Madamba S G, Schweitzer P, Zieglgänsberger W, Siggins G R
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Alcohol Clin Exp Res. 1996 Jun;20(4):651-8. doi: 10.1111/j.1530-0277.1996.tb01667.x.
The taurinate analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA1 pyramidal neurons using an in vitro slice preparation. In current-and voltage-clamp recordings, acamprosate (100 to 100 microM) superfusion had little effect on resting membrane potential or input slope resistance. Acamprosate had no effect on Ca(2+)-dependent action potentials when tetrodotoxin was used to block Na+ spikes. In whole-cell voltage-clamp recordings, and in the presence of tetraethylammonium and Cs+ to block K+ channels, acamprosate had little effect on a Cd(2+)-sensitive inward current likely to be a high voltage-activated Ca2+ current. However, in both current- and voltage-clamp recordings, acamprosate significantly increased the N-methyl-D-aspartate (NMDA) component of excitatory postsynaptic potentials evoked by stimulation of Schaffer collaterals in the stratum radiatum, in the presence of the selective non-NMDA (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid kainate) glutamate receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione and the GABAA receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum-evoked non-NMDA component of the excitatory postsynaptic potentials, in the presence of bicuculline and the NMDA antagonist DL-2-amino-5-phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potentials thought to be mediated by GABAB receptors. In the presence of tetrodotoxin to block synaptic transmission, acamprosate dramatically increased inward current responses in most CA1 neurons to exogenous NMDA applied by pressure or superfusion, with reversal on washout of acamprosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocampal CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor-mediated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.
牛磺酸盐类似物阿坎酸（乙酰高牛磺酸钙）因其预防戒酒者复发的能力在欧洲受到了广泛关注。为了确定阿坎酸在中枢神经系统中的作用机制，我们使用体外脑片制备技术，将阿坎酸灌流到大鼠海马CA1锥体神经元上。在电流钳和电压钳记录中，阿坎酸（100至100微摩尔）灌流对静息膜电位或输入斜率电阻几乎没有影响。当使用河豚毒素阻断钠峰电位时，阿坎酸对钙依赖性动作电位没有影响。在全细胞电压钳记录中，在存在四乙铵和铯离子以阻断钾通道的情况下，阿坎酸对可能是高电压激活钙电流的镉敏感性内向电流几乎没有影响。然而，在电流钳和电压钳记录中，在存在选择性非NMDA（R，S）-α-氨基-3-羟基-5-甲基异恶唑-4-丙酸 （KA）谷氨酸受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮和GABAA受体拮抗剂荷包牡丹碱的情况下，阿坎酸显著增加了由辐射层中刺激Schaffer侧支诱发的兴奋性突触后电位的N-甲基-D-天冬氨酸（NMDA）成分。在存在荷包牡丹碱和NMDA拮抗剂DL-2-氨基-5-磷酸戊酸的情况下，阿坎酸对辐射层诱发的兴奋性突触后电位的非NMDA成分的影响不一致或没有影响。平均而言，阿坎酸对被认为由GABAB受体介导的晚期抑制性突触后电位几乎没有影响。在存在河豚毒素以阻断突触传递的情况下，阿坎酸显著增加了大多数CA1神经元对通过压力或灌流施加的外源性NMDA的内向电流反应，在冲洗阿坎酸后反应逆转。这些数据表明，阿坎酸可能在突触后起作用，以增加向海马CA1锥体神经元的兴奋性传递的NMDA成分。考虑到乙醇与NMDA受体的已知相互作用，阿坎酸对NMDA受体介导的神经传递的这种调节可能提供了阿坎酸临床疗效的潜在作用机制。
