The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.
The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.
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DOI：
10.1080/09652140050111690
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发表时间：
2000-08
期刊：
影响因子：
6
通讯作者：
Anthony A. Grace
中科院分区：
文献类型：
--
作者：
Anthony A. Grace
所有滥用药物都被证明直接或间接地通过增加大脑边缘系统内多巴胺的神经传递而起作用。因此，酒精主要通过激活多巴胺细胞尖峰活动来增加多巴胺的传递，而精神兴奋剂通过抑制多巴胺释放后从突触空间的移除来增加多巴胺的传递。多巴胺的峰依赖性释放是由药物滥用调节的，导致他们的奖励行为，这被称为阶段性多巴胺反应。相反，在反复给药的情况下，多巴胺也会在伏隔核的细胞外空间积聚，其浓度过低，不足以刺激突触后受体，但足以激活抑制多巴胺释放的自受体。此外，胞外多巴胺水平被认为受皮层-伏隔传入事件的调节影响。这种稳定的突触外多巴胺水平被称为强直多巴胺反应。在本文中，我们提出了几个方面的药物成瘾，戒断和渴望与这些药物的持续使用相关的可以解释的基础上，他们对强直性和阶段性多巴胺系统功能的影响。因此，反复用药政府将引起的强直性多巴胺水平的增加，通过刺激多巴胺末端自受体而抑制阶段性多巴胺释放，导致受试者增加给药量以恢复阶段性反应。此外，在停药后，暴露于启动剂量的药物或药物相关刺激会增加强直多巴胺水平，再次触发寻求药物的行为，以恢复强直和相多巴胺系统之间的平衡。因此，持续使用药物的一个后果是，多巴胺系统功能的这些通常用于保持系统稳定的参数将进入一个新的稳态稳态，系统特别容易受到可能导致复发的不稳定影响。
All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike-dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release-inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico-accumbens afferents. This steady-state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug-related stimuli are proposed to increase tonic dopamine levels, again triggering drug-seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a new steady-state homeostasis, from which the system is particularly susceptible to destabilizing influences that may precipitate relapse.