Role of systemic endocannabinoid CB-1 receptor antagonism in the acquisition and expression of fructose-conditioned flavor–flavor preferences in rats

Rats learn to prefer a flavor mixed into a fructose–saccharin solution over a different flavor mixed into a saccharin-only solution which is considered to be a form of flavor–flavor conditioning. Fructose-conditioned flavor preferences are impaired by systemic dopamine D1 and to a lesser degree, D2 receptor antagonism as well as by NMDA, but not opioid, receptor antagonism. Given the emerging role of the endocannabinoid system in mediating hedonically-driven food intake, the present study examined whether systemic administration of the inverse CB-1 receptor agonist, AM-251 would alter fructose-conditioned flavor preferences. In Experiment 1, food-restricted rats were trained over 10 sessions (30 min/day) to drink a fructose–saccharin solution mixed with one flavor (CS+/Fs) and a less-preferred saccharin-only solution mixed with another flavor (CS−/s). Subsequent two-bottle tests with the two flavors in saccharin (CS+/s, CS−/s) occurred 15 min following counterbalanced pairs of AM-251 doses of 0, 0.1, 1 or 3 mg/kg. Preference for CS+/s over CS−/s following vehicle treatment (74%) was significantly reduced by the 0.1 (67%) and 1 (65%) AM-251 doses, whereas CS+/s, but not CS−/s intake was significantly reduced by the 1 and 3 mg/kg AM-251 doses. In Experiment 2, rats received systemic injections of AM-251 (1 mg/kg) or vehicle prior to the 10 CS+/Fs and CS−/s training sessions. In subsequent two-bottle tests (drug-free) the AM-251 and control groups displayed similar preferences for the CS+ flavor (66% vs. 69%). Experiment 3 demonstrated that AM-251 significantly decreased chow intake (24 h), and 1-h intakes of fructose–saccharin and saccharin-only solutions in ad libitum-fed rats. These data indicate that functional CB-1 receptor antagonism significantly reduces the expression, but not the acquisition of fructose-conditioned flavor–flavor preferences. The endogenous endocannabinoid system is therefore implicated in the maintenance of this form of learned flavor preferences.