Adenosine 2A receptors modulate reward behaviours for methamphetamine

Addiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2A) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates; yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2A knockout (KO) mice to assess the role of A2A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2A KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A2A KO mice in a dose-related manner. METH intravenous self-administration was intact in A2A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A2A KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A2A KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A2A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.