Effects of chronic delta9-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment.
Effects of chronic delta9-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment.
复制标题
慢性 delta9-四氢大麻酚对大鼠中脑多巴胺神经元的影响：电生理学评估。
DOI：
10.1016/s0028-3908(99)00140-9
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发表时间：
2000
影响因子：
4.7
通讯作者：
French,ED
中科院分区：
文献类型：
--
作者：
Wu,X;French,ED
-9-四氢大麻酚（Δ9-THC）是大麻的主要精神活性成分，在动物和人类中引起多种生理作用，并且随着反复接触，对其大部分作用产生耐受性。然而，对人类的研究发现，对令人愉悦的大麻“high”并没有产生耐受性。由于腹侧被盖多巴胺神经元在药物强化和奖励中起着关键作用，并且可能在大麻的致喜质量中起着关键作用，因此本研究试图确定是否对Δ9-THC在这些神经元中引起的神经生理反应产生耐受性。在连续14天每天两次注射5 mg/kg Δ9-THC的实验动物中，采用单细胞外记录法测量了中脑腹侧被盖（VTA）和黑质致密部（SNpc）多巴胺神经元的活性。大麻素引起的体温、运动和麻痹的变化也在同一动物中进行了评估。2周后，耐受性发展为Δ9-THC-induced体温过低、嗜睡和运动活动减少。在幼稚动物和每天接受两次载体注射14天的动物中，Δ9-THC分别增加了52%和46%的VTA神经元放电，而SNpc神经元分别增加了23%和30%。然而，在慢性大麻素治疗后，SNpc神经元对Δ9-THC的反应明显减弱，最大增幅仅为3%，而VTA神经元在THC刺激下继续表现出强劲的放电率增加（+45%）。这些结果表明，VTA和SNpc多巴胺神经元在长期大麻素暴露后对Δ9-THC产生不同的反应。这一发现可能与人类对大麻的许多生理效应的耐受性有关，而不是对其致爽作用的耐受性。
Delta-9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive ingredient in marijuana elicits a variety of physiological effects in animals and humans, and with repeated exposure tolerance develops to most of its effects. However, studies in humans found that tolerance did not occur to the pleasurable marijuana “high”. Since ventral tegmental dopamine neurons play a pivotal role in drug reinforcement and reward, and possibly in the euphorigenic quality of marijuana, the present study sought to determine whether tolerance develops to the neurophysiological response elicited in these neurons by Δ9-THC. Using single-unit extracellular recordings the activity of midbrain ventral tegmental (VTA) and substantia nigra pars compacta (SNpc) dopamine neurons was measured in animals that had received twice-daily injections of 5 mg/kg Δ9-THC for 14 days. Cannabinoid-induced changes in body temperature, locomotion, and catalepsy were also assessed in the same animals. After 2 weeks tolerance had developed to Δ9-THC-induced hypothermia, catalepsy and reduction in locomotor activity. In naive animals and in animals that had received twice-daily vehicle injections for 14 days, Δ9-THC increased VTA neuronal firing by 52% and 46%, respectively, while SNpc neurons showed increases of 23% and 30%, respectively. Following chronic cannabinoid treatment, however, SNpc neurons were significantly less responsive to Δ9-THC with a maximum increase in rate of only 3%, while VTA neurons continued to show a robust increase in firing rate (+45%) when challenged with THC. These results suggest that VTA and SNpc dopamine neurons develop a differential response to Δ9-THC following long-term cannabinoid exposure. This finding may be relevant to the observation that in humans tolerance occurs to many of marijuana's physiological effects but not to its euphorigenic actions.