Department of Biology, William Paterson University, Wayne, NJ, 07470, USA.
Department of Psychiatry, Harvard Medical School, Psychiatric Neurogenomics, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital, Belmont, MA, USA.
Behav Brain Res. 2019 Mar 15;360:286-297. doi: 10.1016/j.bbr.2018.11.043. Epub 2018 Nov 30.
Activation of the endocannabinoid system modulate dopaminergic pathways that are involved in the effects of psychostimulants including amphetamine, cocaine, nicotine and other drugs of abuse. Genetic deletion or pharmacological activation of CB2 cannabinoid receptor is involved in the modulation of the effects of psychostimulants and their rewarding properties. Here we report on the behavioral effects of psychostimulants in DAT-Cnr2 conditional knockout (cKO) mice with selective deletion of type 2 cannabinoid receptors in dopamine neurons. There was enhanced psychostimulant induced hyperactivity in DAT-Cnr2 cKO mice, but the psychostimulant-induced sensitization was absent in DAT-Cnr2 cKO compared to the WT mice. Intriguingly, lower doses of amphetamine reduced locomotor activity of the DAT-Cnr2 cKO mice. While cocaine, amphetamine and methamphetamine produced robust conditioned place preference (CPP) in both DAT-Cnr2 cKO and WT mice, nicotine at the dose used induced CPP only in the WT but not in the DAT-Cn2 cKO mice. However, pre-treatment with the CB2R selective agonist JWH133, blocked cocaine and nicotine induced CPP in the WT mice. The deletion of CB2Rs in dopamine neurons modified the levels of tyrosine hydroxylase, and reduced the expression of dopamine transporter gene expression in DAT-Cnr2 cKO midbrain region. Taken together, our data suggest that CB2Rs play a role in the modulation of dopamine-related effects of psychostimulants and could be exploited as therapeutic target in psychostimulant addiction and other psychiatric disorders associated with dopamine dysregulation.
内源性大麻素系统的激活调节多巴胺能通路，这些通路参与包括安非他命、可卡因、尼古丁和其他滥用药物在内的精神兴奋剂的作用。CB2 大麻素受体的基因缺失或药理学激活参与了精神兴奋剂及其奖赏特性的调节。在这里，我们报告了在多巴胺神经元中选择性缺失 2 型大麻素受体的 DAT-Cnr2 条件敲除 (cKO) 小鼠中，精神兴奋剂的行为效应。与 WT 小鼠相比，DAT-Cnr2 cKO 小鼠的精神兴奋剂诱导的过度活跃增强，但精神兴奋剂诱导的敏化缺失。有趣的是，较低剂量的安非他命可降低 DAT-Cnr2 cKO 小鼠的运动活性。虽然可卡因、安非他命和甲基苯丙胺在 DAT-Cnr2 cKO 和 WT 小鼠中均产生强烈的条件位置偏好 (CPP)，但在 WT 小鼠中，而不是在 DAT-Cn2 cKO 小鼠中，尼古丁在使用的剂量下仅诱导 CPP。然而，CB2R 选择性激动剂 JWH133 的预处理阻断了 WT 小鼠中可卡因和尼古丁诱导的 CPP。多巴胺神经元中 CB2R 的缺失改变了酪氨酸羟化酶的水平，并降低了 DAT-Cnr2 cKO 中脑区域多巴胺转运体基因表达。总之，我们的数据表明，CB2R 在内源性大麻素系统调节精神兴奋剂相关的多巴胺效应中发挥作用，可作为精神兴奋剂成瘾和其他与多巴胺失调相关的精神障碍的治疗靶点。
