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Rationale <p>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.</p> Objectives <p>The present study examines the effects of disrupted catabolism of the endocannabinoids 2-arachidonylglycerol (2-AG) and <i>N</i>-arachidonoylethanolamine (AEA) during early adolescence on adolescent and adult behaviors in male rats.</p> Methods <p>Male Sprague-Dawley rats received daily injections with the monoacylglycerol lipase inhibitor JZL184 (JZL; 10&#xa0;mg/kg, ip), the fatty acid amide hydrolase inhibitor URB597 (URB; 0.4&#xa0;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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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Differential effects of adolescent fatty acid amide hydrolase and monoacylglycerol lipase inhibition on adolescent and adult behaviors in male rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月21日

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  • Mary K. Estes,
  • Vishnu Guda,
  • Emei Thompson,
  • Daniela Rodrigues de Oliveira,
  • David B. Nowak,
  • Cecilia J. Hillard,
  • John R. Mantsch

摘要

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.