Abused inhalants enhance GABA-mediated synaptic inhibition.
Abused inhalants enhance GABA-mediated synaptic inhibition.
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滥用吸入剂会增强 GABA 介导的突触抑制。
DOI：
10.1038/npp.2009.57
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
MacIver,MBruce
中科院分区：
文献类型：
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作者：
MacIver,MBruce
滥用吸入剂被广泛使用，特别是在学龄儿童和青少年中，是导致滥用酒精和其他成瘾物质的“入门”药物。尽管被广泛使用，吸入剂对中枢神经系统的影响却鲜为人知。吸入剂和吸入麻醉剂产生的行为效应的相似性，以及它们共同的化学特征，促使我们研究吸入剂对一种具有良好特征的麻醉靶点——GABA突触的作用。采用膜片钳全细胞记录大鼠海马脑CA1锥体神经元，测量其对静息膜特性、动作电位放电和gaba介导的抑制反应的影响。甲苯、1,1,1 -三氯乙烷和三氯乙烯以浓度依赖和可逆的方式抑制CA1的兴奋性。这种抑郁似乎涉及GABA介导的抑制增强，GABA受体拮抗剂明显逆转了这种抑制。与此一致的是，在CNQX和APV阻断兴奋性突触反应和GGP阻断GABA - B反应存在的情况下，滥用吸入剂增加了通过对CA1神经元辐射层输入的最小刺激产生的抑制性突触后电位。增强的抑制作用似乎是由GABA神经末梢的突触前作用引起的，因为自发抑制性突触后电流（IPSC）频率增加而突触后电流的振幅没有变化，无论是否存在用于阻断神经元间动作电位的河豚毒素和用于阻止钙流入神经末梢的镉。甲苯引起的mIPSC频率增加被丹曲林或瑞诺定阻断，表明滥用吸入剂增加了细胞内神经末梢储存钙的释放。滥用吸入剂产生的这种突触前作用与吸入麻醉剂相同，并且会导致两类药物产生的行为效果的改变，并且在滥用吸入剂导致学习和记忆中断的情况下可能特别重要。
Abused inhalants are widely used, especially among school-age children and teenagers, and are ‘gateway’drugs leading to the abuse of alcohol and other addictive substances. In spite of this widespread use, little is known about the effects produced by inhalants on the central nervous system. The similarity in behavioral effects produced by inhalants and inhaled anesthetics, together with their common chemical features, prompted this study of inhalant actions on a well-characterized anesthetic target, GABA synapses. Whole-cell patch clamp recordings were conducted on CA1 pyramidal neurons in rat hippocampal brain slices to measure effects on resting membrane properties, action potential discharge, and GABA-mediated inhibitory responses. Toluene, 1, 1, 1-trichloroethane, and trichloroethylene depressed CA1 excitability in a concentration-dependent and reversible manner. This depression appeared to involve enhanced GABA-mediated inhibition, evident in its reversal by a GABA receptor antagonist. Consistent with this, the abused inhalants increased inhibitory postsynaptic potentials produced using minimal stimulation of stratum radiatum inputs to CA1 neurons, in the presence of CNQX and APV to block excitatory synaptic responses and GGP to block GABA B responses. The enhanced inhibition appeared to come about by a presynaptic action on GABA nerve terminals, because spontaneous inhibitory postsynaptic current (IPSC) frequency was increased with no change in the amplitude of postsynaptic currents, both in the presence and absence of tetrodotoxin used to block interneuron action potentials and cadmium used to block calcium influx into nerve terminals. The toluene-induced increase in mIPSC frequency was blocked by dantrolene or ryanodine, indicating that the abused inhalant acted to increase the release of calcium from intracellular nerve terminal stores. This presynaptic action produced by abused inhalants is shared by inhaled anesthetics and would contribute to the altered behavioral effects produced by both classes of drugs, and could be especially important in the context of a disruption of learning and memory by abused inhalants.