Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.
Department of Neuroscience, Alcohol Research Center, The Scripps Research Institute, La Jolla, California, United States of America.
PLoS Biol. 2019 Apr 16;17(4):e2006421. doi: 10.1371/journal.pbio.2006421. eCollection 2019 Apr.
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.
催产素的给药已被报道可减少几种滥用药物的消耗、戒断和觅药行为，因此代表了一种有前途的治疗药物成瘾的药理学方法。我们使用已建立的酒精依赖大鼠模型来研究催产素对依赖诱导的酒精摄入、增强的酒精动机以及杏仁中央核（CeA）中 GABA 能传递的影响。腹腔内给予催产素可阻断酒精依赖但不依赖大鼠的酒精摄入量增加和增强的酒精动机。鼻内给予催产素完全复制了这些效果。腹腔内给药对运动和非酒精性美味溶液的摄入有轻微但显著的影响，而鼻内给予催产素则没有。在依赖大鼠中，脑室给予催产素或催产素受体激动剂 PF-06655075（不会穿过血脑屏障，即不会扩散到外周），而不是全身给予 PF-06655075（即不会到达大脑），可减少酒精摄入量。给予外周限制的催产素受体拮抗剂并不能逆转鼻内给予催产素对酒精摄入的影响。来自 CeA 神经元的离体电生理记录表明，催产素降低了非依赖大鼠但不降低依赖大鼠的诱发 GABA 传递，而催产素降低了两组的自发性 GABA 反应幅度。催产素阻断了急性酒精对依赖大鼠 CeA 中 GABA 释放的促进作用，但对非依赖大鼠没有这种作用。综上所述，这些结果提供了一致的证据，表明催产素特异性和选择性地阻断了在酒精依赖中发展的增强的酒精摄入动机，这可能是通过一种中枢机制实现的，该机制可能是由于催产素对酒精依赖时 CeA GABA 传递的作用改变所致。内源性催产素信号的神经适应性可能为进一步理解酒精使用障碍提供一种机制。
