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1
Bloomfield, Michael. "Dopaminergic mechanisms underlying psychosis." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/44332.
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Schizophrenia is a potentially devastating mental illness with a complex aetiology, in which the odds ratios for environmental risk factors for the disorder are greater than the odds ratios of any single gene hitherto identified. Within schizophrenia, striatal dopamine dysfunction has been proposed to underlie the development of psychosis. The Aberrant Salience hypothesis provides an explanatory model based on empirical findings to explain how psychotic symptoms may arise from striatal hyperdopaminergia, whereby multiple risk factors converge to elevate striatal dopamine synthesis capacity as the Final Common Pathway to psychosis. Two important epidemiological risk factors for the disorder are chronic cannabis use and longterm psychosocial stress, both of which have evidence supporting effects on the dopamine system. Environmental risk factors are by their very nature modifiable, and so this thesis examined whether these environmental risk factors were associated with the same dopaminergic abnormalities that have been observed in schizophrenia with 3,4-dihydroxy-6- [18F]-fluoro-l-phenylalanine Positron Emission Tomography. This thesis also examined whether cannabis users exhibit aberrant salience processing using a behavioural task, the Salience Attribution Task. This thesis found that long-term cannabis use was associated with reduced dopamine synthesis capacity and no relationship was found between striatal dopamine synthesis capacity and cannabis-induced psychotic-like symptoms. Whilst cannabis use was not associated with increased aberrant salience processing, there was a relationship between cannabis-induced psychotic-like symptoms and aberrant salience processing. This thesis found that long-term psychosocial stress is associated with reduced dopamine synthesis capacity, although this finding may be due confounding factors. However, a positive relationship was observed between childhood and recent adult stressors and dopamine synthesis capacity. These findings call into question the hypothesis that cannabis increases the risk of psychosis by inducing the same changes observed in schizophrenia, although there some evidence to support the hypothesis that psychosocial stressors do increase risk via this mechanism.
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Szostak, Carolyn Margaret. "Dopaminergic mechanisms in conditioned circling." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/29438.
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After unilateral lesions of the mesotelencephalic dopamine (DA) system, the administration of DA receptor agonists results in circling. This response is believed to reflect an asymmetry in mesotelencephalic DA activity. Moreover, drug-induced circling is thought to be directed away from the projection of higher dopaminergic activity. Recently, it has been reported that circling can be established and maintained using operant procedures in surgically intact and drug naive rats. The phenomenon of conditioned circling has been associated with an asymmetrical change in DA metabolism within the striatum and nucleus accumbens. The present series of experiments was designed to characterize further the involvement of mesotelencephalic DA in conditioned circling.
Rats trained to circle for water according to a continuous schedule of reinforcement did not exhibit increased DA metabolism within either the striatum or the nucleus accumbens (Experiment I). However, a bilateral augmentation was observed when rates of responding were increased by implementing an intermittent schedule of reinforcement (Experiment II). Concurrent increases in the biosynthesis of DA, as estimated by accumulation of DOPA following the administration of a DOPA decarboxylase inhibitor, were not observed (Experiment III). Experiments IVa and IVb examined the extent to which inherent directional biases, which play a role in determining the magnitude and direction of drug-induced circling, influenced the acquisition and performance of the conditioned circling response. No effects were evident. Moreover, a symmetrical, bilateral enhancement in DA metabolism was observed in the striatum, irrespective of directional preferences. While conditioned circling can be established and maintained by reinforcing the response with food, food itself influenced DA metabolism and therefore precluded the detection of changes in DA metabolism specific to the circling response. Specifically, striatal and accumbens DA metabolism was augmented to a similar extent in animals given matched amounts of non-contingently presented food (Experiment V). Concentrations of DA, DOPAC and homovanillic acid (HVA) were found to be differentially distributed throughout the striatum (Experiment Via), suggesting a possible chemical basis for the heterogeneity of striatal DAergic functions. Changes in striatal DA metabolism associated with conditioned circling were observed only within localized regions of the anterior striatum (Experiment VIb). All changes noted were, however, bilateral in nature. Finally, unilateral lesions of the mesotelencephalic DA projection, following the establishment of the conditioned circling response, disrupted responding, irrespective of the relative locus of the lesion (i.e. ipsilateral or contralateral to the direction of turning) (Experiment VII). However, the extent of the behavioral deficit was more severe following contralaterally placed lesions.
It is concluded that circling, established and maintained by positive reinforcement, is subserved by a bilateral augmentation in DA metabolism within the nucleus accumbens and discrete regions of the striatum. However, lesion studies indicate an asymmetrical involvement of the ipsilateral and contralateral projections in this response.Medicine, Faculty of
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3
Stopper, Colin Michael. "Dopaminergic mechanisms guiding probabilistic choice." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46395.
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Racz, Karoly. "Peripheral dopaminergic mechanisms in experimental hypertension." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=72776.
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Pöltl, Dominik [Verfasser]. "Degeneration mechanisms in human dopaminergic neurons / Dominik Pöltl." Konstanz : Bibliothek der Universität Konstanz, 2012. http://d-nb.info/1025226135/34.
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Killcross, Andrew Simon. "Dopaminergic mechanisms and latent inhibition : implications for schizophrenia." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261541.
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Ferland, Jacqueline-Marie N. "Investigating the influence of risky decision making on dopaminergic reward mechanisms." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63131.
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Addiction is a chronic relapsing psychiatric disorder affecting millions worldwide. Despite years of research investigating the etiology and phenomenology of substance abuse, there is no cure. Determining factors which promote the addictive phenotype may help to discover new therapeutics. Several clinical studies have shown addicts demonstrate poor cost/benefit decision making as measured by validated tasks such as the Iowa Gambling Task (IGT), a cognitive deficit maintained during periods of abstinence and associated with relapse risk. However, it is unclear whether disadvantageous choice precedes or is the consequence of drug abuse. Furthermore, dopaminergic signalling, actively recruited by drugs of abuse, has also been implicated in decision-making biases, and may contribute to choice deficits after drug exposure. The experiments here explored the role of disadvantageous choice in addiction susceptibility using rodent analogues of the IGT, the rat gambling task (rGT) and cued rat gambling task (crGT). These paradigms require the animal to choose between four different nose poke options which are associated with sugar wins, probabilities of winning, and timeouts. The crGT also includes salient reward-paired cues to enhance risky decision making. The first two experiments assessed whether baseline risk-preference on the rGT and crGT affected drug seeking as measured by cocaine self-administration, and whether drug exposure affected task performance. The third study examined the influence of task experience on the locomotor response to cocaine and responding for conditioned reinforcement, two dopamine-dependent behavioural assays associated with addiction risk. Basal and cocaine-induced nucleus accumbens dopamine release was also assessed using microdialysis after task training. The final study used chemogenetics to reduce nucleus accumbens dopamine to investigate the role of dopaminergic tone in choice biases. Our results show poor decision making precedes drug exposure, and is uniquely susceptible to drug-induced cognitive deficits. crGT rats showed greater drug seeking and sensitivity to cocaine-induced choice impairments, a phenotype linked to basal accumbal dopamine efflux. Finally, by reducing accumbens dopamine, animals showed marked reductions in risky choice. These data support the conclusion that poor decision making may serve as a cognitive endophenotype for addiction via aberrant dopaminergic signaling within the mesostriatal network.Medicine, Faculty of
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8
Narayanaswami, Vidya. "DIET-INDUCED OBESITY: DOPAMINERGIC AND BEHAVIORAL MECHANISMS AS OUTCOMES AND PREDICTORS." UKnowledge, 2013. http://uknowledge.uky.edu/pharmacy_etds/12.
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Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to an 8-wk high-fat diet exposure and were correlated with subsequent body weight gain. Striatal D2 receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and Western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule for food-reinforcers, respectively. Relative to obesity-resistant, obesity-prone rats exhibited 18% greater body weight, 42% lower striatal D2 receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine concentration, and 2-fold greater methamphetamine-evoked [3H]dopamine overflow. Obesity-prone rats exhibited higher motivation for food, but were less impulsive relative to obesity-resistant rats. Neurobehavioral antecedents of DIO included greater motivation for high-fat reinforcers in rats subsequently shown to be obesity-prone relative to obesity-resistant. Impulsivity, DAT function and extracellular dopamine concentration did not predict the DIO-phenotype. Thus, motivation for food is linked to both initiation and maintenance of obesity. Importantly, obesity results in decreased striatal DAT function, which may underlie the maintenance of compulsive food intake in obesity.
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Bradley, Curtis. "Examining the Associative Learning and Accumbal Dopaminergic Mechanisms of Caffeine Reinforcement." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3457.
