Δ9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour

Abstract

Aims: Recent studies suggest that cannabinoid receptor agonists may promote relapse to drug-seeking behaviour after a period of abstinence. In this study, the ability of Δ9-tetrahydrocannabinol (THC) to reinstate previously reinforced responding for alcoholic and non-alcoholic beverages was assessed in rats using a novel lick-based paradigm. Methods: Rats were initially given free access to beer (containing 4.5% ethanol v/v), near-beer (a beverage that looks and tastes like beer but contains <0.5% ethanol v/v) or isocaloric sucrose in their home cages for 3 weeks. They were then trained to lick at a tube to self-administer the pre-exposed beverage in operant chambers under a VR10 schedule in 30-min sessions daily. After ∼3 weeks of such access, the rats underwent an extinction procedure, so that licking at the tube produced no reward. Once responding had ceased, the rats were subjected to various reinstatement tests. Results: In Experiment 1, the cannabinoid receptor agonist Δ9-THC (1 mg/kg) significantly reinstated responding, previously reinforced with beer or near-beer. The effect was unlikely to be caused by increased appetite because 24 h food-deprivation had no such effect. Exposure to cat odour in the test chamber failed to reinstate responding for beer or near-beer and caused a complete inhibition of responding. In Experiment 2, Δ9-THC (0.3 and 1 but not 3 mg/kg) again reinstated beer-seeking behaviour while the 1 mg/kg dose also reinstated responding in sucrose trained animals. Midazolam (0.15 mg/kg but not 0.5 or 1.5 mg/kg) produced a modest reinstatement of beer-seeking but had no effect on sucrose-seeking behaviour. Conclusions: The finding that Δ9-THC can reinstate alcohol-seeking provides the impetus for further research into the involvement of the cannabinoid system in alcohol craving. However, the reinstatement of near-beer and sucrose-seeking behaviour caused by Δ9-THC suggests a relatively non-specific effect. This may perhaps be related to the stressor-like effects of cannabinoids, and their ability to activate key neural circuitry in the amygdala and bed nucleus of the stria terminalis.