, but not during happiness emotions. It was observed a reduction in the scale of self-evaluation of anxiety in responsive group with the use of medication to the difference between irritability-happiness states, compared to the non responsive group; and a reduction in auto evaluation of happiness, in the totality of the sample in use of clomipramine, in difference irritability-neutral. There was a significant increase of BOLD effect in the responsive group during use relative to the period without use of clomipramine, compared to the effect on non-responsive group (p < 0.005). This effect was located in regions that surround the frontoparietal junction to the irritability relative to happiness and to irritability relative to neutral induction, and in the temporo-parieto-occipital junction, exclusively to the irritability relative to happiness induction. CONCLUSIONS: The favorably changes in healthy subjects who respond to prolonged serotonin and noradrenaline blocker use, may relate to changes in neural processes of autobiographical memory of negative emotions
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Cook, Andrew T. "The effect of accelerated aging on peelable medical products seals /." Online version of thesis, 1994. http://hdl.handle.net/1850/11980.
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Sood, Pooja. "Assessment of pharmacokinetics and pharmacodynamics of psychoactive drugs using brain microdialysis." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/8820.
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In order to assess pharmacokinetics and pharmacodynamics (PK/PD) accurately, it is necessary to obtain measurements of the absolute concentrations of compounds in the brain. A major shortcoming of using microdialysis to measure PK/PD is that microdialysis measurements do not give us absolute concentrations of solutes in the brain, since the relationship between dialysate concentrations and true extracellular fluid (ecf) concentrations surrounding the probe is unknown. Several methods have been devised to circumvent this problem. The present study employed a novel method, MetaQuant (MQ) microdialysis, which achieves near 100% recovery, and so enables the measurement of absolute ecf concentrations. I examined the effect of the D4 receptor agonist, PD168077 on extracellular dopamine levels (that is PD) in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of freely moving rats, while simultaneously measuring brain concentrations (that is PK) of the drug. Thus we were able to estimate the PK/PD profile of the drug in the two brain regions. Compared with basal extracellular levels, subcutaneous administration of PD168077 caused significant increase in dopamine in mPFC. Activation of dopamine D4 receptors in the mPFC may improve cognitive function, which is highly impaired in individuals with schizophrenia. Moreover, it has been consistently shown that phencyclidine (PCP) produces robust cognitive disruption, in a novel object recognition (NOR) test. I studied the efficacy of PD168077 to attenuate sub-chronic PCP induced deficit in the NOR task. Sub-chronic PCP induced a robust cognitive disruption and PD168077 (10 mg/kg, s.c. dose) reversed this disruption. Further MQ dialysis data showed that PD168077 (10 mg/kg, s.c. dose) increased dopamine levels in mPFC that was depleted due to PCP suggesting a mechanism for the observed alleviation of PCP induced cognitive deficits.
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Weise-Kelly, Lorraine Ann. "Drug-induced ataxia : effect of the self-administration contingency /." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0030/NQ66245.pdf.
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Bowdens, Christine. "The role of dopamine in depression : a study in human post-mortem brain tissue." Thesis, St George's, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281745.
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Sekhar, Gayathri Nair. "The transport of CNS-active cationic drugs across the blood-brain barrier." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/the-transport-of-cnsactive-cationic-drugs-across-the-bloodbrain-barrier(41ff27df-17ce-4edc-82fe-c4169edf801c).html.