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Caffeine is the most consumed psychoactive substance in the world, and most caffeine consumption in coffee and energy drinks is intended to produce a psychoactive effect. However, caffeine is not a primary reinforcer in preclinical paradigms – non-human species do not reliably take the drug to produce a psychoactive effect. However, caffeine is a ‘reinforcement enhancer’ in preclinical models; the effects of caffeine increase the motivation to obtain other non-drug reinforcers. The overall goal of this project was to determine if these reinforcement enhancing effects of caffeine could promote caffeine self-administration and to subsequently investigate the behavioral and neurochemical underpinnings of this effect. We hypothesized reliable caffeine self-administration would occur by adventitious pairing of caffeine with saccharin, a primary reinforcer. Second, we hypothesized that caffeine enhances reinforcement by increasing the salience of incentive stimuli, which are stimuli that come to evoke approach behaviors through associative learning (e.g., Pavlovian conditioning). Finally, incentive salience is moderated by dopamine release in the nucleus accumbens (NAc), an area highly involved in reward-learning and substance dependence. Therefore, we hypothesized that if caffeine enhanced control of approach behavior by incentives, then it would increase the ability of incentive stimuli to evoke dopamine in the NAc. These studies show that intravenous delivery of caffeine with oral saccharin increases operant relative to control groups responding for intravenous caffeine or oral saccharin. The effect was also dose-dependent, confirming that the psychoactive effects of caffeine increased behavior. We also extended this effect to an oral model of caffeine self-administration, which included a simple sweetener (saccharin) or a complex oral vehicle (saccharin with decaffeinated coffee) to mask the bitter taste of caffeine. Presenting caffeine with oral saccharin promoted self-administration, relative to saccharin alone and did not depend on the nature of the complexity of the vehicle. Caffeine also dose-dependently increased approach to an incentive stimulus and this effect was associated with increased extracellular dopamine in the NAc. These findings suggest caffeine enhances incentive motivation and that this effect may result from increases in CS-evoked striatal dopamine.
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Daniel, James St Vincent Clinical School UNSW. "Studies of neurotransmitter release mechanisms in dopamine neurons." Awarded by:University of New South Wales. St. Vincent Clinical School, 2007. http://handle.unsw.edu.au/1959.4/31934.
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Medications that treat diseases such as Parkinson???s disease work by regulating dopamine transmission at synapses. Surprisingly, little is known about the mechanisms regulating dopamine release at synapses. In this thesis, we study mechanisms that regulate vesicle recycling in axons and dendrites of dopamine neurons. Key questions we addressed were: (1) Are vesicles in axons and dendrites associated with the same regulatory proteins, and thus by implication the same regulatory mechanisms, as in excitatory neurons; (2) Do vesicles undergo recycling, and (3) if so, are they characterised by a distinct pool size and rate of recycling. To study this, we cultured dopamine neurons and used immunocytochemistry to detect vesicular monoamine transporter 2 (VMAT2) and identify axons, dendrites and synaptic proteins, combined with labelling of recycling vesicles using FM 1-43. Vesicles in axons, but not in dendrites, were associated with presynaptic proteins such as Synaptophysin and Bassoon. We identified two kinds of presynaptic sites in axons: ???synaptic??? (located close to soma and dendrites??? and ???orphan???. The recycling vesicle pool size was smaller at orphan sites than at synaptic sites, and the initial rate of vesicle pool release was also lower at orphan sites. Both synaptic and orphan sites exhibited lower rates of vesicle pool release compared to hippocampal synapses, suggesting functional differences in presynaptic physiology between dopamine neurons and hippocampal neurons. In somatodendritic regions, VMAT2 was localised to the endoplasmic reticulum, Golgi, endosome, and large dense-core vesicles, suggesting that these vesicles might function as a part of the regulated secretory pathway in mediating dopamine release. None of the synaptic vesicle proteins we studied were detected in these regions, although some preliminary evidence of vesicle turnover was detected using FM 1-43 labelling. This thesis provides a detailed analysis of neurotransmitter release mechanisms in dopamine neurons. Our data suggests that presynaptic release of dopamine is mediated by mechanisms similar to those observed in excitatory neurons. In somatodendritic regions, our data suggests that VMAT2 is localised to organelles in secretory pathways, and that distinct mechanisms of release might be present at somatodendritic sites to those present in presynaptic sites. This thesis provides novel methods for analysing vesicle recycling in dopamine neurons, which provides the basis for further studies examining presynaptic function of dopamine neurons in normal brain function, disease, and therapeutic approaches.
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Yim, Hyeon Joo. "Study on the mechanism of action of ethanol on dopaminergic function in the nucleus accumbens /." Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
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Tenback, Diederik Egbert. "An epidemiological approach to elucidate dopaminergic mechanisms in tardive dyskinesia in schizophrenia /." Maastricht : Universitaire Pers Maastricht, 2006. http://arno.unimaas.nl/show.cgi?fid=5438.
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McKibbon, Valerie Lynn. "Dopaminergic and glutamatergic mechanisms influence immediate-early gene expression in rodent brain." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283934.
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Bodea, Gabriela [Verfasser]. "Molecular mechanisms involved in midbrain dopaminergic neuron migration during murine development / Gabriela Bodea." Bonn : Universitäts- und Landesbibliothek Bonn, 2014. http://d-nb.info/1051028043/34.
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Cropley, Vanessa Louise. "Molecular imaging of striatal and extrastriatal components of the dopamine system positron emission tomographic studies in healthy subjects and Parkinson Disease /." Australasian Digital Thesis Program, 2008. http://hdl.handle.net/1959.3/40073.
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Thesis (PhD) - Swinburne University of Technology, Faculty of Life and Social Sciences, Brain Sciences Institute, 2008.A thesis for Doctorate of Philosophy, Brain Sciences Institute, Faculty of Life and Social Sciences, Swinburne University of Technology - 2008. Typescript. Includes bibliographical references (p. 193-250).
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Johnson, Brandi Nicole. "Dopaminergic mechanisms involved in estrogen modulation of the prolactin response to Orphanin FQ/Nociceptin." Oxford, Ohio : Miami University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1152115599.
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Kohutek, Jodi Lynn. "Long-term effects of 3,4- Methylenedioxymethamphetamine (MDMA) on serotonergic and dopaminergic functioning." CSUSB ScholarWorks, 2003. https://scholarworks.lib.csusb.edu/etd-project/2305.
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Methylenedioxymethamphetamine (MDMA) popularly known as "Ecstasy" continues to gain popularity as a recreational drug that has been shown to increase serotonin and dopamine levels. The present study has demonstrated that repeated exposure to MDMA produces long-term damage to serotonergic and dopaminergic neurons in various regions of the rat brain.
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Carey, Paul D. (Paul Dermot). "Obsessive-compulsive disorder : serotonergic and dopaminergic system involvement in symptom generation and treatment response." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21602.
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Thesis (PhD)--Stellenbosch University, 2008.ENGLISH ABSTRACT: Investigations into the neurobiology of obsessive-compulsive disorder (OCD) have provided useful insights into this prevalent and disabling disorder in recent decades. Encouraging advances have also been made in the pharmacological treatment of OCD. This has improved the quality of life for many who typically endure chronic unremitting symptoms. Despite the widespread use of first-line agents selective for the serotonergic system in OCD, relatively little is known about the neurobiology of treatment response, the specific components of the serotonin system involved in symptom modulation, and the overlapping and distinct brain regions impacted by alternative treatment options. Despite the advance that selective serotonin re-uptake inhibitors have been, a significant proportion of patients still fail to respond adequately to these agents, and alternative pharmacological interventions are required. The use of dopamine antagonists, a strategy which until recently has had only limited supporting data, presents one such alternative. Little however, is known about which subsets of patients are most likely to respond to these agents. In this thesis, I will present a series of six studies that use pharmacological treatments and single photon emission computed tomography (SPECT) to make contributions to three primary areas in OCD namely; neurobiology, treatment and the intersection of the two. First, I address OCD neurobiology by examining the impact of OCD on resting brain function. I then examine the effects of pharmacological challenge of the serotonin 1B receptor using sumatriptan on regional cerebral blood flow (rCBF) and clinical symptomatology. Second, I examine the intersection of neurobiology and treatment as I explore the changes in rCBF in response to treatment with inositol, a precursor of the phosphoinositol second messenger system. I then examine the distinct and overlapping effects on rCBF of treatment for 12 weeks with the selective serotonin re-uptake inhibitor (SSRI) citalopram across anxiety disorders. Third, I address treatment of OCD by examining the efficacy of controlled augmentation of serotonin re-uptake inhibitors with quetiapine, a dopamine antagonist, in treatment refractory OCD. I then combine this data with a second similar dataset to derive a predictive model for treatment outcome with quetiapine augmentation of SRIs. I demonstrate that rCBF in OCD differs significantly from normal controls, is correlated with severity in frontal brain regions, and remains an important line of investigation for OCD pathophysiology that has yet to fully delineated. Pharmacological challenge of the 5HT1B autoreceptor with the selective agonist sumatriptan results in heterogeneous behavioural and regional brain perfusion changes in OCD. Attenuation of pre-frontal perfusion following 5HT1B agonist administration is in line with the effects of SRIs. This work suggests that direct or indirect effects of SRIs on the 5HT1B receptor may be involved in mediating a clinical response in OCD. In the section exploring the intersection of neurobiology and treatment, I show that changes in rCBF partially parallel treatment response to SSRIs across a range of anxiety disorders. These data suggest that a degree of overlap exists in the neurobiology of treatment response or indeed core neurobiology across different anxiety disorders. I then show that effective treatment with inositol in OCD results in rCBF changes that are partially in line with the effects of SRIs on brain perfusion. These data support suggestions that second messengers may form part of the common pathway of action for effective anti-obsessional compounds. In the study in which we augmented SRIs with quetiapine, no advantage over placebo was found. This data has, however, recently been combined with similar data in meta-analyses and demonstrated a benefit over placebo. Finally, we found that patients who have failed fewer SRI trials, have more severe illness, and clinical dimensions with a putative dopaminergic underpinning, may derive preferential benefit from serotonin/dopamine antagonist augmentation of SRIs. Through this series of clinical treatment and functional brain imaging studies in OCD, I have contributed to the neurobiological understanding of OCD, and its treatment in refractory populations. In addition I have explored the intersection of these two domains using novel as well as conventional treatment across other anxiety disorders. Treatment and pharmacological challenges used, either directly or indirectly impacted the monoamine systems serotonin and dopamine and advanced our understanding of their involvement in symptom generation. Future work should focus on the functional intersection of brain function, treatment response, and functional genetic polymorphisms within the monoamine systems of the brain.
