Ethanol Potentiation of GABAergic synaptic transmission may be self-limiting:: Role of presynaptic GABAB receptors
Ethanol Potentiation of GABAergic synaptic transmission may be self-limiting:: Role of presynaptic GABAB receptors
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DOI：
10.1523/jneurosci.1768-04.2004
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发表时间：
2004-11-24
影响因子：
5.3
通讯作者：
Weiner, JL
中科院分区：
文献类型：
--
作者：
Ariwodola, OJ;Weiner, JL
乙醇增强γ-氨基丁酸能（GABAergic）突触抑制，这种相互作用导致了该药物的许多行为和认知效应。大多数研究表明，乙醇通过对突触后γ-氨基丁酸A（GABA(A)）受体的变构增强作用来增强γ-氨基丁酸能神经传递，该受体在哺乳动物中枢神经系统中介导快速突触抑制。尽管这一假说被广泛接受，但一直难以获得对这种机制的直接支持。乙醇并非在所有脑区或在所有实验条件下都能增强γ-氨基丁酸A受体功能，造成这种差异的因素大多仍不清楚。值得注意的是，阻断γ-氨基丁酸B（GABA(B)）受体显著增强了乙醇对海马γ-氨基丁酸A抑制性突触后电位（IPSPs）和抑制性突触电流（IPSCs）的增强作用，这表明一些未知的γ-氨基丁酸B受体机制限制了乙醇对γ-氨基丁酸能突触的总体增强效应。在本研究中，我们证明在大鼠海马的胞体周围突触中，乙醇增强了突触前γ-氨基丁酸B自身受体功能，并且这种相互作用降低了乙醇在这些突触上的总体增强效应。我们进一步表明，乙醇可能通过增加自发性γ-氨基丁酸释放显著提高了基础的突触前γ-氨基丁酸B受体张力，并且用低于阈值浓度的γ-氨基丁酸B受体激动剂巴氯芬进行预处理可阻断乙醇对γ-氨基丁酸A抑制性突触电流的增强作用，但不能阻断氟硝西泮或戊巴比妥的这种增强作用。这些数据表明，乙醇与突触前γ-氨基丁酸B自身受体活性之间的相互作用调节了γ-氨基丁酸能突触对乙醇的敏感性。鉴于这些突触的体外乙醇敏感性与许多啮齿动物品系的体内乙醇反应性相关，我们的数据进一步表明，突触前γ-氨基丁酸B受体活性可能在调节对乙醇的行为敏感性方面发挥作用。
Ethanol enhances GABAergic synaptic inhibition, and this interaction contributes to many of the behavioral and cognitive effects of this drug. Most studies suggest that ethanol enhances GABAergic neurotransmission via an allosteric potentiation of the postsynaptic GABA(A) receptors that mediate fast synaptic inhibition in the mammalian CNS. Despite widespread acceptance of this hypothesis, direct support for such a mechanism has been difficult to obtain. Ethanol does not enhance GABA(A) receptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABA(B) receptors dramatically enhances ethanol potentiation of hippocampal GABA(A) IPSPs and IPSCs, suggesting that some unknown GABA(B) receptor mechanism limits the overall potentiating effect of ethanol on GABAergic synapses. In this study, we demonstrate that, at perisomatic synapses in the rat hippocampus, ethanol enhances presynaptic GABA(B) autoreceptor function and that this interaction reduces the overall potentiating effect of ethanol at these synapses. We further show that ethanol significantly elevates basal presynaptic GABA(B) receptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABA(B) receptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABA(A) IPSCs. These data suggest that an interaction between ethanol and presynaptic GABA(B) autoreceptor activity regulates the ethanol sensitivity of GABAergic synapses. Given that the in vitro ethanol sensitivity of these synapses correlates with in vivo ethanol responsiveness in a number of rodent lines, our data further suggest that presynaptic GABA(B) receptor activity may play a role in regulating behavioral sensitivity to ethanol.