Oxytocin effects on GABAergic signaling in the alcohol dependent CeA.

Scripps Research Institute, The, La Jolla CA

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Abstract

PROJECT SUMMARY/ABSTRACT Alcoholism is a chronic disorder described by compulsive seeking and consumption of alcohol, the result of a transition from recreational alcohol use to abuse and dependence. Alcohol dependence and withdrawal are characterized by negative emotional states resulting from recruited brain stress systems. The amygdalar nuclei, in particular the central amygdala (CeA), are considered a hub for negative emotional circuitry, and the role of pro- and anti-stress neuropeptides in this brain structure is critical for the development of alcohol dependence. The CeA contains primarily GABAergic neurons, and the inhibitory synapses are very sensitive to acute ethanol and play a critical role in the behavioral effects of acute and chronic ethanol consumption. Pro- stress neuropeptides like corticotropin releasing factor (CRF) have been found to enhance GABAergic transmission in the CeA, while anti-stress neuropeptides like nociceptin/orphanin FQ (N/OFQ) and neuropeptide Y (NPY) decrease GABAergic transmission. The balance between anti- and pro-stress signaling is perturbed during the transition to alcohol dependence, characterized by an overactive CRF system. Importantly, one anti-stress neuropeptide, oxytocin (OT), has been shown to decrease drinking and block withdrawal symptoms when administered to human alcoholics. However, no studies have investigated the effects of OT and its interactions with ethanol on the GABAergic system in the CeA. Therefore, the goal of this proposal is to characterize the effects of OT on CeA GABAergic signaling, its interactions with acute ethanol and the potential neuroadaptations induced by ethanol dependence in the OT system, using electrophysiological techniques. The data generated by this project will elucidate the mechanisms of action of OT in the CeA and provide important information to the neuronal changes that contribute to the transition from recreational alcohol consumption to alcohol dependence, and could lead to the development of better therapeutics in the treatment of alcoholism.