AFRIKAANSE OPSOMMING: Ondersoek na die neurobiologie van obsessief-kompulsiewe steuring (OKS) het in die afgelope dekades sinvolle bydraes gelewer tot die begrip van hierdie algemene en verminkende steuring. Bemoedigende vordering is ook in die farmakologiese behandeling van OKS gemaak. Dit het tot ’n verbetering in kwalitiet van lewe van meeste pasiënte gelei wat normaalweg kronies en onophoudelike simptome moet verduur. Ten spyte van die uiteenlopende gebruik van eerste-linie behandeling wat spesifiek inwerk op die serotonien sisteem in OKS, is relatief min bekend oor die neurobiologie van respons op behandeling. So ook is min bekend oor; eerstens die spesifieke komponente van die serotonien sisteem wat betrokke is by simptoom modulasie, en tweedens die gedeeltelik samevallende en afsonderlike brein streke wat deur alternatiewe farmakologiese behandelings beïnvloed word. Ten spyte van die vooruitgang wat die selektiewe serotonien heropname inhibeerders tot gevolg gehad het, is daar nog altyd ‘n betekenisvolle proporsie van pasiënte wat nie voldoende respondeer op hierdie behandelings opsie nie. Dus word alternatiewe opsies benodig. Een so ‘n opsie is die klas dopamien reseptor blokkeerders wat tot onlangs min ondersteunende data gehad het. So ook, is min bekend oor die subgroepe van pasiënte wat die meeste voordeel uit hierdie alternatief sal trek. In hierdie proefskrif sal ek ‘n reeks van ses studies wat farmakologiese middels en enkel foton emissie rekenaar tomografie (EFERT) gebruik om ‘n bydra tot kennis in drie primêre areas van OKS te maak. By name; neurobiologie, behandeling, en die kruispunt van die twee. Eerstens spreek ek neurobiologie aan deur middel van ’n studie wat rustende brein bloed vloei (rBBV) in OKS ondersoek. Hierna ondersoek ek veranderings op rBBV en simptome na eenmalige toediening van ‘n serotonien 1B reseptor agonis, sumatriptan. Tweedens ondersoek ek die kruispunt van neurobiologie en behandeling deur die effek van behandeling met inositol, ‘n voorloper van die fosfoinositol tweedeboodskapper sisteem, op rBBV. Ek ondersoek dan die rBBV patroon van veranderinge in brein streke wat deur twaalf weke van behandeling met die selektiewe serotonien heropname inhibeerder citalopram in verskeie angversteurings bewerkstellig word. Laastens, spreek ek behandeling van OKS aan deur middel van ‘n gekontroleerde studie wat ondersoek instel na die effektiwiteit van die byvoeging van quetiapien, ‘n dopamien reseptor antagonis, tot serotonien heropname inhibeerders in behandelingsweerstandige OKS. Ek kombineer dan hierdie data met ’n soortgelyke datastel om ‘n model af te lei wat kliniese uitkoms vir hierdie behandelings opsie voorspel. Ek het gedemonstreer dat rBBV in OKS betekenisvol verskil van gesonde vergelykbare kontroles. Hierdie verskille het gekorreleer met ernstigheid van OKS in frontale brein streke. Dus bly hierdie tipe studies ’n belangrike rigting van ondersoek in OKS patofisiologie wat tot op hede nie tenvolle uitgewerk is nie. Eenmalige toediening van sumatriptan, het heterogene gedrags en rBBV veranderings in OKS tot gevolg gehad. Pre-frontale verhogings in rBBV voor behandeling is met 5HT1B sumatriptan toediening verminder, ’n effek wat in lyn staan met die effek van selektiewe serotonien heropname inhibeerders. Hierdie werk stel voor dat direkte of indirekte effekte van selektiewe serotonien heropname inhibeerders op die 5HT1B reseptore betrokke mag wees by die meganisme van behandelingsrespons in OKS. In die afdeling waarin ek die kruispunt van neurobiologie en behandeling ondersoek, demonstreer ek dat rBBV veranderings gedeeltelik oorvleuel met dié wat deur selektiewe serotonien heropname inhibeerders veroorsaak word in verskeie angsversteurings. Hierdie data stel voor dat oorvleueling in die neurbiologie van beide behandelingsrespons en kern neurobiologie van hierdie angversteurings ’n waarskynlikheid is. Ek wys ook dat effektiewe behandeling met inositol in OKS ook veranderings in rBBV bewerkstellig wat gedeeltelik in lyn staan met dié van die selektiewe serotonien heropname inhibeerders. Hierdie data ondersteun dus hipoteses van ‘n gemeenskaplike meganisme, wat tweede boodskapper sisteme insluit, wat in die behandelings respons van effektiewe anti-obsessionale middels betrokke is. Die finale deel van hierdie proefskrif handel oor behandeling van OKS. Ten spyte van die onvermoë om ‘n verskil tussen quetiapien en plasebo te demonstreer, het ons onlangs met hierdie data in ‘n reeks meta-analises wel ‘n voordeel vir hierdie intervensie getoon. Ten slote, het ons gevind dat (1) pasiënte wat minder kursusse selektiewe serotonien heropname inhibeerders gefaal het; (2) voor behandeling ‘n erger vorm van OKS gehad het, en (3) ook voordoen met simptoom dimensies wat oënskynlik ‘n dopaminerge basis het, die grootste waarskynlikheid toon om met quetiapien byvoeging tot selektiewe serotonien heropname inhibeerders te respondeer. Met hierdie reeks behandelings en funksionele breinbeeldings ondersoeke, lewer ek ‘n bydra tot die begrip van OKS. Spesifiek dra ek by tot die begrip van die neurobiologie, hantering van behandelingsweerstandige OKS asook die kruispunt van die twee. Farmakologiese middels wat ons óf eenmalig óf vir ‘n volle behandelingskursus toegedien het, het direkte of indirekte uitwerkings op die serotonien and dopamien sisteme gehad, en dus dra hierdie werk ook by tot kennis oor dié se betrokkenheid al dan nie in simptoom modulasie in OKS. Toekomstige werk in die area sal in die breë fokus op die kruispunt van breinfunksie, behandelingsrespons en funksionele genetiese polimorfismes van die monoamien sisteem.
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Chih-Ta, Tai. "Some neural bases of attentional learning." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670291.
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Jaworski, Jason Noel. "Effect of dopamine D2/D3 receptor antagonist sulpiride on changes in mesolimbic dopamine produced by amphetamine and ethanol /." Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008360.
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Porter, Ailsa. "Immediate early gene expression in the mesopontine tegmentum and midbrain after acute or chronic nicotine administration." Thesis, St Andrews, 2008. http://hdl.handle.net/10023/507.
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Chu, Joanne Chen. "The effects of acoustic signals and sex steroids on dopaminergic function in male anurans /." Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
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Rung, Johan. "Dopaminergic stabilizers for the treatment of schizophrenia : rat studies focusing on negative symptoms and mechanisms of action /." Göteborg : Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Göteborg University, 2007. http://hdl.handle.net/2077/7535.
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Nomikos, George Goulielmos. "In vivo neurochemical effects of antidepressant treatments studied by microdialysis." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/31076.
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The present experiments investigated the effects of different antidepressant treatments on dopamine (DA) transmission by employing in vivo microdialysis in the nucleus accumbens (NAC) and the striatum of freely moving rats. The treatments were: a) the tricyclic antidepressant desipramine (DMI), b) the novel antidepressant drug bupropion, and c) electrically induced seizures (ECS). The following results were obtained:
1) Neither acute (5 mg/kg), nor chronic (5 mg/kg, b.i.d. X 21) DMI influenced basal interstitial concentrations of DA in the NAC or the striatum. Chronic DMI did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. In contrast, d-amphetamine (1.5 mg/kg, s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC (not in striatum) of the chronic DMI group. d-Amphetamine-induced hypermotility was also enhanced in the chronic DMI group.
2) Bupropion (10, 25 and 100 mg/kg, i.p.) increased extracellular striatal DA concentrations in a dose-, time-, and action potential-dependent manner. Bupropion produced similar responses in the NAC. The in vivo neurochemical effects of bupropion were compared with the effects of other DA uptake inhibitors such as d-amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, and benztropine by direct administration of the drugs to the striatum via the perfusion fluid in increasing concentrations (1 to 1000 μM). The rank order of potency of these drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was: GBR 12909> benztropine> amphetamine= nomifensine= methylphenidate> cocaine> bupropion. Simultaneous in vivo microdialysis in the NAC and striatum was employed to investigate the effects of chronic (10 mg/kg, b.i.d. X 21) bupropion treatment on bupropion (25 mg/kg, i.p.)-induced increases in extracellular DA concentrations. The effect of the challenge bupropion injection was significantly enhanced in the NAC (not in striatum) of
the chronic bupropion group. Bupropion-induced hyperlocomotion was also enhanced in the chronic bupropion group.
