Estes_2026_Psychopharmacology.(Berl)__

RATIONALE: Endocannabinoid signaling during adolescence plays a critical role in brain development and shapes both healthy and maladaptive behaviors, influencing the risk for neuropsychiatric disorders in adulthood. OBJECTIVES: The present study examines the effects of disrupted catabolism of the endocannabinoids 2-arachidonylglycerol (2-AG) and N-arachidonoylethanolamine (AEA) during early adolescence on adolescent and adult behaviors in male rats. METHODS: Male Sprague-Dawley rats received daily injections with the monoacylglycerol lipase inhibitor JZL184 (JZL; 10 mg/kg, ip), the fatty acid amide hydrolase inhibitor URB597 (URB; 0.4 mg/kg, ip) or vehicle (saline) for ten days during early adolescence (PND31-40) and were tested for play behaviors and behavior on the elevated plus maze in adolescence and social preference, open field behavior and cocaine self-administration and seeking in adulthood. RESULTS: Administration of JZL during adolescence increased interactive but not solo play or exploratory behaviors. Adolescent administration of JZL increased cocaine self-administration under a progressive ratio schedule of reinforcement and cocaine seeking, without effects on fixed-ratio cocaine self-administration or cocaine-primed reinstatement during adulthood, suggesting that elevated levels of 2-AG during adolescence may influence the risk for adult substance use disorders. Adolescent administration of URB promoted social preference during adulthood, but only for a familiar partner, consistent with a role for adolescent AEA in shaping social behavior during adulthood. Neither drug altered anxiety-associated behaviors during adolescence or adulthood. CONCLUSIONS: These findings are consistent with a critical role of endocannabinoid signaling during adolescence in shaping long-term behavioral outcomes, including vulnerability to addiction and social functioning in adulthood.