Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

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Abstract
The cannabinoid CB1 receptor antagonist SR141716A decreases cue-induced reinstatement of sucrose and drug seeking in rats. Reinstatement behavior is not well characterized in C57Bl/6 mice, including CB1 receptor knockout mice generated on a C57Bl/6 background. In the present study, male C57Bl/6, CB1 knockout (CB1 KO), and wild-type littermate (WT) mice were trained to respond for the sweet reinforcer Ensure® or corn oil. Responding was maintained on a fixed ratio 1 (FR1) schedule of reinforcement for 10 days, and then extinguished by the removal of the reinforcer and associated cues. Subsequently, the effect of either pretreatment with SR141716A or CB1 receptor knockout on cue-induced reinstatement of Ensure® or corn-oil seeking was assessed. Both 1.0 and 3.0 mg/kg SR141716A decreased reinstatement of Ensure® seeking in C57Bl/6 mice. A tenfold higher dose of SR141716A (10.0 mg/kg) was required to attenuate reinstatement behavior in C57Bl/6 mice responding for corn oil, suggesting that CB1 receptors may be selectively involved in the neurobiology underlying reinstatement of responding for some food reinforcers but not others. Whereas CB1 receptor antagonism selectively attenuated reinstatement of responding for Ensure®, genetic deletion of the CB1 receptor produced only a trend in decreasing reinstatement of Ensure® seeking, and did not attenuate reinstatement of corn-oil seeking. Baseline differences in levels of operant responding were also observed in WT vs CB1 KO mice maintained by Ensure® and corn oil. This and other possible reasons for the observed discrepancy between pharmacological blockade vs genetic invalidation of the CB1 receptor on reinstatement of Ensure® seeking are discussed.

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