Olive M F, Mehmert K K, Messing R O, Hodge C W
Department of Neurology, Ernest Gallo Clinic & Research Center, University of California San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA.
Eur J Neurosci. 2000 Nov;12(11):4131-40. doi: 10.1046/j.1460-9568.2000.00297.x.
There is increasing evidence that individual protein kinase C (PKC) isozymes mediate specific effects of ethanol on the nervous system. In addition, multiple lines of evidence suggest that the mesoaccumbens dopamine reward system is critically involved in the rewarding and reinforcing effects of ethanol. Yet little is known about the role of individual PKC isozymes in ethanol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKCepsilon) show reduced operant ethanol self-administration and an absence of ethanol-induced increase in extracellular dopamine levels in the nucleus accumbens. PKCepsilon null mice exhibited a 53% decrease in alcohol-reinforced operant responses under basal conditions, as well as following ethanol deprivation. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKCepsilon null mice demonstrated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis experiments showed that, in contrast to wild-type mice, PKCepsilon null mice exhibited no change in extracellular levels of dopamine in the nucleus accumbens following acute administration of ethanol (1 and 2 g/kg i.p.), while mesolimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (100 mM) in these mice were comparable with that of wild-types. These data provide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKCepsilon may be useful in the treatment of alcohol dependence.
越来越多的证据表明，蛋白激酶C（PKC）的各个同工酶介导乙醇对神经系统的特定作用。此外，多条证据表明，中脑伏隔核多巴胺奖赏系统在乙醇的奖赏和强化作用中起关键作用。然而，关于PKC各同工酶在乙醇强化过程或中脑边缘系统调节中的作用，人们所知甚少。在本研究中，我们报告称，缺乏PKCε同工型（PKCepsilon）的小鼠表现出操作性乙醇自我给药减少，且乙醇诱导的伏隔核细胞外多巴胺水平升高不存在。PKCepsilon基因敲除小鼠在基础条件下以及乙醇剥夺后，酒精强化的操作性反应减少了53%。行为分析显示，虽然两种基因型在剥夺后饮酒发作次数相同，但PKCepsilon基因敲除小鼠每次发作的乙醇强化物数量减少了61%，乙醇强化反应率降低了57%。体内微透析实验表明，与野生型小鼠相比，急性给予乙醇（腹腔注射1和2 g/kg）后，PKCepsilon基因敲除小鼠伏隔核细胞外多巴胺水平无变化，而这些小鼠中脑边缘多巴胺对可卡因（腹腔注射20 mg/kg）或高钾（100 mM）的反应与野生型相当。这些数据进一步证明，细胞外中脑边缘多巴胺水平的升高有助于乙醇的强化作用，并表明抑制PKCepsilon的药物制剂可能对治疗酒精依赖有用。
