Abstract
We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a “hyper-sensitive” form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model.
Highlights
Ethanol intake and preference were modestly increased in a concentration-depedent mannner in the S426A/S430A mutant mouse model, no changes in ethanol reward, sensitivity, or metabolism were detected
A number of experiments were performed to ascertain the possible reason for the modest increase in consumption 6% ethanol in the S426A/S430A mutant mice
The possibility that increased drinking of 6% ethanol in the S426A/S430A mtuants was caused by an enhancement of the reinforcing effect of ethanol was assessed by testing ethanol Conditioned place preference (CPP)
Summary
Conditioned place preference (CPP) assays were performed to measure whether the rewarding properties of morphine, ethanol, or cocaine were potentiated in S426A/S430A mutant mice. CPP for ethanol (1 and 2 g/kg) was assessed in 31 S426A/S430A mutant and 30 wild-type littermates (14–16 mice/group). The development of a CPP was determined by assessing the amount of time (in seconds) that mice spent in the drug (CS+)-paired chamber in pre- versus post-conditioning test sessions.
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