The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA

Adenosine A2a receptors are crucial for the rewarding and neuroinflammatory effects of MDMA. In mice lacking these receptors, MDMA failed to support self-administration, indicating a complete loss of its reinforcing properties. Additionally, the neurotoxic regimen of MDMA caused increased glial activation in the striatum of normal mice, but this inflammatory response was attenuated in mice without A2a receptors. Acute effects on body temperature, locomotion, and anxiety were similar in both genotypes. This work identifies the A2a adenosine receptor as a key mediator of MDMA's addictive potential and neurotoxicity.

Study at a glance

Abstract

Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA on body temperature, locomotor activity and anxiety-like responses were measured in A2a knockout mice and wild-type littermates. Second, MDMA reinforcing properties were evaluated using the intravenous self-administration paradigm. Finally, we assessed striatal astrogliosis and microgliosis as markers of MDMA neurotoxicity. Our results showed that acute MDMA produced a biphasic effect on body temperature and increased locomotor activity and anxiogenic-like responses in both genotypes. However, MDMA reinforcing properties were dramatically affected by the lack of A2a adenosine receptors. Thus, wild-type mice maintained MDMA self-administration under a fixed ratio 1 reinforcement schedule, whereas the operant response appeared completely abolished in A2a knockout mice. In addition, the MDMA neurotoxic regime produced an enhanced inflammatory response in striatum of wild-type mice, revealed by a significant increase in glial expression, whereas such activation was attenuated in mutant mice. This is the first report indicating that A2a adenosine receptors play a key role in reinforcement and neuroinflammation induced by the widely used psychostimulant.