3) Following a single ECS (150 V, 0.75 sec) interstitial concentrations of DA in the NAC and striatum increased sharply to 130% and 300%, respectively. The ECS-induced DA increase in the striatum was Ca⁺⁺-sensitive, partially TTX-independent, and was not influenced by barbiturate-induced anaesthesia. Seizure activity induced by flurothyl did not influence dialysate DA concentrations from the striatum, but increased dialysate DA from the NAC to 150%. These results suggest that the ECS-induced DA release in the striatum (not in the NAC) is related to the passage of current and not to the seizure activity. A course of ECS (8 treatments, one every second day) did not influence basal extracellular DA concentrations in the striatum or the NAC, while it significantly increased the DA metabolites in the striatum. Chronic ECS did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. d-Amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC of the chronic ECS group. d-Amphetamine-induced hypermotility was also enhanced in the chronic ECS group.
These results provide in vivo neurochemical confirmation that chronically administered DMI or ECS do not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI- or chronic ECS-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a potentiation of its effects on interstitial DA concentrations in the NAC. Moreover, these results demonstrate that chronic bupropion-induced behavioral sensitization is accompanied by a selective potentiation of its effects on interstitial DA concentrations in the NAC. Taken together, the present data provide direct neurochemical evidence that these antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system.Medicine, Faculty of
Graduate
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Ellis, Kathryn Anne, and kellis@unimelb edu au. "The dopaminergic system and human spatial working memory : a behavioural, eletrophysiological and cerebral blood flow investigation." Swinburne University of Technology. Brain Sciences Institute, 2005. http://adt.lib.swin.edu.au./public/adt-VSWT20060306.111015.
Full textAbstract:
Dopamine appears to play a critical role in regulating spatial working memory
(SWM) in non-human primates, and SWM deficits are observed in patients with
Parkinson�s disease and schizophrenia. Unfortunately, the current experimental
literature in humans is marred by inconsistent behavioural findings, and there is a void
in neuroimaging studies examining dopaminergic manipulation of SWM-related brain
activity. The present thesis used a combination of behavioural neurocognitive testing
and brain imaging to further examine dopaminergic manipulation of SWM in healthy
humans, using two pharmacological challenges: 1) acute tyrosine depletion (TPD) (to
acutely deplete tonic dopamine), and 2) D1/D2 receptor activation using the dopamine
receptor agonist pergolide (to stimulate dopamine neurotransmission) under
conditions of TPD.
The effects of TPD on behavioural performance were examined using three SWM
tasks: 1) a delayed-recognition task previously impaired by TPD (Experiment 1) and
2) two delayed-response tasks designed to vary only in response requirements
(Experiment 2). The findings demonstrated an apparent failure of TPD to impair
performance on any of the tasks. Further, the effects of TPD on SWM-related brain
activity during a SWM n-back task were examined using regional Cerebral Blood
Flow (rCBF) measured by H2
150 Positron Emission Tomography (Experiment 2), and
Steady State Visually Evoked Potentials (SSVEP) measured by Steady State Probe
Topography (Experiment 4). TPD failed to produce discernable effects on either
neural networks (task-related rCBF) or temporal electrophysiological activity
(SSVEP) associated with the SWM n-back task. In contrast, D1/D2 receptor
stimulation under dopamine depleted conditions impaired performance on both a
SWM delayed-response task (Experiment 1) and SWM n-back task (Experiment 2),
and resulted in task-related increases in fronto-temporal SSVEP latency (suggestive of
increased inhibition) and decreases in parieto-occipital SSVEP amplitude (suggestive
of increased activation) during the early delay period of the SWM n-back task
(Experiment 4). These changes are consistent with the undisputed role of frontal and
parietal regions in n-back task performance, and with previous evidence of
dopaminergic modulation of these regions in animals and humans.
In summary, TPD did not modulate SWM behavioural performance on four different
SWM tasks with differing task demands, and failed to produce measurable changes to
either SWM-related neural networks (task-related rCBF) or cortical
electrophysiological activity (SSVEP) associated with the SWM n-back task. The
implication of these findings, when taken together with previous studies, is that the
degree of dopaminergic depletion achieved with TPD may be insufficient to
consistently and robustly modulate SWM networks in healthy humans, questioning
the utility of TPD as a probe of dopaminergic function. In addition, these findings
demonstrate the complexity of stimulating D1/D2 receptors under dopamine depleted
conditions, and highlight the critical importance of baseline dopamine levels in
influencing the effects of acute dopamine challenge on SWM performance.
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Burton, Susan Frances. "A study of the effects of the pineal hormone, melatonin, on dopaminergic transmission in the central nervous system of rats." Thesis, Rhodes University, 1990. http://hdl.handle.net/10962/d1001463.
Full textAbstract:
Dopamine mechanisms in the central nervous system are important in the control of both normal and abnormal motor function. The recent observations in both animal and human studies, that melatonin, the principal hormone of the pineal gland, may have a role in the control of movement and the pathophysiology of movement disorders, have given rise to the concept that melatonin may have a modulatory influence on central dopaminergic neurotransmission. This study makes use of three animal behavioural models as well as a biochemical model of central dopaminergic function to further investigate the concept. Results from studies using the biochemical model, which investigated the effect of melatonin on dopamine and apomorphine stimulation of dopamine-sensitive adenylate cylase, suggest that melatonin is neither a competitive antagonist nor agonist at the D₁ receptor level, although the possibility of physiological stimulation or antagonism is not excluded. In behavioural studies, prior melatonin mg/kg administration (1 and 10 (8M) ip) inhibited apomorphine induced stereotypy and locomotor activity in normal rats, and apomorphine-induced rotational behaviour in 6-hydroxydopamine and quinolinic acid lesioned rats. The possibility that these results may have physiological significance is borne out by the observation that, under enviromental lighting conditions that are associated with raised endogeous melatonin levels, apomorphine- induced stereotypy and locomotor activity is attenuated. The general conclusion is that melatonin has an inhibitory influence on central nervous system dopaminergic function, suggesting therefore, that the pineal gland and melatonin may have a role in the pathophysiology and treatment of movement and behavioural disorders associated with dopaminergic dysfunction
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Ma, Thong Chi. "The molecular mechanisms of free 3-nitrotyrosine neurotoxicity." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189707727.
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Janeczek, Paulina. "Mechanisms of Gene Regulation in Alcoholism: Role of α-Synuclein in the Pathophysiology of Alcohol Misuse." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367052.
Full textAbstract:
The pathophysiology of alcohol addiction is still unknown. Current research is focusing on understanding the mechanisms involved in the neurotoxic effects of ethanol on the brain and the genetic risk factors associated with alcohol misuse. The prefrontal cortex is particularly susceptible to neurotoxic damage, and neuronal loss in this region has been associated with long-term alcohol misuse. As the prefrontal cortex is involved in the development and persistence of alcohol addiction, ethanol induced neurotoxic damage in this region is likely to amplify the reinforcing effects of alcohol. α-Synuclein (SNCA), a protein abundantly expressed in neurons and involved in the dopaminergic reward pathway, has a well-established role in neurodegenerative and neuropsychological disorders, and is a candidate gene for alcohol misuse. Changes to α- synuclein expression may therefore have severe consequences on these key pathways and may increase susceptibility to alcohol addiction. This thesis investigated the regulation of α-synuclein expression and its potential role in the pathophysiology of chronic alcohol misuse.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Vergoz, Vanina, and n/a. "Effects of queen mandibular pheromone on locomotor behaviour and learning in worker honey bees Apis mellifera." University of Otago. Department of Zoology, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081121.161845.
Full textAbstract:
In a honey bee colony, the queen uses queen mandibular pheromone (QMP) to induce young worker bees to feed and groom her. Among its many behavioural and physiological effects, QMP reduces dopamine levels in the brains of young worker bees. Dopamine is a biogenic monoamine involved in numerous functions including motor control and aversive learning. This study investigates the effects of QMP on motor activities and aversive learning behaviour and the potential link between QMP and dopamine levels in the brain of young bees.
In young bees under the age of 15-days, QMP dramatically reduced locomotor activity and inhibited aversive learning behaviour. Interestingly in older bees these behaviours were not affected by pheromone. Treating young bees with the dopamine precursor, L-dopa (3.25 [mu]g/mI), partially rescued the levels of locomotor activity in QMP-treated bees, and reduced QMP�s effects on aversive learning. This suggests that blocking effects of QMP on both locomotor activity and aversive learning result at least in part from QMP-induced changes in brain dopamine levels.
Two components of the QMP blend, 4-hydroxy-3-methoxyphenylethanol (HVA) and methyl p-hydroxybenzoate (HOB) were examined more closely. Both HVA and HOB are structurally similar to dopamine. HVA was found to mimic the effects of the full QMP blend on aversive learning. Treating bees with HVA reduced aversive learning in young bees. In contrast, treatment with HOB did not affect learning ability. This strongly suggests that HVA is one of the key components that mediates the actions of QMP on aversive learning.
The final section of this thesis investigates why it might be advantageous to honey bee queens to block aversive learning and reduce locomotor activity in young worker bees. The study reveals age-related differences in behaviours that individual worker bees display towards QMP. Young bees reared with QMP or collected from a queenright hive showed attraction to QMP. Conversely, older bees displayed avoidance behaviour towards QMP. By blocking the establishment of aversive memories, young bees may be prevented from forming an association between QMP and any unpleasant side effects induced by this pheromone. This may confer significant benefit to the queen by increasing the likelihood of young workers remaining in her attendance.
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Reinel, Claudia. "Multidisziplinäre Untersuchung dopaminerger Mechanismen der repetitiven Störungen anhand von zwei Rattenmodellen dopaminerger Dysregulation." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2015. http://dx.doi.org/10.18452/17390.
