GLUTAMATE RECEPTORS AS A THERAPEUTIC TARGET FOR DRUG & ALCOHOL ABUSE

摘要

Purpose: We have utilised neuropharmacological and genetic approaches to examine systems implicated in drug-seeking behaviour and/or drug induced plasticity. Methods: Multiple strains of alcohol-preferring rats and mice were treated with the selective mGlu5 receptor antagonist, MTEP, and/or the selective adenosine A2a receptor antagonist, SCH58261, to examine the effect on alcohol self-administration. In addition, mice lacking either the mGlu5 receptor or the adenosine A2a receptor were also examined for alcohol, morphine and cocaine-related behaviours. Results: MTEP caused dose-related reductions in operant responding for alcohol in rats and mice. In C57/B16J mice, MTEP dose-dependently reduced appetitive and consummatory phases of alcohol self-administration. In mGlu5 receptor knockout mice on a C57BL/6J background, consumption and preference for alcohol was reduced compared to wildtypes, whereas consumption and preference for saccharin was normal. Combination treatment of rats with individually sub-threshold doses of MTEP and an adenosine A2a receptor antagonist reduced alcohol self-administration and relapse, suggestive of functional interactions and/or synergy between mGlu5 and adenosine A2a receptors. We have also investigated the impact of adenosine A2a receptor deletion on behavioral responses to morphine in a number of reward related paradigms. Decreased morphine self-administration and breakpoint in A2a knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A2a knockout mice. In support, a place preference to morphine was not observed in A2a knockout mice but was present in wildtypes. In wildtype mice, MTEP can prevent a conditioned place preference to cocaine. In contrast, in mice lacking the adenosine A2a receptor, MTEP does not prevent a place preference to cocaine. In both genotypes, MTEP attenuates the acute cocaine-induced locomotor activation. These data suggest that a functional A2a receptor is implicated in the ability of MTEP (an mGlu5 antagonist) to dampen the conditioned reinforcement of cocaine, at least in CD1 mice. Conclusion: Overall, these studies suggest that mGlu5 and adenosine A2a receptors can interact to regulate drug and alcohol-seeking.