Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Eur Neuropsychopharmacol. 2019 Dec;29(2):247-256. doi: 10.1016/j.euroneuro.2018.12.003. Epub 2018 Dec 12.
Cannabis is the most commonly used illicit drug and is known to alter state of consciousness and impair neurocognitive function. However, the mechanisms underlying these effects have yet to be fully elucidated. Rodent studies suggest that Δ9-tetrahydrocannabinol (THC) activates dopaminergic neurons in the limbic system, subsequently enhancing dopamine, which is implicated in the rewarding effects of cannabis. Additional evidence suggests that THC may act indirectly on dopamine firing by modulating GABA and glutamate release. This double-blind, placebo-controlled study assessed the acute influence of two doses of THC on brain kinetics of glutamate, GABA, and dopamine, in relation to behavioral outcomes, by using magnetic resonance spectroscopy and functional magnetic resonance imaging. Twenty occasional cannabis users received acute doses of cannabis (300 µg/kg THC) and placebo, in one of two dose regimes (full dose and divided dose), during two separate testing days. Administration of THC increased striatal glutamate concentrations, and dopamine as indicated by a reduction in functional connectivity (FC) between the nucleus accumbens (NAc) and cortical areas. Alterations in glutamate and FC were dose dependent and evident in the full dose group where THC serum concentrations exceeded 2 ng/ml at T-max. Average glutamate changes correlated strongly with FC alterations. Additionally, THC induced changes in FC correlated with feelings of subjective high and decreased performance on an attention task. Taken together, this suggests that THC elicits subjective and cognitive alterations via increased striatal dopaminergic activity and loss of corticostriatal connectivity, which is associated with an increase in striatal glutamate.
大麻是最常被使用的非法药物，已知会改变意识状态并损害神经认知功能。然而，这些影响的机制尚未完全阐明。啮齿动物研究表明，Δ9-四氢大麻酚（THC）激活边缘系统中的多巴胺能神经元，随后增强多巴胺，这与大麻的奖赏效应有关。额外的证据表明，THC 可能通过调节 GABA 和谷氨酸的释放间接作用于多巴胺的发射。这项双盲、安慰剂对照研究通过磁共振波谱和功能磁共振成像，评估了两种剂量的 THC 对谷氨酸、GABA 和多巴胺的脑动力学的急性影响，以及与行为结果的关系。二十名偶尔使用大麻的患者在两个单独的测试日中，接受了两种剂量方案（全剂量和分剂量）中的一种，接受了急性大麻（300μg/kg THC）和安慰剂的治疗。THC 的给药增加了纹状体谷氨酸的浓度，并降低了伏隔核（NAc）和皮质区域之间的功能连接（FC），表明多巴胺的减少。谷氨酸和 FC 的改变与剂量有关，在全剂量组中更为明显，其中 THC 血清浓度在 T-max 时超过 2ng/ml。平均谷氨酸变化与 FC 变化密切相关。此外，THC 诱导的 FC 变化与主观感觉和注意力任务表现下降有关。综上所述，这表明 THC 通过增加纹状体多巴胺能活动和皮质纹状体连接的丧失引起主观和认知改变，这与纹状体谷氨酸的增加有关。
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