Full textAbstract:
Repetitive Störungen manifestieren sich als Leitsymptom in der Zwangsstörung und dem Tourette-Syndrom. Die Symptome werden als enthemmte Stereotypien eines desinhibierten Basalganglien-thalamo-kortikalen (BGTC) Regelkreises verstanden. Überdies wird als neurochemisches Korrelat ein dysregulatives Dopamin (DA)-System innerhalb dieser Kerngebiete nahegelegt, welches über ein überaktives Dopamintransporter (DAT)-System erklärt werden könnte. In der Induktion repetitiver Erkrankungen ist die Interaktion des BGTC Regelkreises und des DA-Systems dennoch unklar. In der vorliegenden Arbeit wurden daher anhand von zwei Pathologiemodellen (Ratte) mit unterschiedlich induzierter Dysregulation des DA-Systems (transgen versus pharmakologisch) die dysfunktionalen Einheiten im BGTC Regelkreises vergleichend untersucht. Im transgenen Modell führte die zentralnervöse DAT-Überexpression: (1) zu einer verstärkten Genexpression des vesikulären Monoamintransporter 2 (VMAT2) sowie des DA-Rezeptors 1 und DA–Rezeptors 2 (DRD1, DRD2), (2) zu einem reduzierten DA-Spiegel mit erhöhter DA-Umsatzrate und veränderten serotonergen- und GABAergen-System, und (3) zu perserverativen Verhalten. Im Gegensatz dazu zeigte die chronische Applikation mit dem D2-Agonisten Quinpirol im pharmakologischen Modell: (1) eine Reduktion des DAT, VMAT2 und DRD2, (2) eine reduzierte DA-Umsatzrate und (3) zwanghaftes Kontrollverhalten. Die Ergebnisse legen nahe, dass die unterschiedlichen klinischen Subtypen der Zwangsstörung unterschiedlichen neurobiologischen Veränderungen zugrunde liegen könnten. Ferner bietet das hier vorgestellte transgene Modell erfolgsversprechende Ansatzpunkte um als neues valides Tiermodell der repetitiven Störungen etabliert zu werden.Repetitive disorders manifest as the cardinal symptom in obsessive-compulsive disorder and Tourette syndrome. The symptoms are understood as disinhibited stereotypies of a basal ganglia-thalamo-cortical (BGTC) circuit. Furthermore, it is suggested that a dysregulated dopamine (DA) system within this circuit is the underlying neurochemical correlate which could be explained by an overactive dopamine transporter (DAT). At this point, it is still unclear how the BGTC circuit and the DA system interact in the induction of repetitive disorders. Therefore we investigated the dysfunctional unities within the BGTC circuit by comparing two pathological rat models (transgenic versus pharmacologic) with different induced dopaminergic dysregulation. The DAT overexpressing rat model showed: (1) increased gene expression of the vesicular monoamine transporter 2 (VMAT2), DA receptor D1 (DRD1) and DA receptor D2 (DRD2), (2) lower levels of DA with an increased DA metabolism and alterations in the serotonin- and GABA system, and (3) perseverative behavior. In contrast, the chronic application of the D2 receptor agonist quinpirole resulted in the pharmacologic model in: (1) lower gene expressions of the DAT, VMAT2 and DRD2, (2) reduced DA-turnover and (3) compulsive control behavior. These results suggest that different clinical subtypes of obsessive-compulsive disorder caused by different neurobiological alterations. In addition, the presented transgenic model provides the opportunity to be established as a new valid animal model of repetitive disorders.
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Dunkel, Gregor [Verfasser], and Oliver [Akademischer Betreuer] Pogarell. "Dopaminerge Mechanismen neurophysiologischer Parameter / Gregor Dunkel ; Betreuer: Oliver Pogarell." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1154683737/34.
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Reinel, Claudia [Verfasser], Werner [Akademischer Betreuer] Kloas, Christine [Akademischer Betreuer] Winter, and Imke [Akademischer Betreuer] Puls. "Multidisziplinäre Untersuchung dopaminerger Mechanismen der repetitiven Störungen anhand von zwei Rattenmodellen dopaminerger Dysregulation / Claudia Reinel. Gutachter: Werner Kloas ; Christine Winter ; Imke Puls." Berlin : Lebenswissenschaftliche Fakultät, 2015. http://d-nb.info/1081211199/34.
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Chavanon, Mira-Lynn [Verfasser], and Gerhard [Akademischer Betreuer] Stemmler. "Die dopaminerge Verankerung der Extraversion : Mechanismen und EEG-Indikatoren / Mira-Lynn Chavanon. Betreuer: Gerhard Stemmler." Marburg : Philipps-Universität Marburg, 2011. http://d-nb.info/1014851807/34.
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Barnett, Scott Thomas Charles. "Glutamate receptors in the ventral tegmental area : a potential mechanism involved in long term potentiation : a thesis submitted in partial fulfilment of the requirements of the degree of Masters of Science in Psychology at the University of Canterbury /." Thesis, University of Canterbury. Psychology, 2006. http://hdl.handle.net/10092/1358.
Full textAbstract:
In the present study, footshock, which produces a powerful aversive emotional response was used in a Pavlovian conditioning experiment as an unconditioned stimulis (UCS), and was paired with the presentation of a light used as a conditioned stimulis (CS). There is an accumulation of evidence that supports the assertion that dopaminergic (DA) neurons within the ventral tegmental area (VTA) are active in processes that contribute to the amygdala-based circuitry involved in regulating emotionally salient responses. To build upon findings implicating VTA DA, excitatory glutamate (Glu), NMDA and AMPA receptors, were examined with respect to their role in Pavlovian conditioned fear responding. Fear potentiated startle (FPS) was used to assess the effects of intra-VTA infused AP5, and intra-VTA infused CNQX on conditioned fear responding in laboratory rats. The administration of the NMDA receptor antagonist AP5 (at 1.0, 2.5, and 5.0ug doses), blocked the ability of a conditioned stimulus (CS) previously paired with footshock to become conditioned to the UCS. Similarly, administration of the AMPA receptor antagonist CNQX (at 1.0, 2.5, 5.0ug doses), inhibited the ability of the CS to become conditioned to the UCS. The results of this study indicate the VTA is an important site for synaptic modifications associated with fear learning, and that activation of excitatory Glutamatergic receptors in the VTA play a necessary part of the processing underlying fear conditioning. Measures of shock reactivity demonstrated that the infusion of AP5 and CNQX into the VTA did not inhibit baseline startle amplitudes. The administration of AP5 and CNQX did not suppress the perception of footshock as an aversive stimulus. This study provides further definition to established knowledge surrounding the neural processes whereby neutral environmental cues gain negative emotional salience as occurs in fear conditioning. It was hypothesised that the action of excitatory glutamatergic transmission within the VTA acts on NMDA and AMPA receptors is to assist in the acquisition of Pavlovian conditioned fear, possibly through the same synaptic mechanisms that govern LTP.
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Speck, Sascha [Verfasser], Martin [Akademischer Betreuer] Sommer, Jochen [Akademischer Betreuer] Weishaupt, and Thomas [Akademischer Betreuer] Crozier. "Untersuchungen der Mechanismen kortikaler Neuroplastizität und Exzitabilität durch niederfrequente rTMS und dopaminerges Pharmakon - Eine doppelblinde und placebokontrollierte Probandenstudie / Sascha Speck. Gutachter: Martin Sommer ; Jochen Weishaupt ; Thomas Crozier. Betreuer: Martin Sommer." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/104273531X/34.
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Verma, Aditi. "Mechanisms of Dopaminergic Neurodegeneration in Parkinson's Disease." Thesis, 2018. http://etd.iisc.ac.in/handle/2005/3853.
Full textAbstract:
Parkinson’s disease (PD) is a debilitating movement disorder. The cardinal symptoms of PD are bradykinesia, resting tremors and rigidity. PD is characterized by degeneration of dopaminergic neurons of A9 region, substantia nigra pars compacta (SNpc) and loss of dopaminergic terminals in striatum while the dopaminergic neurons of A10 region, ventral tegmental area (VTA) are relatively protected. Putative mechanisms, such as mitochondrial dysfunction, dysregulation of the ubiquitin proteasome system and increased oxidative stress have been hypothesized to mediate PD pathology. However, precise mechanisms that underlie selective vulnerability of SNpc dopaminergic neurons to degeneration are unknown. The aim of this thesis was to evaluate the pathological mechanisms that may contribute to degeneration of SNpc dopaminergic neurons in PD.
Dopaminergic neurons of SNpc are pacemakers and constant calcium entry through L-type calcium channel, Cav1.3 has been reported in these neurons during pacemaking. In addition, these neurons have poor calcium buffering capacity. Together, this leads to dysregulation of calcium homeostasis in the SNpc dopaminergic neurons leading to increased oxidative stress. Gene expression of the full length channel and the variant was investigated in the mouse midbrain and further their presence was verified in mouse SNpc and VTA and also in SNpc and VTA in the MPTP mouse model of PD. Gene expression of Cav1.3 -42 and its variant was also studied in SNpc from autopsy tissue from PD patients and age matched controls.
Having studied differential expression of the calcium channels, global changes in gene expression in SNpc from the MPTP mouse model of PD and PD autopsy tissues were next examined. This is the first report of transcriptome profile alterations from SNpc in mouse model and PD tissue performed using RNA-seq. Gene expression profiles were examined from SNpc 1 day post single exposure to MPTP, in which case there is no neuronal death and 14 days after daily MPTP treatment where SNpc has undergone ~50% cell death. Further, RNA- seq was performed to study gene expression alterations in SNpc from human PD patients and age- matched controls. The RNA-seq data was taken through extensive analyses; analysed for differential gene expression, gene-set enrichment analysis, pathway analysis and network analysis.
