The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA.
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.
Grup de Recerca en Neurobiologia del Comportament (GRNC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Jessica
J
Ruiz-Medina
Catherine
C
Ledent
Olga
O
Carretón
Olga
O
Valverde
D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D001253:Astrocytes / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration
D000697:Central Nervous System Stimulants; D018836:Inflammation Mediators; D043705:Receptor, Adenosine A2A; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine