Sim-Selley Laura J
Department of Pharmacology & Toxicology, Institute for Drug & Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Richmond, Virginia 23298, USA.
Crit Rev Neurobiol. 2003;15(2):91-119. doi: 10.1615/critrevneurobiol.v15.i2.10.
Marijuana produces a number of characteristic behaviors in humans and animals, including memory impairment, antinociception, and locomotor and psychoactive effects. However, tolerance and dependence to cannabinoids develops after chronic use, as demonstrated both clinically and in animal models. The potential therapeutic benefits of certain cannabinoid-mediated effects, as well as the use of marijuana for its psychoactive properties, has raised interest in understanding the cellular adaptations produced by chronic administration of this class of drugs. The primary active constituent of marijuana, delta9-tetrahydrohydrocannabinol (THC), binds to specific G-protein-coupled receptors. The central nervous system (CNS) effects of THC are mediated by CB1 receptors, which couple primarily to inhibitory G-proteins. High levels of CB1 receptors are found in the basal ganglia, hippocampus, cortex, and cerebellum, consistent with the profile of behavioral effects. Studies over the past decade have determined that CB1 receptors undergo downregulation and desensitization following chronic administration of THC or synthetic cannabinoid agonists. In general, these adaptations are regionally widespread and of considerable magnitude, and are thought to contribute to tolerance to cannabinoid-mediated behavioral effects. Adaptation at the effector level has been more difficult to characterize, although it appears that alterations in cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity may be particularly important in cannabinoid dependence. A striking characteristic of CB 1 receptor adaptation is the region dependence of the magnitude and rate of development of downregulation and desensitization. These regional differences may provide interesting insights into the mechanisms of CB1 receptors receptor signaling in different brain regions. Moreover, region-specific adaptations in CB1 receptors following chronic cannabinoid administration may produce differential adaptations at the in vivo level.
大麻在人类和动物身上会产生一系列特征性行为，包括记忆障碍、抗伤害感受以及运动和精神活性作用。然而，正如临床和动物模型所表明的那样，长期使用大麻素后会产生耐受性和依赖性。某些大麻素介导的效应所具有的潜在治疗益处，以及因大麻的精神活性特性而对其加以使用，引发了人们对于了解这类药物长期给药所产生的细胞适应性的兴趣。大麻的主要活性成分Δ9-四氢大麻酚（THC）与特定的G蛋白偶联受体结合。THC对中枢神经系统（CNS）的作用是由CB1受体介导的，CB1受体主要与抑制性G蛋白偶联。在基底神经节、海马体、皮层和小脑中发现了高水平的CB1受体，这与行为效应的特征相符。过去十年的研究已经确定，长期给予THC或合成大麻素激动剂后，CB1受体会发生下调和脱敏。一般来说，这些适应性变化在区域上广泛存在且程度相当大，并且被认为有助于对大麻素介导的行为效应产生耐受性。效应器水平的适应性变化更难描述，尽管环磷酸腺苷（cAMP）和蛋白激酶A（PKA）活性的改变在大麻素依赖性中可能特别重要。CB1受体适应性的一个显著特征是下调和脱敏的程度及发展速度存在区域依赖性。这些区域差异可能为不同脑区CB1受体信号传导机制提供有趣的见解。此外，长期给予大麻素后CB1受体的区域特异性适应性变化可能在体内水平产生不同的适应性变化。