Glutaredoxin 1 (Grx1) is a thiol disulfide oxidoreductase that catalyses the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. Down-regulation of Grx1 has been established to exacerbate neurodegeneration through impairment of cell survival signalling. Previous work from our laboratory has demonstrated that perturbation of protein thiol redox homeostasis through diamide injection into SNpc leads to development of PD pathology and motor deficits. It was therefore investigated if Grx1 down-regulation in vivo, leading to increased glutathionylation and protein thiol oxidation, could result in PD pathology.
This work is thus the first study of RNA-seq based transcriptomic profile alterations in SNpc from human PD patients. This work also highlights several differences between mouse model and human PD tissue indicating that the underlying mechanisms of PD pathogenesis differ from mouse to humans in addition to developing a novel model for PD.
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Verma, Aditi. "Mechanisms of Dopaminergic Neurodegeneration in Parkinson's Disease." Thesis, 2018. http://etd.iisc.ernet.in/2005/3853.
Full textAbstract:
Parkinson’s disease (PD) is a debilitating movement disorder. The cardinal symptoms of PD are bradykinesia, resting tremors and rigidity. PD is characterized by degeneration of dopaminergic neurons of A9 region, substantia nigra pars compacta (SNpc) and loss of dopaminergic terminals in striatum while the dopaminergic neurons of A10 region, ventral tegmental area (VTA) are relatively protected. Putative mechanisms, such as mitochondrial dysfunction, dysregulation of the ubiquitin proteasome system and increased oxidative stress have been hypothesized to mediate PD pathology. However, precise mechanisms that underlie selective vulnerability of SNpc dopaminergic neurons to degeneration are unknown. The aim of this thesis was to evaluate the pathological mechanisms that may contribute to degeneration of SNpc dopaminergic neurons in PD.
Dopaminergic neurons of SNpc are pacemakers and constant calcium entry through L-type calcium channel, Cav1.3 has been reported in these neurons during pacemaking. In addition, these neurons have poor calcium buffering capacity. Together, this leads to dysregulation of calcium homeostasis in the SNpc dopaminergic neurons leading to increased oxidative stress. Gene expression of the full length channel and the variant was investigated in the mouse midbrain and further their presence was verified in mouse SNpc and VTA and also in SNpc and VTA in the MPTP mouse model of PD. Gene expression of Cav1.3 -42 and its variant was also studied in SNpc from autopsy tissue from PD patients and age matched controls.
Having studied differential expression of the calcium channels, global changes in gene expression in SNpc from the MPTP mouse model of PD and PD autopsy tissues were next examined. This is the first report of transcriptome profile alterations from SNpc in mouse model and PD tissue performed using RNA-seq. Gene expression profiles were examined from SNpc 1 day post single exposure to MPTP, in which case there is no neuronal death and 14 days after daily MPTP treatment where SNpc has undergone ~50% cell death. Further, RNA- seq was performed to study gene expression alterations in SNpc from human PD patients and age- matched controls. The RNA-seq data was taken through extensive analyses; analysed for differential gene expression, gene-set enrichment analysis, pathway analysis and network analysis.
Glutaredoxin 1 (Grx1) is a thiol disulfide oxidoreductase that catalyses the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. Down-regulation of Grx1 has been established to exacerbate neurodegeneration through impairment of cell survival signalling. Previous work from our laboratory has demonstrated that perturbation of protein thiol redox homeostasis through diamide injection into SNpc leads to development of PD pathology and motor deficits. It was therefore investigated if Grx1 down-regulation in vivo, leading to increased glutathionylation and protein thiol oxidation, could result in PD pathology.
This work is thus the first study of RNA-seq based transcriptomic profile alterations in SNpc from human PD patients. This work also highlights several differences between mouse model and human PD tissue indicating that the underlying mechanisms of PD pathogenesis differ from mouse to humans in addition to developing a novel model for PD.
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Cui, Guohong. "Differential regulation of Ca²⁺ signals in dopamine neurons: a potential mechanism for neuroadaptive changes underlying drug addiction." Thesis, 2007. http://hdl.handle.net/2152/3022.
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Cui, Guohong 1974. "Differential regulation of Ca²⁺ signals in dopamine neurons : a potential mechanism for neuroadaptive changes underlying drug addiction." 2007. http://hdl.handle.net/2152/13188.
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Woolley, Sarah Cushing. "Genetic and experiential effects on dopaminergic systems." Thesis, 2002. http://wwwlib.umi.com/cr/utexas/fullcit?p3110709.
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Ellis, Kathryn Anne. "The dopaminergic system and human spatial working memory : a behavioural, eletrophysiological and cerebral blood flow investigation /." 2005. http://adt.lib.swin.edu.au/public/adt-VSWT20060306.111015/index.html.
Full textAbstract:
Thesis (PhD) - Swinburne University of Technology, Brain Sciences Institute, 2005.Submitted for the degreee of Doctor of Philosophy, Brain Sciences Institute, Swinburne University of Technology - 2005. Typescript. Bibliography: p. 159-197.
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Tang, Man Amanda. "Involvement of mu-opiate receptors in ethanol-induced accumbal dopamine response." 2003. http://wwwlib.umi.com/cr/utexas/fullcit?p3116452.
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da, Costa Araújo S. "Unravelling the activity patterns of midbrain dopaminergic neurons during male sexual behaviour." Doctoral thesis, 2021. http://hdl.handle.net/10362/132857.
Full textAbstract:
"In most species, male sexual behaviour involves a complicated sequence of events that culminates
with the delivery of sperm and fertilisation of the female egg. However, despite decades of
research, very little is still known regarding the mechanics controlling this behaviour. In this thesis,
by using mice as our model system, we aimed to understand the neuronal mechanisms underlying
male sexual behaviour, in particular the involvement of the midbrain dopaminergic neurons.(...)"
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Mahadevia, Darshini. "Developmental plasticity and circuit mechanisms of dopamine-modulated aggression." Thesis, 2018. https://doi.org/10.7916/D8P28FMD.
Full textAbstract:
Aggression and violence pose a significant public health concern to society. Aggression is a highly conserved behavior that shares common biological correlates across species. While aggression developed as an evolutionary adaptation to competition, its untimely and uncontrolled expression is maladaptive and presents itself in a number of neuropsychiatric disorders. A mechanistic hypothesis for pathological aggression links aberrant behavior with heightened dopamine function. However, while dopamine hyper-activity is a neural correlate of aggression, the developmental aspects and circuit level contributions of dopaminergic signaling have not been elucidated. In this dissertation, I aim to address these questions regarding the specifics of dopamine function in a murine model of aggressive behavior. In chapter I, I provide a review of the literature that describes the current state of research on aggression. I describe the background elements that lay the foundation for experimental questions and original data presented in later chapters. I introduce, in detail, published studies that describe the clinical manifestation and epidemiological spread, the dominant categories, the anatomy and physiology, and the pharmacology of aggression, with a particular emphasis on the dopaminergic system. Finally, I describe instances of genetic and environmental risk factors impacting aggression, concluding with studies revealing an important role for interactions among genetics, environmental factors, and age in the development of aggression. In chapter II, I investigate the developmental origins of aggression by examining sensitive periods during which perturbations to the dopaminergic system impact adult aggressive behavior. Previous work in our laboratory has concluded that periadolescent (postnatal days 22-41) elevation in dopamine, via transient dopamine transporter blockade, leads to increased adult aggression and heightened response to amphetamine. I expanded on these findings by temporally refining the opening and closing of this window of sensitivity, specifically to postnatal days 32 to 41, during which increases in dopaminergic tone increase adult aggression and behavioral sensitivity to psychostimulants. The potentiated response to amphetamine indicated to us a state of altered dopaminergic physiology. We next validated this hypothesis and found increased firing rate (in vitro), and increased bursting and population activity (in vivo) at baseline. These data indicate that elevated periadolescent dopamine impacts maturation of the dopamine system, leading to a hyper-active dopaminergic and aggressive predisposition. In conclusion, this chapter introduces a developmental component to the hyper-dopaminergic model of aggression. In chapter III, I report a series of experiments exploring the direct and causal involvement of dopamine in driving aggression. While dopamine hyper-activity is a neural correlate of aggression, the precise brain circuits involved have not been elucidated. Using optogenetics, I established a causal role for the ventral tegmental area (a key source of dopamine) in aggression modulation. I further advanced this finding by demonstrating that the modulatory role of dopamine, is population- and projection-specific. I found that activity of ventral tegmental area, but not substantia nigra, dopamine neurons promotes aggression. Furthermore, controlled stimulation of ventral tegmental area dopaminergic terminals in the lateral septum, but not the nucleus accumbens, mediates increased aggression. I selectively traced connectivity between the lateral septum and the ventral tegmental area using a Cre-driven, population-specific viral vector. I used this virus to show that anatomically distinct clusters of ventral tegmental area dopamine cells send projections to the lateral septum and the nucleus accumbens, thereby dissociating the two target sites both behaviorally and anatomically. Furthermore, I found that while local dopamine release in the lateral septum increases aggression, it has no bearing on reward behaviors thus indicating a stronger association with impulsive, and not motivated, aggression. In conclusion, this chapter offers causal evidence for dopamine’s role in modulating impulsive aggression by identifying a distinct pathway from the ventral tegmental area to the lateral septum that controls aggression. In the work described in chapter IV, my aim was to determine the mechanism underlying ventral tegmental area to lateral septum dopamine-mediated aggression. I first characterized the expression of dopamine receptors in the lateral septum and found that D2 receptors heavily colocalize with the dominant population of neurons in the lateral septum, i.e. GABAergic cells. Moreover, the D2 receptors are perfectly aligned with incoming dopamine afferents. Next we investigated, in acute brain slices, how D2 signaling affects lateral septum function. We revealed that activating D2 receptors hyperpolarizes D2-expressing lateral septum neurons. This effect was abolished with bath application of the D2 receptor antagonist, sulpiride. We validated the functional involvement of post-synaptic D2 signaling in a behavioral test, and found that the aggression induced by direct terminal release of dopamine at the lateral septum is reversed by acutely blocking local D2 receptor signaling. In conclusion, this chapter demonstrates that the ventral tegmental area to lateral septum dopamine pathway, via D2-mediated inhibition of GABAergic lateral septum neurons, is necessary to drive ventral tegmental area-triggered aggression. In chapter V, I engage in a general discussion addressing how the findings from each chapter can be linked to provide a more comprehensive outlook on environmental and genetic risk factors that can modulate ventral tegmental area-triggered aggression. I discuss possible pre- and post-synaptic mechanisms that could impact the functionality of the identified dopaminergic ventral tegmental area to lateral septum pathway. Moreover, in distinguishing this specific dopamine circuit and lateral septum D2 signaling as an underlying correlate of violent pathology, this dissertation aims to evoke deeper understanding of the mechanism of current antipsychotics used to manage aggression. I end this dissertation by proposing new empirical questions, techniques and lines of research that could further develop my findings as well strengthen the links between dominant models of aggression that exist in the field today.
