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 (A(2A)) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A(2A) 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 A(2A) knockout (KO) mice to assess the role of A(2A) in behaviours relevant to METH addiction. METH conditioned place preference was absent in A(2A) KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A(2A) KO mice in a dose-related manner. METH intravenous self-administration was intact in A(2A) KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A(2A) KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A(2A) KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A(2A) KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A(2A) signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.