Pidoplichko Volodymyr I, Noguchi Jun, Areola Oluwasanmi O, Liang Yong, Peterson Jayms, Zhang Tianxiang, Dani John A
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Learn Mem. 2004 Jan-Feb;11(1):60-9. doi: 10.1101/lm.70004.
Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic system, which serves a fundamental role in the acquisition of behaviors that are inappropriately reinforced by addictive drugs. Here we show that nicotine, in the same concentration and time ranges as obtained from tobacco, has three main actions that regulate the activity of midbrain dopamine (DA) neurons. Nicotine first activates and then desensitizes nAChRs on the DA neurons. This process directly excites the DA neurons for a short period of time before the nAChRs desensitize. Nicotine also enhances glutamatergic excitation and decreases GABAergic inhibition onto DA neurons. These events increase the probability for synaptic plasticity, such as long-term potentiation. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence necessary to initiate synaptic potentiation. In total, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons. Consistent with other summarized studies, this work indicates that the synaptic changes normally associated with learning and memory can be influenced and commandeered during the nicotine addiction process.
烟草使用是一个重大的健康问题,据估计全球每年有400万人因烟草死亡。尼古丁是烟草的主要成瘾成分。它作为一种激动剂,激活烟碱型乙酰胆碱受体(nAChRs)并使其脱敏。尼古丁成瘾力的一个因素归因于其对中脑边缘多巴胺能系统的作用,该系统在由成瘾药物不适当强化的行为习得中起基本作用。在此我们表明,在与从烟草中获得的浓度和时间范围相同的情况下,尼古丁有三种主要作用来调节中脑多巴胺(DA)神经元的活动。尼古丁首先激活然后使DA神经元上的nAChRs脱敏。在nAChRs脱敏之前,这个过程会在短时间内直接兴奋DA神经元。尼古丁还增强对DA神经元的谷氨酸能兴奋并减少GABA能抑制。这些事件增加了突触可塑性的可能性,如长时程增强。DA神经元短暂的直接兴奋与增强的谷氨酸能传入活动相结合,提供了启动突触增强所需的突触前和突触后同步。总的来说,这些突触事件导致中脑DA神经元的活动相对持久地增强。与其他综述研究一致,这项工作表明,通常与学习和记忆相关的突触变化在尼古丁成瘾过程中会受到影响并被利用。