Cannabinoid-serotonin interactions in alcohol-preferring vs. alcohol-avoiding mice.

Because cannabinoid and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether cannabinoid 1 (CB1) and 5-HT1A receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6 J and DBA/2 J, with marked differences in native alcohol preference. When offered progressively (3–10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (� 70%) in DBA/2 J than in C57BL/6 J mice. In DBA/2 J mice, chronic treatment with the cannabinoid receptor agonist WIN 55,212– 2 increased alcohol intake. WIN 55,212–2 effect was prevented by concomitant, chronic CB1 receptor blockade by rimonabant or chronic 5-HT1A receptor stimulation by 8-hydroxy-2-(di-n-propylamino)-tetralin, which, on their own, did not affect alcohol intake. In C57BL/6 J mice, chronic treatment with WIN 55,212–2 had no effect but chronic CB1 receptor blockade or chronic 5-HT1A receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN 55,212–2 significantly decreased 5-HT1A-mediated [ 35 S]guanosine triphosphate-c-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6 J mice. These results show that cannabinoid neurotransmission can exert a permissive control on alcohol intake, possibly through CB1–5–HT1A interactions. However, the differences between C57BL/6 J and DBA/2 J mice indicate that such modulations of alcohol intake are under genetic