Hopf F Woodward, Martin Miquel, Chen Billy T, Bowers M Scott, Mohamedi Maysha M, Bonci Antonello
Ernest Gallo Clinic and Research Center, University of California San Francisco, Department of Neurology, Emeryville, CA 94608, USA.
J Neurophysiol. 2007 Oct;98(4):2297-310. doi: 10.1152/jn.00824.2007. Epub 2007 Aug 15.
Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I(h) was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.
腹侧被盖区（VTA）多巴胺能神经元活动模式从起搏器样发放转变为爆发式发放被认为会增加诸如意外奖励等刺激的显著性，并可能导致与戒断相关的觅药行为。相应地，药理学、行为学和电生理学数据表明VTA在介导酒精依赖行为中起重要作用。然而，反复乙醇暴露对VTA多巴胺能神经元离子通道功能的影响却知之甚少。在此，我们将大鼠反复暴露于乙醇（2 g/kg乙醇，腹腔注射，每天两次，共5天），然后在戒断7天后体外检测VTA多巴胺能神经元的放电模式。与生理盐水处理的动物相比，乙醇处理的动物中小电导钙依赖性钾通道（SK）的功能降低。与SK在调节爆发式发放中的作用一致, 在发放过程中应用NMDA可促进乙醇处理而非生理盐水处理的动物向爆发式发放的转变；当SK被抑制时，NMDA仅在生理盐水处理的动物中持续诱导爆发式发放。此外，乙醇处理动物中增强的爆发式发放并非NMDA诱导的去极化差异所致。此外，乙醇处理的动物中I(h)也降低，这延迟了超极化后的恢复，但不能解释乙醇处理动物中NMDA诱导的爆发式发放增加的原因。最后，反复乙醇暴露和戒断也增强了可卡因（15 mg/kg，腹腔注射）的急性运动激活作用。因此，反复乙醇暴露后的戒断导致VTA多巴胺能神经元生理特性发生多种改变，这最终可能增加VTA神经元产生爆发式发放的能力，从而可能导致成瘾相关行为。
