Cannabinoid receptor type 1 antagonists alter aspects of risk/reward decision making independent of toluene-mediated effects.

Drugs of abuse including cannabis and inhalants impair risk/reward decision making. Cannabis use is often concurrent with inhalant intoxication; yet, preclinical studies investigating the role of endocannabinoids in inhalant misuse are limited. To address this gap in the literature, we used the well-validated probabilistic discounting task to assess risk/reward decision making in rodents following combinations of toluene vapor (a common inhalant) and manipulations of cannabinoid receptor type 1 (CB1R) signaling. As reported previously, acute exposure to toluene vapor disrupted behavioral flexibility during probabilistic discounting. Systemic administration of the CB1R inverse agonist AM281 did not prevent toluene-induced alterations in risky choices, but did independently reduce win-stay behavior, increase choice latency, and increase omissions. Toluene-induced deficits in probabilistic discounting are thought to involve impaired medial prefrontal cortex (mPFC) activity. As we previously reported that some of toluene's inhibitory effects on glutamatergic signaling in the mPFC are endocannabinoid-dependent, we tested the hypothesis that mPFC CB1R activity mediates toluene-induced deficits in discounting. However, bilateral injection of the CB1R inverse agonist AM251 prior to toluene vapor exposure had no effect on toluene-induced changes in risk behavior. In a final set of experiments, we injected the CB1R inverse agonist AM251 (5 and 50 ng), the CB1R agonist WIN55,212-2 (50 ng and 500 ng), or vehicle into the mPFC prior to testing. While mPFC CB1R stimulation did not affect any of the measures tested, the CB1R inverse agonist caused a dose-dependent reduction in win-stay behavior without altering any other measures. Together, these studies indicate that toluene-induced deficits in probabilistic discounting are largely distinct from CB1R-dependent effects that include decreased effectiveness of positive reinforcement (mPFC CB1Rs), decision making speed, and task engagement (non-mPFC CB1Rs).