Nie Z, Madamba S G, Siggins G R
The Scripps Research Institute, Department of Neuropharmacology and Alcohol Research Center, La Jolla, California 92037, USA.
J Pharmacol Exp Ther. 2000 May;293(2):654-61.
The nucleus accumbens (NAcc) may be a key area in the rewarding effects of abused drugs. We previously showed that low ethanol concentrations decreased both N-methyl-D-aspartate (NMDA)-induced and kainate-induced currents in NAcc core neurons. To explore the effects of ethanol on gamma-aminobutyric acid (GABA) responses in NAcc, we used intracellular voltage-clamp recordings and locally applied GABA in a slice preparation containing the NAcc. Ethanol (11-200 mM) had no effect on resting membrane properties, but 11, 22, 44, 100, and 200 mM ethanol increased GABA currents in 17, 33, 45, 50, and 22% of cells, respectively. Superfusion of low glutamate concentrations that had no direct effect on membrane properties enhanced ethanol potentiation of GABA currents in more than half the NAcc cells. Neither alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor nor NMDA receptor antagonists affected the percentage of cells showing ethanol enhancement of GABA responses or the degree of ethanol enhancement of GABA currents in NAcc neurons. However, in ethanol-sensitive cells, the metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the ethanol enhancement of GABA currents. In addition, the metabotropic receptor agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid enhanced GABA responses in 50% of cells tested, an effect blocked by MCPG. These data suggest that NAcc core neurons possess both ethanol-sensitive and -insensitive GABA receptors and that glutamate can mimic and enhance the ethanol potentiation of GABA currents in many of these neurons. Furthermore, the ethanol potentiation of GABA currents may involve metabotropic glutamate receptors, perhaps via a phosphorylation mechanism that regulates ethanol sensitivity of GABA receptors in some NAcc neurons.
伏隔核（NAcc）可能是滥用药物奖赏效应的关键区域。我们之前发现，低浓度乙醇可降低NAcc核心神经元中N-甲基-D-天冬氨酸（NMDA）诱导的电流和红藻氨酸诱导的电流。为了探究乙醇对NAcc中γ-氨基丁酸（GABA）反应的影响，我们在包含NAcc的脑片标本中使用细胞内电压钳记录并局部施加GABA。乙醇（11 - 200 mM）对静息膜特性无影响，但11、22、44、100和200 mM乙醇分别使17%、33%、45%、50%和22%的细胞中GABA电流增加。用对膜特性无直接影响的低浓度谷氨酸进行灌流，可增强半数以上NAcc细胞中乙醇对GABA电流的增强作用。α-氨基-3-羟基-5-甲基异恶唑-4-丙酸/红藻氨酸受体拮抗剂和NMDA受体拮抗剂均不影响显示乙醇增强GABA反应的细胞百分比，也不影响NAcc神经元中乙醇增强GABA电流的程度。然而，在对乙醇敏感的细胞中，代谢型受体拮抗剂α-甲基-4-羧基苯甘氨酸（MCPG）可阻断乙醇对GABA电流的增强作用。此外，代谢型受体激动剂反式-1-氨基环戊烷-1,3-二羧酸可使50%的受试细胞中GABA反应增强，该作用可被MCPG阻断。这些数据表明，NAcc核心神经元同时拥有对乙醇敏感和不敏感的GABA受体，并且谷氨酸可以模拟并增强许多此类神经元中乙醇对GABA电流的增强作用。此外，乙醇对GABA电流的增强作用可能涉及代谢型谷氨酸受体，或许是通过一种调节某些NAcc神经元中GABA受体乙醇敏感性的磷酸化机制。
