Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons
Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons
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DOI：
10.1016/j.bbr.2018.11.043
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发表时间：
2019-03-15
影响因子：
2.7
通讯作者：
Onaivi, Emmanuel S.
中科院分区：
文献类型：
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作者：
Canseco-Alba, Ana;Schanz, Norman;Onaivi, Emmanuel S.
内源性大麻素系统的激活调节多巴胺能途径，该途径参与精神兴奋剂的作用，包括安非他明、可卡因、尼古丁和其他滥用药物。 CB2 大麻素受体的基因缺失或药理学激活涉及精神兴奋剂的作用及其奖励特性的调节。在此，我们报告了精神兴奋剂对选择性删除多巴胺神经元中 2 型大麻素受体的 DAT-Cnr2 条件敲除 (cKO) 小鼠的行为影响。 DAT-Cnr2 cKO 小鼠中精神兴奋剂诱导的多动症增强，但与 WT 小鼠相比，DAT-Cnr2 cKO 小鼠中不存在精神兴奋剂诱导的致敏作用。有趣的是，较低剂量的安非他明降低了 DAT-Cnr2 cKO 小鼠的运动活性。虽然可卡因、苯丙胺和甲基苯丙胺在 DAT-Cnr2 cKO 和 WT 小鼠中产生了强烈的条件性位置偏好 (CPP)，但所用剂量的尼古丁仅在 WT 中诱导 CPP，而在 DAT-Cn2 cKO 小鼠中则不诱导 CPP。然而，用 CB2R 选择性激动剂 JWH133 进行预处理，可阻断 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，并减少了DAT-Cnr2 cKO中脑区域多巴胺转运蛋白基因的表达。总而言之，我们的数据表明，CB2R 在调节精神兴奋剂的多巴胺相关作用中发挥作用，并且可以用作精神兴奋剂成瘾和与多巴胺失调相关的其他精神疾病的治疗靶点。
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.