Drugs of abuse elicit dopamine release unconditionally, sensitizing the reward system to drugs and drug-associated stimuli resulting in compulsive drug-seeking and drug-taking behaviour. It has been discovered that these same dopamine neurons consistently respond to natural rewards when the reward delivery is at maximum uncertainty (50%). Reward uncertainty is a defining feature of gambling. Therefore, chronic increases in dopamine release from gambling-like stimuli could lead to sensitization of the reward pathways and contribute to gambling pathology. This study investigated the effects of repeated exposure to different probabilities of sucrose reward (0, 25%, 50%, 75%, 100%) on sensitivity to an amphetamine challenge (0.5 mg/kg) and development of sensitization after multiple amphetamine doses (5 x 1.0/kg) in Sprague–Dawley and Lewis rats. No significant group differences were found during the amphetamine challenge or amphetamine sensitization in either strain. Opportunities for improvement in the experimental paradigm and for future research are discussed.

Drugs of abuse elicit dopamine release unconditionally, sensitizing the reward system to drugs and drug-associated stimuli resulting in compulsive drug-seeking and drug-taking behaviour. It has been discovered that these same dopamine neurons consistently respond to natural rewards when the reward delivery is at maximum uncertainty (50%). Reward uncertainty is a defining feature of gambling. Therefore, chronic increases in dopamine release from gambling-like stimuli could lead to sensitization of the reward pathways and contribute to gambling pathology. This study investigated the effects of repeated exposure to different probabilities of sucrose reward (0, 25%, 50%, 75%, 100%) on sensitivity to an amphetamine challenge (0.5 mg/kg) and development of sensitization after multiple amphetamine doses (5 x 1.0/kg) in Sprague–Dawley and Lewis rats. No significant group differences were found during the amphetamine challenge or amphetamine sensitization in either strain. Opportunities for improvement in the experimental paradigm and for future research are discussed.

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Graduation date: 1972

Dramatic growth in substituted amphetamines (‘Ecstasy’) use since the 1980’s has correlated with increased incidence of acute toxicity and residual neuropsychological deficits. This thesis aimed to characterise the acute neurochemical mechanisms and residual neurochemical alterations produced by p-methoxyamphetamine (PMA), which is usually sold as ‘ecstasy’ and is associated with greater acute toxicity than 3,4-methylenedioxymethamphetamine (MDMA). While both PMA and MDMA primarily modulate dopaminergic and serotonergic neurotransmission, little is known of the differences in the neurochemical effects of PMA within the central nervous system, in vivo. This thesis used in vivo chronoamperometry to elucidate the acute neurochemical alterations in monoaminergic pharmacology in vivo after local application of PMA or MDMA within discrete brain nuclei in anaesthetised rats. Measurement of evoked release of monoamines including serotonin (5-HT), and inhibition of neurotransmitter uptake via membrane transporters were assessed. Initial studies compared pharmacodynamic responses of PMA and MDMA, showing PMA to have greater efficacy and potency for alteration of core body temperature in rats, a primary cause of acute toxicity, within minimal alteration in locomotion. Dose-response studies indicated local PMA application within striatum resulted in significantly greater 5-HT evoked release than MDMA, yet lesser dopaminergic release, as predicted by the pharmacodynamic data. Only PMA-evoked release could be partially blocked by pre-treatment with a 5-HT reuptake inhibitor (SERT). Differences in both the qualitative and quantitative nature of striatal evoked-release of 5HT and dopamine were noted for both drugs, which had not been previously seen. Both PMA and MDMA inhibited 5-HT clearance, but only MDMA inhibited dopamine clearance in striatum. Doseresponse studies in the CA3 region of hippocampus indicated PMA was also more efficacious than MDMA in the inhibition of 5-HT clearance in vivo. While the question of whether long term MDMA use induces selective neurodegeneration (reductions in serotonergic in vitro biomarkers) is still unclear, it was not known for PMA prior to this work. Repeated PMA administration was shown to result in reductions in cortical SERT (indicative of potential loss of 5-HT terminal axons), cortical 5-HT content was unaltered. A subsequent comprehensive study followed, comparing the residual effects of PMA or MDMA administration on in vitro serotonergic biomarkers (markers of selective neurodegeneration) and SERT function in vivo. PMA administration resulted in reductions in hippocampal SERT binding and [3H]-5HT synaptosomal uptake, correlating with in vitro biomarkers previously used. SERT function in vivo using chronoamperometric techniques was reduced, as would be predicted. However, hippocampal 5-HT content was again not reduced, indicating that selective neurodegeneration of 5-HT fibres may not in fact be occurring. MDMA administration reduced all measured in vitro serotonergic biomarkers, however SERT function in vivo was completely unaltered. These data indicate that reductions of in vitro biomarkers of 5-HT axonal degeneration do not necessarily predict the potential compensatory mechanisms that maintain SERT function in vivo. Compensatory mechanisms appear to exist in vivo to maintain clearance of extracellular 5- HT that may be disrupted or eliminated during tissue preparation for in vitro assays. In summary, while PMA produced significantly greater alterations, compared to MDMA, in processes intrinsic to 5-HT neurotransmission in both striatum and hippocampus, the magnitude of these responses did not explain the significantly higher risk of acute toxicity seen clinically with PMA use. The second component of the thesis extended beyond prior work, investigating the potential neurodegenerative effects of PMA and MDMA through the assessment of changes in key functional processes in 5-HT neurotransmisson. It is hoped this will contribute to the subsequent characterisation of the mechanism(s) of functional compensation in 5-HT neurotransmission which may lead to more targeted treatments to modulate potential psychological/psychiatric deficits that occur in regular ‘ecstasy’ users. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346193 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2008

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.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. / Vita. Includes bibliographical references.

Thesis (M.S.)--Auburn University, 2008. / Abstract. Vita. Includes bibliographical references (p. 50-52).

Thesis (M. Phil.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 59-75).