Koob G F, Weiss F
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
Recent Dev Alcohol. 1992;10:201-33. doi: 10.1007/978-1-4899-1648-8_11.
Drug addiction includes two important characteristics, chronic compulsive or uncontrollable drug use and a withdrawal syndrome when use of the drug is stopped. Animal models for the motivational components of drug dependence have been developed allowing a systematic exploration of the neurobiological mechanisms of drug dependence. The reinforcing actions of acute cocaine as measured by intravenous cocaine self-administration appear to be mediated by the presynaptic release of dopamine in the region of the nucleus accumbens and may preferentially involve the dopamine D-1 receptor subtype. The nucleus accumbens circuitry involved in the reinforcing actions of cocaine may include the ventral pallidum and may be modulated by serotonin. Chronic cocaine produces increases in brain reward thresholds that may reflect the "dysphoria" and anhedonia associated with cocaine dependence and suggests a dysregulation of brain reward systems possibly involving dopamine. Reliable measures for the acute reinforcing effects of ethanol in nondependent animals have been established in the rat using a lever press operant and a taste habituation procedure. Important roles have been established for serotonin, GABA, dopamine, and opioids in the acute reinforcing properties of ethanol, perhaps acting on some of the same neural circuitry subsuming the reinforcing actions of other drugs of abuse. Studies of the motivational aspects of ethanol dependence have suggested a functional role for brain corticotropin-releasing factor. These results suggest that the neurobiology of drug dependence involves not only neurotransmitters that mediate the acute reinforcing properties of drugs, but also the aversive motivational and emotional aspects of drug withdrawal. Advances in our understanding of brain changes associated with the switch from acute effects to chronic actions may provide a key to our understanding of not only drug dependence, but also psychopathology such as, anxiety, and affective disorders.
药物成瘾包括两个重要特征，即长期强迫性或无法控制的药物使用，以及停止使用药物时出现的戒断综合征。已经开发出用于药物依赖动机成分的动物模型，从而能够系统地探索药物依赖的神经生物学机制。通过静脉注射可卡因自我给药所测量的急性可卡因强化作用，似乎是由伏隔核区域多巴胺的突触前释放介导的，并且可能优先涉及多巴胺D-1受体亚型。参与可卡因强化作用的伏隔核神经回路可能包括腹侧苍白球，并且可能受到5-羟色胺的调节。长期使用可卡因会导致大脑奖赏阈值升高，这可能反映了与可卡因依赖相关的“烦躁不安”和快感缺失，并表明大脑奖赏系统失调，可能涉及多巴胺。在大鼠中，利用杠杆按压操作和味觉习惯化程序，已经建立了对非依赖性动物乙醇急性强化作用的可靠测量方法。5-羟色胺、γ-氨基丁酸、多巴胺和阿片类物质在乙醇的急性强化特性中发挥了重要作用，它们可能作用于与其他滥用药物强化作用相同的一些神经回路。对乙醇依赖动机方面的研究表明，脑促肾上腺皮质激素释放因子具有功能性作用。这些结果表明，药物依赖的神经生物学不仅涉及介导药物急性强化特性的神经递质，还涉及药物戒断的厌恶动机和情感方面。我们对与从急性效应转变为慢性作用相关的大脑变化理解的进展，可能不仅为我们理解药物依赖，而且为理解诸如焦虑和情感障碍等精神病理学提供关键。
