Ethanol Self‐Administration Is Regulated by CB1 Receptors in the Nucleus Accumbens and Ventral Tegmental Area in Alcohol‐Preferring AA Rats

Abstract

Endogenous cannabinoids and their receptors, CB1 receptors in particular, have been implicated in mediation of ethanol reinforcement. Previously, suppression of ethanol drinking by CB1 antagonists has been demonstrated in many experimental paradigms. However, the exact mechanism by which CB1 antagonists modulate ethanol drinking remains elusive. In the present study, we assessed the role of CB1 receptors within the key regions of the mesolimbic dopamine pathway, the nucleus accumbens (NAcc) and ventral tegmental area (VTA), in regulation of ethanol self-administration. Adult male alcohol-prefer AA rats were trained to self-administer either 10% (w/v) ethanol or 0.1% (w/v) saccharin under an FR1 schedule during daily 30-minute sessions. Following stable baseline responding, rats were tested after systemic administration of the CB1 antagonist SR141716A (0 to 10 mg/kg) and the agonist WIN55,212-2 (0 to 2 mg/kg). Separate groups of rats were implanted with bilateral cannulas aimed at the NAcc or VTA, and tested after microinjections of SR141716A (0 to 3 microg) and WIN55,212-2 (0 to 5 microg) into the NAcc or VTA. The highest intracerebral doses were tested also in rats responding for a 0.1% saccharin solution. SR141617A dose-dependently suppressed ethanol responding after systemic administration. Microinjections of SR141617A both into NAcc and VTA attenuated ethanol responding. In addition, intra-NAcc injections of SR141617A suppressed saccharin intake. Although low doses of systemically given WIN55,212-2 increased ethanol responding, no effects were seen after WIN55,212-2 microinjections into NAcc or VTA. Bidirectional changes in ethanol self-administration by the systematically administered CB1 agonist and antagonist show that ethanol reinforcement is controlled by CB1 receptors in alcohol-preferring AA rats. Replication of the suppressive effects by CB1 antagonism in the NAcc and VTA suggests that endocannabinoids and their receptors mediate ethanol reinforcement through interaction with the mesolimbic dopamine pathway.