Abstract
The mechanism by which the adenosine A2A receptor mediates the actions of multiple drugs of abuse is thought to be partly attributable to interactions with dopamine D2 receptors in the striatum; a key structure in drug-related reward, reinforcement and motor responses. Evidence now suggests that this interaction could be further influenced by actions of the metabotropic glutamate receptor, mGlu5, which is coexpressed with striatal A2A and D2 receptors. This work aimed to identify the role of A2A receptors in mediating the locomotor and stereotypic responses to chronic administration of cocaine, morphine and methamphetamine with the use of wild-type (WT) and adenosine A2A receptor knockout (KO) mice. Further, via quantitative autoradiography in WT and A2A KO mice, the experiments described in this thesis also investigated whether the A2A receptor was involved in the regulation of D2 and mGlu5 receptor binding, both under physiological conditions and following chronic cocaine, morphine and methamphetamine administration. A significant reduction of mGlu5, but not D2 receptor density was observed in the ventral striatum of treatment-naive A2A KO mice, giving further evidence for the presence of a striatal A2A-mGlu5 interaction at the receptor level. Chronic administration of methamphetamine, but not cocaine or morphine, caused a significant upregulation of striatal mGlu5 receptors in WT mice. This was accompanied by the manifestation of a stereotypic rearing behaviour in methamphetamine-treated WT mice, both of which were completely abolished in A2A KO mice, suggesting a drug-specific role of an A2A-mGlu5 receptor interaction in the methamphetamine-induced rearing response. Furthermore, the combination of sub-threshold doses of A2A and mGlu5 receptor antagonists significantly attenuated methamphetamine-induced rearing in WT mice, confirming that a striatal A2A-mGlu5 interaction was specifically involved in the mediation of this response. Chronic morphine treatment caused an upregulation of thalamic mGlu5 receptors in A2A KO mice, indicating that an A2A-mGlu5 interaction may also be of relevance in the mediation of morphine-induced antinociceptive tolerance. No changes in D2 receptor binding were observed in either treatment-naive WT or A2A KO mice, or those mice treated chronically with cocaine, morphine or methamphetamine, suggesting that the A2A receptor is not involved in modulating the receptor density of D2 receptors either physiologically, or following chronic drug administration. Collectively, the results described in this thesis show that the contribution of the A2A receptor in mediating the locomotor and stereotypic responses to chronic drug administration is drug-dependent, as is the ability of A2A to regulate mGlu5 receptor binding. Specifically, the therapeutic relevance of the novel A2A-mGlu5 interaction identified following chronic methamphetamine administration merits further investigation, as it adds to a growing body of evidence which suggest simultaneous targeting of A2A and mGlu5 receptors has implications for the improved efficacy of treatments of basal ganglia disorders and drug addiction.