Effect of adenosine 2A receptor knockdown in the nucleus accumbens shell on conditioned reward for methamphetamine

Background: Addiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A receptor (A2A) provides an interesting therapeutic avenue, this receptor modulates reward behaviour for METH (Chesworth et al. 2015. Addiction Biology). Of critical interest was the neural locus where A2A mediates reward behaviour for METH. Methods: To address this question, we employed viral-mediated knockdown of A2A, by injecting the adeno-associated virus Cre-recombinase (AAV-Cre) into the nucleus accumbens shell (NAcc shell) of A2A loxP/loxP mice. This region was selected due to high A2A expression and the strong implication of the NAcc shell in reward processing. Following a 3 week transduction period, A2A loxP/loxP mice injected with AAV-Cre or mCherry (a fluorophore control, n = 10-13 per treatment group) were tested for METH conditioned reward behaviour using conditioned place preference (CPP). Site validation and knockdown quantification was conducted following behavioural assessments. Results: Our injections resulted in Cre recombinase expression in ~70% of the NAcc shell. Viral mediated knockdown of A2A had no effect on the development or expression of METH CPP, nor the development or expression of psychomotor sensitization. Conclusions: These results suggest the NAcc shell may not be the sole locus where A2A modulates conditioned reward or psychomotor behaviour for METH.