Cortical mechanisms of cocaine sensitization.

Jeffery D Steketee
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引用次数: 98

Abstract

Behavioral sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine. Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use. Much research has been conducted to determine the neural mechanisms of sensitization. The bulk of this effort has focused on the nucleus accumbens and ventral tegmental area (VTA) that comprise a portion of the mesolimbic dopamine system. Recently, studies have begun to also explore the role of the medial prefrontal cortex (mPFC) in sensitization, in part because this region provides glutamatergic innervation to the VTA and nucleus accumbens. The present review will coalesce these studies into a working hypothesis that states that cocaine sensitization results from a decrease in inhibitory modulation of excitatory transmission from the mPFC to the VTA and nucleus accumbens. The discussion will revolve around how repeated cocaine exposure alters dopamine, gamma-aminobutyric acid (GABA), and glutamate regulation of pyramidal cell activity. It will be proposed that cocaine-induced alterations in cortical transmission occur in two phases. During early withdrawal from repeated cocaine exposure, changes in neurotransmitter release are thought to underlie the decreased inhibitory modulation of pyramidal projection neurons. Following more prolonged withdrawal, the attenuation in inhibitory transmission appears to occur at the receptor level. A model will be presented that may serve to direct future studies on the involvement of the mPFC in the development of cocaine sensitization, which ultimately could lead to development of pharmacotherapies for cocaine addiction.

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可卡因致敏的皮质机制。
行为致敏是一种增强的运动刺激反应,这种反应发生在反复、间歇性地接触大多数滥用药物(包括可卡因)时。致敏是一种持久的现象,被认为是毒品渴望和吸毒复发的基础。已经进行了大量的研究来确定致敏的神经机制。这项研究主要集中在伏隔核和腹侧被盖区(VTA),它们构成了中脑边缘多巴胺系统的一部分。最近,研究也开始探索内侧前额叶皮层(mPFC)在致敏中的作用,部分原因是该区域为VTA和伏隔核提供谷氨酸神经支配。本综述将把这些研究合并成一个有效的假设,即可卡因致敏是由于从mPFC到VTA和伏隔核的兴奋传递的抑制性调节减少所致。讨论将围绕反复的可卡因暴露如何改变多巴胺、γ -氨基丁酸(GABA)和谷氨酸对锥体细胞活性的调节。它将提出,可卡因引起的皮层传递的改变发生在两个阶段。在早期从反复可卡因暴露中戒断时,神经递质释放的变化被认为是锥体投射神经元抑制性调节降低的基础。在更长时间的停药后,抑制传递的衰减似乎发生在受体水平。将提出一个模型,可能有助于指导未来关于mPFC参与可卡因致敏发展的研究,这最终可能导致可卡因成瘾药物治疗的发展。
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