Temlett, James Alexander
A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, for the degree of Doctor of Philosophy (Medicine) / Idiopathic Parkinson's disease remains one of the commonest neurodegenerative diseases known today. It causes incapacita ting symptoms untreated but when given replacement neurotransmitters, principally levodopa or dopamine, corrects the major features of the illness. The fundamental cause of nigral dopaminergic cell decline remains unknown, is not principally genetic, but may be due to abnormal hepatic handling of neurotoxins. One such putative neurotovin is MPTP which causes parkinsonism in man and primates. The MPTP-treated primate model is thus a useful model within which new drugs, including dopamine receptor agonists may be tested. Levodopa remains the mainstay of successful pharmacotherapy in the treatment of parkinson's disease. However the last decades have taught us that levodopa treatment with time produces problems of dyskinesias and unpredictable motor fluctuations. Hence alternate pharmacotherapy is sought to supplement levodopa or possibly to circumvent its necessity. (Abbreviation abstract) / Andrew Chakane 2019
5-Ht2c serotonin receptors cellular localization and control of dopaminergic pathways in the rat brain /Alex, Katherine D. January 2007 (has links)
Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Neurosciences. Includes bibliographical references. Available online via OhioLINK's ETD Center.
Nomikos, George Goulielmos
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
Dopamine related signaling pathways on generation of projection pattern at the Mouse chiasm. / CUHK electronic theses & dissertations collectionJanuary 2013 (has links)
Chen, Tingting. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 100-109). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong,  System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
A Role for Neuronal Nicotinic Acetylcholine Receptors in Dopamine-Mediated Behaviors and the Hypnotic Response to Anesthetics: A DissertationSoll, Lindsey G. 17 December 2013 (has links)
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels that most notably influence dopamine (DA) release. In this thesis, I examine the role of nAChRs in mediating DA-related behaviors such as movement and drug dependence. To accomplish this, I utilized a “gain-offunction” knock-in mouse (the Leu9’Ala line) containing agonist-hypersensitive α4* nAChRs (* indicates other nAChR subunits in addition to α4 are within the receptor complex) that renders receptors 50-fold more sensitive to nicotine and acetylcholine than wild-type (WT) receptors. I found that DHβE, a selective antagonist for α4β2* nAChRs, induced reversible and robust motor dysfunction characterized by hypolocomotion, akinesia, catalepsy, tremor, and clasping in Leu9’Ala but not WT mice. Reversal of the phenotype was achieved by targeting dopamine signaling. Blockade of mutant α4* nAChRs elicited activation of brain regions in the basal ganglia including dorsal striatum and substantia nigra pars reticulata indicated by c-Fos immunoreactivity. These data indicate that blocking α4* nAChRs in Leu9’Ala mice activates the indirect motor pathway resulting in a motor deficit. We also determined that α4* nAChRs involved in motor behaviors did not contain the α6 subunit, a nAChR subunit highly expressed in DAergic neurons suggesting that different nAChR subtypes modulating striatal DA release have separate functions in motor output. Conditioned place aversion and hypolocomotion, behaviors elicited during nicotine withdrawal, were also induced by DHβE in nicotine-naïve Leu9’Ala but not WT mice. Together these data suggest that DHβE globally reduces DA release in the CNS. In a separate project, I determined that α4* and α6* nAChRs modulate drug-induced hypnosis. Activation of nAChRs increased sensitivity to ketamine-induced hypnosis; whereas antagonizing nAChRs had the opposite effect. Additionally, α4 knockout (KO) mice were less sensitive to the hypnotic effects of ketamine, but α6 KO were more sensitive. High doses of ethanol induce an anesthesia-like state characterized by immobility, analgesia, and hypnosis. Testing the effects of ethanol hypnosis in α4 KO revealed that α4* nAChR do not play a large role in the acute effects of ethanol-induced hypnosis, but are involved in tolerance to this ethanol-induced behavior. The mechanisms of anesthetic-induced hypnosis are still largely unclear, despite the wide use of anesthesia. Future work on these receptors and their involvement in the anesthetic response will help to define a mechanism for hypnosis and improve the use of anesthetic drugs.
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