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Theile, Jonathan William. "Mechanisms in ethanol modulation of GABA release onto dopaminergic neurons of the ventral tegmental area." Thesis, 2009. http://hdl.handle.net/2152/ETD-UT-2009-12-491.
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Activation of ventral tegmental area (VTA) dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. While at most central synapses ethanol generally increases inhibitory synaptic transmission, no studies have explored the effect of acute ethanol on GABAergic transmission in the VTA. Here we investigated how ethanol modulates GABAergic transmission in the VTA in relation to the overall action of ethanol on VTA-DA neuron activity. We demonstrated that ethanol dose-dependently enhances action potential-dependent and -independent GABA release onto VTA-DA neurons. Utilizing whole-cell voltage clamp recording techniques, ethanol increased both spontaneous and miniature inhibitory postsynaptic current (s/mIPSC) frequency while having minimal effect on s/mIPSC amplitude. The ethanol enhancement in GABA release was independent of GABAB auto-receptor inhibition of release. Intra-terminal calcium levels regulate neurotransmitter release, thus we investigated how modulation of calcium levels would affect the ethanol-enhancement in GABA release. Ethanol enhanced mIPSC frequency in the presence of the voltage-gated calcium channel blockers, cadmium chloride and nicardipine. However, blockade of intracellular calcium stores with 2-APB and cyclopiazonic acid eliminated the ethanol-enhancement of mIPSC frequency. Intracellular calcium stores are regulated via Gq protein-coupled receptors such as the 5-HT2C receptor. 5-HT2C receptor activation robustly enhanced mIPSC frequency whereas blockade inhibited the ethanol-enhancement in mIPSC frequency. These observations suggest that increased calcium release from intracellular stores via 5-HT2C receptor activation is involved in the ethanol-enhancement of GABA release onto VTA-DA neurons. Utilizing cell-attached current-clamp recordings, we demonstrated that the ethanol-enhancement of VTA-DA neuron activity is modulated by the concurrent enhancement in GABA release. Blockade and activation of GABAA receptors enhanced and reversed, respectively, the stimulatory effect of ethanol on VTA-DA neurons. Mu-opioid receptors (MORs) on GABAergic interneurons have been demonstrated to modulate both basal and ethanol-enhanced VTA-DA activity in vivo, though we failed to demonstrate such an effect in vitro. Overall, the results of this study suggest that the 5-HT2C receptor and intra-terminal calcium-dependent ethanol enhancement in GABA release acts to regulate the overall stimulatory effect of ethanol on VTA-DA activity.text
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Yen, Shih-Hui, and 顏世慧. "The Action Mechanisms of Progesterone on Tuberoinfundibular Dopaminergic Neuronal Activity and Prolactin Secretion." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/15023197216882911804.
Full textAbstract:
博士國立陽明大學
生理學研究所
87
The ovary is the major site for synthesis and secretion of progesterone (P4) in mammals. The major physiological functions of P4 include: control of ovulation, facilitation of implantation, and maintenance of pregnancy by promoting uterine growth and suppressing myometrial contractility. A diurnal change of tuberoinfundibular dopaminergic (TIDA) neuronal activity exists in female rats, which is prerequisite for the estrogen-induced afternoon PRL-surge. In adult ovariectomized (OVX) and estrogen (E2)-primed Sprague-Dawley rats, P4 (2 mg/kg sc, given at 0800 h) exhibited a significant effect in advancing and amplifying the afternoon PRL surge, as determined by both chronic catheterization and decapitation methods of blood sampling. The afternoon decrease of TIDA neuronal activity, as determined by 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the median eminence (ME), was also advanced from 1400 to 1300 h. These effects of P4 on PRL surge and TIDA neuronal activity were shown to be dose- (from 0.5-4 mg/kg) and estrogen-dependent. To determine whether the effect of P4 was through specific P4 receptor (PR), I used RU486 (a PR antagonist), antisense oligodeoxynucleotide (ODN; against PR mRNA), and antibody against PR in this study to prove this hypothesis. Treatment of RU486 (5 mg/kg, sc) for 1-2 days before and on sampling day was effective in antagonizing the effect of P4 on TIDA neuronal activity and PRL secretion. Intracerebroventricular (ICV) injection of antisense ODN (4 nM) or PR antibody (1:1 and 1:5) for 2 days were also effective. The involvement of P4 or PR on modulating the TIDA neuronal rhythm and the PRL surge was also shown in proestrous rats. In summary, P4 may play an important role in rhythmic changes of the TIDA neuronal activity and the PRL surge in the female rats. Our lab has previously shown central opioidergic, cholinergic and serotonergic neurons are involved in the control of TIDA rhythms and PRL surge on estrogen-treated OVX rats. Systemic injection of P4 (2 mg/kg) had no significant effect on DOPAC concentration in ME and PRL levels in serum at 30-300 min post-treatment, in the morning in both OVX and OVX+E2 rats. However, acute treatment of P4 resulted in decreased DOPAC concentration in striatum in OVX rats but increased DOPAC levels in OVX+E2 rats. RU486 alone had no significant effect on the estrogen-induced afternoon PRL surge and the TIDA rhythm change. On the contrast, RU486 prevented the advanced TIDA neural activity change and PRL secretion at 1300 h in OVX+E2+P4 rats. Meanwhile, I proved that mecamylamine (6 mg/kg, ip), naloxone (10 mg/kg, ip), or kertanserin (10 mg/kg, ip) significantly prevented the advancing effects of P4 on TIDA neuronal activity and PRL secretion. These results implied the complicated interactions existing in the modulation of P4 ''s effect at 1300 h. In summary, P4 could play a different regulatory role on the rhythmic changes of TIDA neuronal activity in OVX or OVX+E2 rats. P4''s effect may involve modulatory inputs from central opioidergic, cholinergic and serotonergic neurons. Nitric oxide (NO) has been shown to play a significant role of PRL surge in proestrous rat. To test the involvement of NO in the diurnal change of TIDA neuronal activity and PRL secretion, a NO synthase (NOS) inhibitor, NG-nitro-L-arginine(L-NA, 50 mg/kg, ip at 1000 and 1200 h), was systemically injected to OVX+E2 rats. It was found that L-NA significantly blocked the diurnal change of TIDA neuronal activity and PRL secretion at 1500 and 1700 h in OVX+E2 rats. Co-administration of L-arginine (300 mg/kg, ip) with L-NA completely prevented the effects of L-NA. Total nitrite/nitrate levels in the serum of L-NA and L-NA+L-arginine-treated rats substantiated the effects of L-NA and L-arginine on NO production. Moreover, pretreatment of antisense ODNs (1 mg/3 ml, icv; against the mRNA of nNOS or eNOS) were also effective in preventing the diurnal change of TIDA neuronal activity and PRL surge at 1500 h. Antisense ODN against mNOS mRNA had no such effect. I further demonstrated that L-NA dose-dependently blocked the effect of P4 on TIDA neuronal activity and serum PRL at 1300 h. This effect could be negated by simultaneous administration of L-arginine. Antisense ODNs against the mRNA of nNOS or eNOS was also effective in preventing P4''s effect on TIDA neuronal activity and PRL secretion at 1300 h. In summary, NO might play an regulatory role in the E2- and P4-regulated diurnal changes of TIDA neuronal activity and PRL secretion. Angiotensin II (AII) has been considered as one of the PRL-releasing factors in the central and peripheral nervous system. Moreover, the distribution of ANP and AII and their receptors in the CNS overlaps considerably. It is found that central or peripheral administration of ANP could antagonize the effects of AII. The effects of angiotensin II (AII) and atrial natriuretic peptide (ANP) on TIDA neuronal activity and serum PRL levels were examined in this part. ICV injection of AII induced by time (5-60 min)- and dose (0.01-1 mg)-dependent effects to stimulate TIDA neuronal activity and inhibit serum PRL levels in OVX, E2-treated rats. ANP (0.01-1 mg) had no significant effect on TIDA neuronal activity and serum PRL at 30 min. When ANP (0.1-1 mg) was co-administered with AII (1 mg), ANP dose-dependently attenuated the effect of AII on TIDA neuronal activity and PRL secretion. Using single-unit recording of neuronal activity from dorsomedial arcuate nucleus (dmARC) in brain slices, AII stimulated 68.0% (n=49) of recorded neurons. A few (5.6%) units were inhibited and the remainings were not responsive. ANP alone was almost ineffective on dmARC neurons (63.0% of 54 units). ANP stimulated and inhibited 22.2 and 14.8 % of dmARC neurons, respectively. When ANP was co-administered with AII to AII responsive units, however, ANP significantly attenuated the effects of AII. Thus, the neurochemical results indicate that ANP could negatively regulate the stimulatory effect of AII on TIDA neuronal activity and serum PRL levels. On the other hand, electrophysiological results substantiated the observations by demonstrating that ANP exerts a similar modulating effect on dmARC neurons. ICV injection of CNP had no significant effects on DOPAC and DOPA accumulation in ME, serum PRL levels in OVX E2-treated rats. We also found that AII (1 mg/3ml, icv) significantly prevented the decrease of TIDA neuronal activity and PRL surge at 1500 h in E2-treated OVX rats. Moreover, saralasin (an AII receptor antagonist) dose-dependently prevented the AII''s effect in estrogen-primed OVX rats. However, AII alone and/or saralasin had no effect on the effect of P4 in advancing TIDA neuronal activity and amplified PRL secretion at 1300 h. In summary, AII play a modulatory effect on diurnal change of TIDA neuronal activity and PRL surge at estrogen-primed OVX rats, but not involved in the P4 ''s effect. In all, P4 plays an important physiological role in the control of the rhythmic changes of TIDA neuronal activity and PRL secretion. A complex neuronal circuit including nitric oxide, serotonin, acetylcholine and opioids may be involved in the process.
