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Both cannabinoid CB1 receptor knockout and antagonism produce well-established attenuation of palatable food and drug self-administration behavior. Although cannabinoid drugs have received attention as pharmacotherapeutics for various disorders, including obesity and addiction, it is unclear whether these agents produce equivalent behavioral effects in females and males. In this study, acquisition of 32% corn oil or 10% Ensure self-administration, and maintenance of corn oil, Ensure, or 0.56 mg/kg/infusion cocaine self-administration under both fixed ratio (FR)-1 and progressive ratio (PR) schedule of reinforcement, was compared in male and female wild type (WT) and CB1 knockout (KO) mice. Furthermore, the effect of pretreatment with the CB1 antagonist SR141716 (0.3-3.0) on Ensure self-administration in male and female WT and CB1 KO mice was assessed. CB1 genotype and sex significantly interacted to produce an attenuation of acquisition and maintenance of Ensure self-administration and PR self-administration for both Ensure and cocaine in male CB1 KO mice. In contrast, male CB1 KO mice showed no deficit in acquisition and maintenance of FR-1 responding or in PR responding maintained by corn oil. Sex differences also arose within genotypes for responding maintained under all three reinforcers. Lastly, pretreatment with SR141716 attenuated Ensure self-administration in WT and CB1 KO mice but was approximately five-fold more potent in WT mice than in CB1 KOs. The present data add to a small but growing literature suggesting that the cannabinoid system may be differentially sensitive in its modulation of appetitive behavior in males versus females.

Sex and cannabinoid CB1 genotype differentiate palatable food and cocaine self-administration behaviors in mice