An examination of factors affecting cannabinoid reward, aversion, and potential reinforcement: drug history, sex and drug combinations

These studies examined adolescent drug history, sex and drug combinations as factors that may attenuate the aversive and potentiate the rewarding effects of THC in an effort to establish a rodent preclinical model of THC self-administration.Methods. In Experiment 1, male rats were exposed in adolescence to either an intermediate dose of THC (3.2 mg/kg) or vehicle and then tested in a combined taste and place conditioning procedure with THC (1 or 5 mg/kg) as adults. In Experiment 2, adolescent male and female rats were tested in the same combined taste and place conditioning procedure with a number of doses of THC (0, 0.37, 0.75 and 1.25 mg/kg). In Experiment 3, male and female rats were trained to self-administer THC (0.003, 0.01, 0.03 mg/kg/infusion) over a 3-week period. After completion of this period, half of the animals were ran through a brief cocaine self-administration (0.25 mg/kg/infusion) procedure as a positive control for drug self-administration. The other half of the animals were given an infusion of cannabidiol (1:1 and 1:10 CBD:THC ratio) prior to THC self-administration to assess whether the addition of CBD would impact THC intake.Results. In Experiment 1, THC induced dose-dependent taste avoidance, but no place conditioning, in adult rats. These effects were unaffected by adolescent THC exposure. In Experiment 2, THC induced dose-dependent taste avoidance, with females showing faster and more robust acquisition of this avoidance in comparison to males, while also failing to induce a place preference at any dose tested. Finally, while approximately 50% of the animals in Experiment 3 acquired THC self-administration (at modest levels), it was unaffected by pretreatment with CBD. Further, there was no clear sex differences in THC self-administration (alone or with CBD).Conclusions. These studies suggest that THC is relatively aversive and only weakly rewarding, having effects that are not impacted by manipulations known to affect other drugs of abuse. Although THC may support self-administration, this was only evident in 50% of the subjects and at relatively low levels, and was again unaffected by factors reported to affect THC's subjective effects and again suggest that the drug is only modestly rewarding. Together, these data indicate that further research should examine the difference between THC's positive and negative reinforcing properties in an attempt to develop new animal models that may better approximate human marijuana use and abuse. Thorough examination of multiple factors that may influence the reinforcing properties of THC in preclinical models could lead to a better understanding of marijuana drug abuse and dependence, as well as treatment and prevention strategies.