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The physical, transport, and metabolic barriers presented by the cerebral microvessel endothelium - the blood- brain barrier (BBB) - protect the brain from damage from toxic substances and ensure the delivery of nutrients required for the functioning of the brain thus creating a stable neuronal microenvironment. However, the BBB poses a challenge to many CNS-active drugs which must cross the BBB to reach their target. Of the drugs that target the brain, many are cationic at physiological pH making their transport into the brain even harder with the additional potential for drug-drug interactions. Therefore, this thesis has been an attempt to understand the transport characteristics of cationic therapeutic drugs across the BBB. One of the foci of this study has been the anti-human African trypanosomiasis (HAT) drugs pentamidine and e ornithine, both positively charged at physiological pH. Pentamidine is a stage 1 drug for HAT that was previously found in our laboratory to not cross the mouse BBB in vivo as it was a substrate for eux transporters, particularly P-glycoprotein. The present study observed that pentamidine is taken up by Organic Cation Transporter 1 (OCT1) in hCMEC/D3 (human) and bEnd.3 (mouse) cell lines where it accumulates and is euxed by ATP-dependent mechanisms out of the cell. In addition, the predominant localisation of OCT1 at the luminal membrane of the BBB may explain the low permeability of pentamidine into the brain. Considering pentamidine is a substrate for P-glycoprotein at the BBB, inhibitors of Pglycoprotein were used to increase pentamidine delivery into the brain. Pluronic® triblock polymers P85, P105, and F68 were thus chosen for their proven ability to inhibit P-glycoprotein and for their promising results from clinical trials. They were used at concentrations of 0.01%, 0.025%, 0.1%, and 0.5% along with pentamidine in an attempt to increase its delivery across the BBB, concomitantly reducing any side-e ects. In vitro assays carried out on MDCK-hMDR cell line suggested high concentrations of P85 and P105 were cytotoxic even though P85 was able to signi cantly increase pentamidine permeability at 0.5% and 0.1%. Greater speci city to a target could circumvent toxicity issues in the future. The second anti-HAT drug studied was e ornithine that treats stage 2 of HAT. To treat stage 2 of the disease it must cross the BBB, yet it was not found to cross the BBB in the in vivo study on mice carried out in our laboratory. Results obtained from assessing the accumulation of e ornithine in hCMEC/D3 and bEnd.3 cell lines, the in vitro models of the BBB, also suggested limited entry of e ornithine into the BBB. Nonetheless, the assays indicated that e ornithine could be a weak substrate for system y+ at the BBB. There was also evidence for its interaction with OCTs in the bEnd.3 cell line. Second part of the thesis focussed on the antipsychotic drugs haloperidol and amisulpride, both cationic drugs at physiological pH. Haloperidol, an extensively used drug both as an antipsychotic and for palliative care, has the potential to interact with other drugs at the BBB. Haloperidol was found to be a substrate for OCTs at the BBB in both hCMEC/D3 and bEnd.3 cell lines and was found to accumulate readily inside the BBB cells. Similarly, amisulpride is an antipsychotic that is also used to treat delusions and aggression in Alzheimer's disease (AD). Previous studies found increased central dopamine receptor occupancy in AD patients when amisulpride was administered at very low doses. Unlike haloperidol, amisulpride had very low accumulation inside the BBB cells. Results suggested amisulpride to be a substrate for the OCTs and the eux transporters MATE1 and PMAT at the BBB. Amisulpride entry into the brain was also tested in wildtype and transgenic AD mice to nd that amisulpride entry into the transgenic mice brains was signi cantly greater than wildtype mice brains and this was not due to a `leaky' BBB of the AD model. Changes to the expression levels of OCT1, 2, 3 and P-glycoprotein transporters in wildtype and AD model mice BBB were determined using Western blotting and no di erences were found. Further exploration of capillaries isolated from human brain samples from control and AD a ected patients was carried out and signi cant region-speci c changes to the expression levels of MATE1 was observed. There was also a tendency for region-speci c decrease in PMAT expression levels. MATE1 and PMAT are proton-dependent transporters that eux substrates out of the BBB. This decrease in eux transporter expression at the BBB of AD patients could explain the increased sensitivity in AD patients to amisulpride.
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Viana, Soares Ricardo. "Study of the antiepileptic drugs transport through the immature blood-brain barrier." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB087/document.
