Wu X, French E D
Department of Pharmacology, University of Arizona, College of Medicine, Tucson 85724, USA.
Neuropharmacology. 2000 Jan 28;39(3):391-8. doi: 10.1016/s0028-3908(99)00140-9.
Delta-9-tetrahydrocannabinol (delta9-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 delta9-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 delta9-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 delta9-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, delta9-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 delta9-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 delta9-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.
Δ⁹-四氢大麻酚（Δ⁹-THC）是大麻中的主要精神活性成分，可在动物和人类中引发多种生理效应，并且随着反复接触，对其大多数效应会产生耐受性。然而，对人类的研究发现，对令人愉悦的大麻“快感”并未产生耐受性。由于腹侧被盖区多巴胺神经元在药物强化和奖赏中起关键作用，并且可能在大麻的致欣快特性中也起作用，因此本研究旨在确定对Δ⁹-THC在这些神经元中引发的神经生理反应是否会产生耐受性。使用单细胞细胞外记录技术，在每天接受两次5mg/kg Δ⁹-THC注射，持续14天的动物中，测量中脑腹侧被盖区（VTA）和黑质致密部（SNpc）多巴胺神经元的活动。还在相同的动物中评估了大麻素引起的体温、运动和僵住症变化。2周后，对Δ⁹-THC引起的体温过低、僵住症和运动活动减少产生了耐受性。在未接触过的动物和每天接受两次赋形剂注射，持续14天的动物中，Δ⁹-THC分别使VTA神经元放电增加52%和46%，而SNpc神经元分别增加23%和30%。然而，经过慢性大麻素治疗后，SNpc神经元对Δ⁹-THC的反应明显降低，最大放电率仅增加3%，而当用THC刺激时，VTA神经元的放电率继续显著增加（+45%）。这些结果表明，长期接触大麻素后，VTA和SNpc多巴胺神经元对Δ⁹-THC产生了不同的反应。这一发现可能与以下观察结果相关：在人类中，对大麻的许多生理效应会产生耐受性，但对其致欣快作用却不会产生耐受性。
