Estes Mary, Guda Vishnu, Thompson Emei, de Oliveira Daniela Rodrigues, Nowak David, Hillard Cecilia, Mantsch John R
Medical College of Wisconsin.
Res Sq. 2025 Sep 18:rs.3.rs-7512305. doi: 10.21203/rs.3.rs-7512305/v1.
Endocannabinoid signaling during adolescence plays a critical role in brain development and shapes both healthy and maladaptive behaviors, influencing the risk of neuropsychiatric disorders in adulthood.
The present study examines the effects of disrupted catabolism of the endocannabinoids 2-arachidonylglycerol (2-AG) and -arachidonoylethanolamine (AEA) during early adolescence on adolescent and adult behaviors in male rats.
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.
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 increase the risk for adult substance use disorders. Adolescent administration of URB promoted social choice during adulthood, consistent with a role for adolescent AEA in shaping social behavior during adulthood. Neither drug altered anxiety-associated behaviors during adolescence or adulthood.
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.
青春期内源性大麻素信号传导在大脑发育中起关键作用，塑造健康和适应不良行为，影响成年期神经精神疾病风险。
本研究考察青春期早期内源性大麻素2-花生四烯酸甘油酯（2-AG）和花生四烯酸乙醇胺（AEA）分解代谢中断对雄性大鼠青春期和成年期行为的影响。
雄性Sprague-Dawley大鼠在青春期早期（出生后第31 - 40天）连续10天每日腹腔注射单酰甘油脂肪酶抑制剂JZL184（JZL；10 mg/kg）、脂肪酸酰胺水解酶抑制剂URB597（URB；0.4 mg/kg）或溶剂（生理盐水），并在青春期测试其玩耍行为和高架十字迷宫行为，在成年期测试其社会偏好、旷场行为、可卡因自我给药及觅药行为。
青春期给予JZL增加了互动玩耍行为，但未增加单独玩耍或探索行为。青春期给予JZL在渐进比率强化程序下增加了可卡因自我给药及可卡因觅药行为，对成年期固定比率可卡因自我给药或可卡因激发的复吸行为无影响，提示青春期2-AG水平升高可能增加成年期物质使用障碍风险。青春期给予URB促进成年期社会选择，与青春期AEA在塑造成年期社会行为中的作用一致。两种药物均未改变青春期或成年期与焦虑相关的行为。
这些发现与青春期内源性大麻素信号传导在塑造长期行为结果中的关键作用一致，包括成年期成瘾易感性和社会功能。
