Cajiao-Manrique María Del Mar, Casadó-Anguera Verònica, García-Blanco Alejandra, Maldonado Rafael, Martín-García Elena
Laboratory of Neuropharmacology-Neurophar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Front Psychiatry. 2023 May 25;14:1148993. doi: 10.3389/fpsyt.2023.1148993. eCollection 2023.
Cannabis addiction is a chronically relapsing disorder lacking effective treatment. Regular cannabis consumption typically begins during adolescence, and this early cannabinoid exposure may increase the risk for drug addiction in adulthood.
This study investigates the development of cannabis addiction-like behavior in adult mice after adolescent exposure to the main psychoactive component of cannabis, Δ-tetrahydrocannabinol (THC).
Adolescent male mice were exposed to 5 mg/kg of THC from postnatal days 37 to 57. Operant self-administration sessions of WIN 55,212-2 (12.5 μg/kg/infusion) were conducted for 10 days. Mice were tested for three addiction-like criteria (persistence of response, motivation, and compulsivity), two parameters related to craving (resistance to extinction and drug-seeking behavior), and two phenotypic vulnerability traits related to substance use disorders (impulsivity and reward sensitivity). Additionally, qPCR assays were performed to detect differentially expressed genes in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HPC) of "addicted" and "non-addicted" mice.
Adolescent THC exposure did not modify WIN 55,212-2 reinforcement nor the development of cannabis addiction-like behavior. Inversely, THC pre-exposed mice displayed impulsive-like behavior in adulthood, which was more pronounced in mice that developed the addiction-like criteria. Moreover, downregulated and gene expression in NAc and HPC was revealed in THC pre-exposed mice, as well as a downregulation of expression in mPFC of vehicle pre-treated mice that developed addiction-like behaviors.
These findings suggest that adolescent THC exposure may promote impulsivity-like behavior in adulthood, associated with downregulated and expression in NAc and HPC.
大麻成瘾是一种缺乏有效治疗方法的慢性复发性疾病。定期吸食大麻通常始于青春期，而这种早期的大麻素暴露可能会增加成年后药物成瘾的风险。
本研究调查了青春期暴露于大麻主要精神活性成分Δ-四氢大麻酚（THC）的成年小鼠中大麻成瘾样行为的发展情况。
青春期雄性小鼠在出生后第37天至第57天暴露于5mg/kg的THC。对WIN 55,212-2（12.5μg/kg/输注）进行操作性自我给药实验，持续10天。对小鼠进行三项成瘾样标准（反应持续性、动机和强迫性）、两项与渴望相关的参数（消退抵抗和觅药行为）以及两项与物质使用障碍相关的表型易感性特征（冲动性和奖励敏感性）的测试。此外，进行qPCR分析以检测“成瘾”和“未成瘾”小鼠内侧前额叶皮质（mPFC）、伏隔核（NAc）、背侧纹状体和海马体（HPC）中差异表达的基因。
青春期THC暴露并未改变WIN 55,212-2的强化作用，也未改变大麻成瘾样行为的发展。相反，预先暴露于THC的小鼠在成年后表现出冲动样行为，在出现成瘾样标准的小鼠中更为明显。此外，预先暴露于THC的小鼠NAc和HPC中 和 基因表达下调，以及在出现成瘾样行为的预先接受载体处理的小鼠mPFC中 表达下调。
这些发现表明，青春期THC暴露可能会促进成年后的冲动样行为，与NAc和HPC中 和 表达下调有关。
