The endocannabinoid 2‐arachidonoylglycerol (2‐AG) is intravenously self‐administered by nonhuman primates

Endogenous cannabinoid anandamide is intravenously self‐administered by squirrel monkeys and its reinforcing effects are mediated by cannabinoid CB1 receptors. Here, we evaluated another endocannabinoid, 2‐arachidonoylglycerol (2‐AG), for reinforcing effects. Squirrel monkeys trained to self‐administer anandamide (FR10 schedule, 60‐s timeout after each injection) had their self‐administration behavior extinguished by substituting vehicle for anandamide and then dose of 2‐AG was varied from 0.1 to 100 μg/kg/injection. Each 2‐AG dose was studied for 5 daily sessions and 4–5 sessions of vehicle extinction followed each 2‐AG dose. 2‐AG maintained significantly higher numbers of self‐administered injections per session and higher rates of responding than vehicle at doses of 1 to 100 μg/kg/injection. The cannabinoid CB1 inverse agonist/antagonist rimonabant (0.3 mg/kg, i.m., 60 min) blocked self‐administration of the peak dose of 2‐AG (3 μg/kg/injection). Thus, 2‐AG is an effective reinforcer of drug‐taking behavior when self‐administered by squirrel monkeys and its reinforcing effects appear to be mediated by CB1 receptors. Intravenous self‐administration of 2‐AG by squirrel monkeys provides a new procedure for studying the involvement of the endocannabinoid system in brain reward mechanisms and for evaluating abuse liability of potential medications that interfere with endogenous 2‐AG signaling. Supported by Intramural Research Program of NIDA, NIH, DHHS.