1. ¹Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
2. ²IRIBHM, Université Libre de Bruxelles, Bruxelles, Belgium

Correspondence: Dr O Valverde, Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain. Tel: +34 93 542 28 30; Fax: +34 93 542 28 02; E-mail: ovalverde@imim.es

Received 1 March 2005; Accepted 18 July 2005; Published online 17 August 2005.

Abstract

Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. A_2A adenosine and D₂ dopamine receptors are colocalized in the same neurons in discrete brain areas, and the dopaminergic transmission plays a crucial role in the addictive properties of drugs of abuse, such as cocaine. In the present study, we have investigated the specific role of A_2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. For this purpose, we have evaluated the acute locomotor effects produced by cocaine and the development of locomotor sensitization by repeated cocaine administration. In addition, we have also examined cocaine acute rewarding properties using the conditioned place preference. Finally, we used the intravenous drug self-administration paradigm to investigate the acquisition of an operant response maintained by cocaine self-administration and the reinforcing efficacy of the drug in these knockout animals. Acute cocaine induced a similar increase of locomotor activity in mice lacking A_2A adenosine receptors and wild-type littermates. Cocaine-induced locomotor sensitization and conditioned place preference were also maintained in A_2A knockout mice. Nevertheless, these knockout mice showed a lower rate of cocaine self-administration than wild-type mice in both fixed ratio 1 and 3 schedules of reinforcement. Moreover, a reduction in the maximal effort to obtain a cocaine infusion was found in A_2A knockout mice under a progressive ratio schedule. In addition, a vertical shift of the cocaine dose–response curve was observed in mice lacking A_2A adenosine receptors in comparison with wild-type littermates. Our study demonstrates that A_2A adenosine receptors play an important role in cocaine addictive properties, and these receptors seem to be required to develop the addictive effects of this drug.