4.3 Article

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

Journal

JOURNAL OF PSYCHOPHARMACOLOGY
Volume 25, Issue 4, Pages 550-564

Publisher

SAGE PUBLICATIONS LTD
DOI: 10.1177/0269881110389210

Keywords

A2a adenosine receptors; astrocytes; MDMA; microglia; neurotoxicity; reinforcement

Funding

  1. Spanish Ministry of Science and Innovation [SAF 2007/60249]
  2. Spanish Ministry of Health [RD06/0001/1001]
  3. Generalitat de Catalunya [SGR 2009/684]
  4. Alianza 4 Universidades

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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.

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