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首页> 美国卫生研究院文献>PLoS Biology >Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala
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Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala

机译：催产素可以阻止酒精依赖的酒精动机增加并阻止酒精对杏仁核中央GABA能传递的影响

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Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin’s effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.
机译：据报道，服用催产素可以减少与几种滥用药物有关的消耗，戒断和寻求药物，因此代表了一种有前途的药理方法来治疗药物成瘾。我们使用建立的酒精依赖大鼠模型来研究催产素对依赖诱导的饮酒，增强饮酒动机以及改变杏仁核（CeA）中枢GABA能传递的影响。腹腔内催产素的给药阻止了酒精依赖型但非依赖型大鼠的饮酒量增加，并且增加了饮酒的动机。鼻内催产素递送完全复制了这些作用。腹膜内给药对减少运动和摄取非酒精性可口溶液的影响很小但很明显，而鼻内催产素给药则没有。在成年大鼠中，脑室内施用催产素或催产素受体激动剂PF-06655075，它不会穿过血脑屏障（即不会扩散到外周），但不能全身性施用PF-06655075（即不会到达大脑），减少饮酒。给予外周限制性催产素受体拮抗剂并不能逆转鼻内催产素对饮酒的影响。 CeA神经元的离体电生理学记录表明，催产素在非依赖性大鼠中降低了诱发的GABA传递，但在非依赖性大鼠中没有，而两组中的催产素均降低了自发GABA能反应的幅度。催产素阻断了急性酒精对依赖但非依赖大鼠的CeA中GABA释放的促进作用。在一起，这些结果提供了越来越多的证据，表明催产素特异性地和选择性地阻断了饮酒的动机，这种动机可能是通过改变催产素对CeA GABA传播的依赖于酒精依赖而产生的中枢机制而导致的。内源性催产素信号传导中的神经适应可能提供一种机制，使我们进一步了解酒精使用障碍。

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