The influence of mGlu₅, A₂[A] and CB₁ receptor interactions on drug-seeking behaviour

Alcohol is the most widely used addictive drug. Alcohol consumption results in a global burden of disease similar to that of tobacco, and imposes significant financial costs relating to healthcare, justice, and lost productivity. However, the available pharmacotherapies to treat alcohol dependence display only mild clinical effectiveness. Previous work has identified the mGlu5, A2a and CB, receptors to be implicated in alcohol self-administration and relapse, as antagonists of these receptors are able to dose-dependently attenuate alcohol self-administration and block relapse in rodent models. The initial aims of this thesis was to further explore the role of mGlu5, A2A and CB, receptors (and others) in alcohol self-administration and relapse with a focus on receptor-receptor interactions. Utilizing Indiana Preferring rats, a synergistic interaction between the A2A and mGlu5 receptors was identified in the context of an operant, alcohol self-administration paradigm. SCH58261 and MTEP administered at subthreshold doses significantly attenuated alcohol self administration and blocked relapse. CBX and A, receptors were also examined, but no more than an additive effect on ethanol self-administration was found. These data indicated that MTEP alone is effective in attenuating ethanol self administration and relapse, highlighting the role the mGlu5 receptor plays within this paradigm. The next objective was to examine where this synergistic interaction was occurring within the brain. The locus of interaction between the mGlu5 and A2A receptors we had behaviourally observed has been examined in other contexts. Colocalization studies and work to do with Parkinson’s disease suggested that this synergistic interaction was occurring within the striatum. Eos immunohistochemistry on sections of naive, reinstated, and drug-treated groups of iP rats revealed that this mGlu5- A2a receptor interaction seems to be taking place both within the striatum and hippocampus within this paradigm. 1- Lastly, examination of mRNA expression between the Indiana Preferring and NonPreferring rat was undertaken to examine phenotypic and drug-induced differentials in expression. mRNA encoding various receptor and receptorinteracting proteins were chosen and examined via in situ hybridization histochemistry. Of interest was significantly greater expression of mGlu5 receptor mRNA in iP rats compared to NP rats. In conclusion, this thesis reveals a synergistic interaction between A2A and mGlu5 receptors within the context of operant, alcohol self-administration and relapse which seems to be occurring within the striatum and hippocampus. Additionally, the mGlug receptor, consistently implicated within this paradigm, also potentially represents a marker of high alcohol intake. These data provide evidence for the potential of combined mGlu5-A2A receptor pharmacotherapy in the treatment of alcohol use disorders.