1. ¹Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Jeune Equipe, Université de Picardie Jules Verne, Faculté de Pharmacie, 1 rue des Louvels, Amiens, France
2. ²Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHN), Université libre de Bruxelles, Bat C, Bruxelles, Belgium

Correspondence: Dr M Naassila, Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Jeune Equipe, Université de Picardie Jules Verne, Faculté de Pharmacie, 1 rue des Louvels, 80000 Amiens, France. Tel: +33 3 22 82 77 58; Fax: +33 3 22 82 76 72; E-mail: mickael.naassila@u-picardie.fr

Received 24 March 2004; Revised 11 August 2004; Accepted 12 August 2004; Published online 22 September 2004.

Abstract

Cannabinoids and ethanol activate the same reward pathways, and recent advances in the understanding of the neurobiological basis of alcoholism suggest that the CB₁ receptor system may play a key role in the reinforcing effects of ethanol and in modulating ethanol intake. In the present study, male CB₁ receptors knockout mice generated on a CD1 background displayed decreased ethanol-induced conditioned place preference (CPP) compared to wild-type (CB₁^+/+) mice. Ethanol (0.5, 1.0, 1.5, and 2.0 g/kg) induced significant CPP in CB₁^+/+ mice at all doses tested, whereas it induced significant CPP only at the highest dose of ethanol (2.0 g/kg) in CB₁^-/- mice. However, there was no genotypic difference in cocaine (20 mg/kg)-induced CPP. There was also no genotypic difference, neither in cocaine (10–50 mg/kg) nor in D-amphetamine (1.2–5 mg/kg)-induced locomotor effects. In addition, mutant and wild-type mice did not differ in sensitivity to the anxiolytic effects of ethanol (1.5 g/kg) when tested using the elevated plus maze. Interestingly, this decrease in ethanol efficacy to induce CPP in CB₁^-/- mice was correlated with an increase in D2/D3 receptors, as determined by [³H]raclopride binding, whereas there was no difference in D1-like receptors, as determined by [³H]SCH23390 binding, measured in the striatum from drug-naïve mice. This increase in D2/D3 binding sites observed in CB₁ knockout mice was associated with an altered locomotor response to the D2/D3 agonist quinpirole (low doses 0.02–0.1 mg/kg) but not to an alteration of quinpirole (0.1–1.0 mg/kg)-induced CPP compared to wild-type mice. Altogether, the present results indicate that lifelong deletion of CB₁ receptors reduced ethanol-induced CPP and that these reduced rewarding effects of ethanol are correlated to an overexpression of striatal dopamine D2 receptors.