Because cannabinoid (CB) and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether CB1 and 5-HT1A receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6J and DBA/2J, with marked differences in native alcohol preference. When offered progressively (3% to 10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (~70%) in DBA/2J than in C57BL/6J mice. In DBA/2J mice, chronic treatment with the CB receptor agonist WIN 55,212-2 increased alcohol intake. This effect was prevented by both chronic CB1 receptor blockade by rimonabant or chronic 5-HT1A receptor stimulation by 8-OH-DPAT, which, on their own, did not affect alcohol intake. In C57BL/6J mice, WIN 55,212-2 had no effect but CB1 receptor blockade or 5-HT1A receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN55,212-2 significantly decreased 5-HT1A-mediated [35S]GTP-γ-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6J mice.

These results show that CB neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT1A interactions. However, the differences between C57BL/6J and DBA/2J mice indicate that such modulations of alcohol intake are under genetic control.