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La résistance aux médicaments antiépileptiques (MAEs) est un des problèmes majeurs des épilepsies infantiles, comme par exemple le syndrome de Dravet. La pharmacoresistance de l’épilepsie pourrait s’expliquer par une diminution du passage des MAEs dans le cerveau, à travers la Barrière Hémato-Encéphalique (BHE). La BHE comporte des transporteurs des familles « ATP-binding cassette » (ABC) et « SoLute Carrier » (SLC) localisés au niveau de la membrane des cellules endothéliales qui contrôlent leur passage entre le sang et le cerveau. La pharmacoresistance des épilepsies a été associée à ces transporteurs car des MAEs ont été identifiés comme substrats de transporteurs comme la glycoprotéine-P (P-gP) et la « Breast Cancer Resistance Protein » (BCRP). L’hypothèse de cette relation est confortée par l’observation de l’augmentation de l’expression de ces transporteurs d’efflux dans le foyer épileptogène et par l’identification des polymorphismes dans les gènes des transporteurs chez des patients pharmacorésistants. L’interaction au cours du développement cérébral entre les cellules endothéliales et les neurones et astrocytes pourrait modifier le profil des transporteurs de la BHE. Les MAEs sont aussi connus pour être soit des inducteurs, soit des inhibiteurs des enzymes du métabolisme des médicaments et des transporteurs membranaires. Ces données nous permettent de faire les hypothèses suivantes: 1) La BHE en développement présente un profil de transporteurs différent de la BHE mature qui pourrait modifier le passage des MAEs vers le cerveau ; et 2) le traitement chronique administré au cours du syndrome de Dravet pourrait changer le phénotype des transporteurs de la BHE en développement. Nous résultats ont montré que la P-gP et la BCRP augment leur expression au cours du développement. La maturation de la BHE a aussi un impact sur le passage des MAEs étudiés. Nous avons constaté une augmentation de l’expression des différents transporteurs ABC et SLC étudiés pendant le développement de la BHE, suite au traitement chronique avec la thérapie du Syndrome de Dravet. L’acide valproïque, un des MAEs utilisé dans ce traitement, diminue l’activité d’efflux de la P-gP chez les rats en développement et adultes, ce qui a été confirmé dans un modèle in-vitro de BHE immature. Ces résultats mettent en évidence l’interaction entre la BHE en développement et le traitement chronique par les MAEs peut modifier leur distribution au niveau du cerveau et la réponse aux MAEsResistance to Antiepileptic Drugs (AEDs) has been a major concern in infantile epilepsies such as for example the Dravet Syndrome. One hypothesis concerning the pharmacoresistance in epilepsy is that a decreased delivery of these drugs to the brain may occur in relation to changes in the Blood-Brain Barrier (BBB) function. BBB exhibits ATP-binding cassette (ABC) and SoLute Carrier (SLC) transporters at the surface of endothelial cells that control the blood-brain transport. Pharmacoresistance in epilepsy may be linked to changes in the functions of these transporters since some AEDs are substrates of the P-glycoprotein (P-gP) and Breast Cancer Resistance Protein (BCRP) transporters. The increased expression of efflux transporters in epileptogenic tissue and the identification of polymorphisms in the efflux transporters genes of resistant patients further support this potential relationship. The interaction of endothelial cells with astrocytes and neurons during brain development could change the pattern of transporters in the BBB. AEDs are also known as either inducers or inhibitors of drug metabolic enzymes and membrane transporters. Taken together, these facts led us to test the following hypothesis: 1) the developing BBB in immature animals presents a different pattern of transporters that could change AEDs disposition in the brain of immature subjects; and 2) the chronic pharmacotherapy used in infantile epilepsies such as the Dravet Syndrome may change the transporters phenotype of the BBB. Our work showed that the expression of P-gP and BCRP increases during development as a function of age. We also showed the maturation of the BBB has an impact on brain disposition of the studied AEDs. We finally observed an increase in the expression of various ABC and SLC transporters induced by the pharmacotherapy of the Dravet Syndrome in immature animals. One of the drugs used, valproic acid, appeared nonetheless to reduce the efflux activity of P-gP in developing and adult animals, which was confirmed in an in-vitro model of the immature BBB. Taken together, these results demonstrated that the interaction between the developing BBB and the AEDs chronic treatment may lead to differences in brain disposition of the AEDs that may impact on the response to AEDs
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Bai, Shuang. "Effect of immunosuppressive agents on drug metabolism in rats." Thesis, Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008270.
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Hammann, Felix. "Prediction of transport, pharmacokinetics, and effect of drugs /." Basel : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8905.
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