Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Cannabis Cannabinoid Res. 2023 Oct;8(5):812-823. doi: 10.1089/can.2022.0005. Epub 2022 May 31.
The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and plays an important role in the neurobiological processes underlying drug addiction. Impaired endocannabinoid (eCB) signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, and craving that propel addiction. Therefore, we hypothesized that boosting the ECS by exogenous administration of selective eCBs will attenuate cocaine-induced behaviors. The behavioral paradigms included psychomotor sensitization (PS) and conditioned place preference (CPP). Liquid chromatography-mass spectrometry analysis was used for quantitative profiling of eCBs in mouse brain. We first measured the levels of eCBs in different brain areas of the reward system following chronic cocaine treatment. We found that following daily administration of cocaine, the levels of N-oleoyl glycine (OlGly) were significantly elevated in the nucleus accumbens (NAc) in a region-specific manner. We next tested whether administration of OlGly will attenuate cocaine-induced behaviors. We found that administration of OlGly during withdrawal, but not during acquisition of PS, attenuated the expression of cocaine sensitization. In addition, the administration of OlGly during the acquisition of cocaine CPP, but not during withdrawal, attenuated the expression of cocaine-conditioned reward. To enhance the stability of OlGly and its duration of action, two methylated derivatives of OlGly were synthesized, the monomethylated OlGly (HU-595) and dimethylated OlGly (HU-596). We found that the effect of administration of HU-595 or HU-596 during cocaine conditioning did not differ from the OlGly-induced decrease in the expression of CPP. Our findings suggest that the ECS is involved in the common neurobiological mechanisms underlying the development and expression of cocaine reward and drug-seeking. Boosting the ECS exogenously has beneficial effects against cocaine-induced behaviors.
内源性大麻素系统（ECS）在大脑中的突触可塑性和动态平衡过程中发挥着关键的调节作用，并在药物成瘾的神经生物学过程中起着重要作用。内源性大麻素（eCB）信号的损伤导致突触可塑性失调、应激反应性增加和渴望加剧，从而推动成瘾的发生。因此，我们假设通过外源性给予选择性 eCB 来增强 ECS，将减轻可卡因引起的行为。行为范式包括精神运动敏感化（PS）和条件性位置偏好（CPP）。我们使用液相色谱-质谱分析定量分析了小鼠大脑中的 eCB 谱。我们首先测量了慢性可卡因处理后不同脑区奖赏系统中 eCB 的水平。我们发现，在每天给予可卡因后，N-油酰甘氨酸（OlGly）的水平在伏隔核（NAc）中以区域特异性的方式显著升高。我们接下来测试了 OlGly 的给药是否会减轻可卡因引起的行为。我们发现，在戒断期间给予 OlGly，但不在 PS 获得期间，可减轻可卡因敏化的表达。此外，在可卡因 CPP 的获得期间给予 OlGly，但不在戒断期间，可减轻可卡因条件性奖励的表达。为了提高 OlGly 的稳定性及其作用持续时间，合成了两种 OlGly 的甲基化衍生物，单甲基化 OlGly（HU-595）和二甲基化 OlGly（HU-596）。我们发现，在可卡因条件作用期间给予 HU-595 或 HU-596 的效果与 OlGly 诱导的 CPP 表达降低没有区别。我们的研究结果表明，ECS 参与了可卡因奖赏和觅药发展和表达的共同神经生物学机制。外源性增强 ECS 对可卡因引起的行为有有益的影响。