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Nakamura, Ken. "Intrinsic antioxidant and mitochondrial properties of dopaminergic neurons : significance to the pathogenesis of Parkinson's disease /." 1999. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:9943098.
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Shieh, Kun-Ruey, and 謝坤叡. "The Circadian Change of Hypothalamic Tuberoinfundibular Dopaminergic Neuron Activity: Its Ontogeny and Neural Control Mechanisms." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/90785877695158618106.
Full textAbstract:
博士國立陽明大學
生理學研究所
87
A diurnal rhythm of the tuberoinfundibular dopaminergic (TIDA) neural activity, i.e., high in the morning and low in the afternoon, was recently reported in ovariectomized rats treated with or without estrogen. Whether this variation of TIDA neural activity is a true circadain rhythm, exhibits a sexual and age difference, and which factor(s) is involved in its control were the focus of this study. Serum prolactin (PRL) levels were measured at the same time for comparison with the TIDA neural activity. Male and female Sprague-Dawley rats at specific days of age, i.e., 28-, 35-, 39-, 42-, 49-, 56-day-old, were used. They were housed in a temperature (23 1℃)- and light (lights on from 0600 to 2000 h)-controlled room with free access to rat chow and tap water. Some rats were left intact and some were gonadectomied with or without estrogen (E2) treatment before decapitation. Some rats received drugs injections through pre-implanted cannlae in the lateral cerebroventricle at specific time points of the day in conscious state and some received drugs by intraperitoneal injection. All rats were quickly decapitated without anesthesia and the brains were quickly removed and frozen on dry ice. The median eminence (ME), nucleus accumbens (NA), striatum (ST), paraventricular nucleus (PVN), periventriclar nucleus (A14) and suprachiasmatic nucleus (SCN) of each rat were dissected out by micropunch technique. DA neuronal activity was determined by measuring the levels of DOPAC, DOPA, and DA with high performance liquid chromatography with electrochemical detector. Their serum PRL samples were collected and stored at -20℃ until assayed. Central DA neural activities exist two types of circadan rhythms in ovariectomized (OVX) rats treated with estrogen. DOPAC or DOPA levels in the ST and NA were significantly higher during the dark phase (2100-0500 h). Significant decreases in DOPAC and DOPA levels in the ME were observed at 1700 and 2100 h, which correlated with the afternoon PRL surge. This variation of TIDA neural activity was found not only in OVX + E2 rats but also in intact female and OVX rats, but not in intact and orchidectomized male rats with or without E2 treatment. Furthermore, this variation was found in the pubertal and postpubertal but not prepubertal rats, nor could it be found in the male rats at any age. Serum PRL levels and the basal activity of TIDA neurons exhibit parallel increases from pre- to postpubertal rats. A reciprocal relationship exists between TIDA neuron and PRL: the former inhibits the latter, while the latter stimulates the former. To determine the cause-effect relationship between serum PRL and TIDA neural activity, we used repeated injection of a PRL depletor, cysteamine, and exogenous injection of PRL in prepubertal rats. We found that cysteamine can inhibit the gradual increase of basal TIDA neural activity during peripubertal age. Exogenous PRL can restore the TIDA neural activity in prepubertal rats with or without cysteamine treatment. Additionally, cysteamine treatment lowered the DA neural activities in the ME, NA and ST, but increased those in the PVN and A14. Since cysteamine also can deplete somatostatin (SS), we used exogenous SS-14 to study its effect on central DA neural activity. We found that SS-14 can inhibit the DA neural activities in the ME, PVN and A14, but stimulate those in the NA and ST in a dose- and time-dependent manner in adult OVX+E2 rat. I have previously shown that an endogenous cholinergic tone acting on opioidergic neurons is involved in the circadian change of TIDA neural activity. I further showed that the same cholinergic rhythm also existed in intact female, but not male, rats, which may be one of the underlying mechanisms for the sexual difference observed. The use of a specific nicotinic receptor, mecamylamine, instead of atropine further indicates the involvement of nicotinic receptors. The findings that exogenous injection of nicotine exhibited a dose- and time-dependent inhibitory effect on TIDA neurons and stimulation on PRL secretion also substantiate the results obstained with cholinergic antagonists. In addition, the effects of nicotine could be prevented not only by mecamylamine, but also by naloxone, indicating that nicotine was acting first on opioidergic neurons and in turn on TIDA neurons. The effects of nicotine in the morning and those of naloxone and mecamylamine in the afternoon could only be observed in post- (56-day-old), but not in prepubertal (28-day-old) female rats. Thus the maturation of cholinergic-opioidergic control mechanism may occur during peripubertal stage. In summary, a circadian rhythm of TIDA neural activity, i.e., high in the morning and low in the afternoon, exists in the postpubertal or adult female rats, but not in the male and prepubertal female rats. Serum PRL is important for the maturation and/or maintenance of DA systems in the ME, NA and ST, while SS exhibits inhibitory and stimulatory effects on hypothalamic and midbrain DA systems, respectively. Endogenous cholinergic neurons may act through activating the opioidergic neurons to exhibit an inhibitory effect on TIDA neural activity and a stimulatory one on serum PRL secretion during the afternoon of adult female rats.
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Tang, Man Amanda 1972. "Involvement of mu-opiate receptors in ethanol-induced accumbal dopamine response." 2003. http://hdl.handle.net/2152/12545.
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Marvin, Caroline Braun. "How curiosity drives actions and learning: Dopamine, reward, and information seeking." Thesis, 2015. https://doi.org/10.7916/D8V40TX6.
Full textAbstract:
Curiosity drives many of our daily pursuits and interactions; yet, we know surprisingly little about how it works. Here, I harness an idea implied in many conceptualizations of curiosity – that information has value in and of itself. Reframing curiosity as the motivation to obtain reward – where the reward is information – allows me to leverage major advances in theoretical and computational mechanisms of reward-motivated learning. Using willingness to wait, an established measure of reward-motivated behavior, I test the reward value of information, finding that people are more willing to wait for information about which they’re more curious. I then provide new evidence supporting several predictions that emerge from this information-as-reward framework.
In Chapter 1, I examine whether the valence of information affects its reward value, finding an asymmetric effect of positive vs. negative information, with positive valence associated with both enhanced curiosity and enhanced long-term memory for information. I then test an idea drawn from computational and neurobiological accounts of reward learning, which suggest that it is not the absolute value of information that drives learning, but, rather, the gap between the reward expected and the reward received. By asking people to rate both their curiosity about a question and their satisfaction with the answer, I obtain measures of the values of the reward expected (curiosity) and the reward received (satisfaction) and find that the discrepancy between the two – the information prediction error – facilitates learning.
These findings suggest a conceptual correspondence between dopaminergic mechanisms of reward learning and curiosity. Aging is associated with decrements in dopaminergic functioning, but it is unclear whether these deficits extend to curiosity, as few behavioral investigations of curiosity and aging exist. In Chapter 2, I, therefore, sought to explore the effects of aging on curiosity, providing behavioral evidence that curiosity is not diminished in aging, but, rather, that it is enhanced. These findings also revealed that older adults are more likely to wait for more positive information, consistent with existing theories of emotional processing.
In Chapter 3, I sought to test whether the dopaminergic reward system, particularly the striatum, plays a necessary and causal role in curiosity by examining curiosity in patients with Parkinson’s disease, a neurological disorder characterized by dopamine depletion in the striatum and striatal dysfunction. I provide evidence for diminished curiosity in people with Parkinson’s disease, relative to age- and education-matched controls. In particular, I find that participants with Parkinson’s disease are less likely to wait for lower-value rewards, i.e., information about which they’re less curious.
Taken together, these results support the idea that information functions as a reward – much like money or food – guiding choices and driving learning in systematic ways.