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Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence.

ABSTRACT: During the transition to alcohol and drug addiction, neuromodulator systems in the extended amygdala are recruited to mediate aspects of withdrawal and relapse via convergence on inhibitory gamma-aminobutyric acid (GABA) neurons in central amygdala (CeA).This study investigated the role of neuropeptide Y (NPY) in excessive alcohol drinking by making rats dependent on alcohol via alcohol vapor inhalation. This study also utilized intracellular and whole-cell recording techniques to determine the effects of NPY on GABAergic inhibitory transmission in CeA, synaptic mechanisms involved in these NPY effects, and NPY interactions with alcohol in the CeA of alcohol-naive and alcohol-dependent rats.Chronic NPY treatment blocked excessive operant alcohol-reinforced responding associated with alcohol dependence, as well as gradual increases in alcohol responding by intermittently tested nondependent control animals. Neuropeptide Y decreased baseline GABAergic transmission and reversed alcohol-induced enhancement of inhibitory transmission in CeA by suppressing GABA release via actions at presynaptic Y(2) receptors.These results highlight NPY modulation of GABAergic signaling in central amygdala as a promising pharmacotherapeutic target for the treatment of alcoholism. Gamma-aminobutyric acid neurons in the CeA likely constitute a major point of convergence for neuromodulator systems recruited during the transition to alcohol dependence.

SUBMITTER: Gilpin NW

PROVIDER: S-EPMC3090491 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence.

Gilpin Nicholas W NW Misra Kaushik K Herman Melissa A MA Cruz Maureen T MT Koob George F GF Roberto Marisa M

Biological psychiatry 20110403 11

<h4>Background</h4>During the transition to alcohol and drug addiction, neuromodulator systems in the extended amygdala are recruited to mediate aspects of withdrawal and relapse via convergence on inhibitory gamma-aminobutyric acid (GABA) neurons in central amygdala (CeA).<h4>Methods</h4>This study investigated the role of neuropeptide Y (NPY) in excessive alcohol drinking by making rats dependent on alcohol via alcohol vapor inhalation. This study also utilized intracellular and whole-cell rec ...[more]

PMID: 21459365

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Project description: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.

Project description:Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor are involved in a number of complex disorders, including substance abuse. No variants of the commonly studied GABA receptor genes that have been associated with substance dependence have been determined to be functional or pathogenic. To reconcile the conflicting associations with substance dependence traits, we performed a meta-analysis of variants in the GABAA receptor genes (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12) using genotype data from 4739 cases of alcohol, opioid, or methamphetamine dependence and 4924 controls. Then, we combined the data from candidate gene association studies in the literature with two alcohol dependence (AD) samples, including 1691 cases and 1712 controls from the Study of Addiction: Genetics and Environment (SAGE), and 2644 cases and 494 controls from our own study. Using a Bonferroni-corrected threshold of 0.007, we found strong associations between GABRA2 and AD (P=9 × 10(-6) and odds ratio (OR) 95% confidence interval (CI)=1.27 (1.15, 1.4) for rs567926, P=4 × 10(-5) and OR=1.21 (1.1, 1.32) for rs279858), and between GABRG2 and both dependence on alcohol and dependence on heroin (P=0.0005 and OR=1.22 (1.09, 1.37) for rs211014). Significant association was also observed between GABRA6 rs3219151 and AD. The GABRA2 rs279858 association was observed in the SAGE data sets with a combined P of 9 × 10(-6) (OR=1.17 (1.09, 1.26)). When all of these data sets, including our samples, were meta-analyzed, associations of both GABRA2 single-nucleotide polymorphisms remained (for rs567926, P=7 × 10(-5) (OR=1.18 (1.09, 1.29)) in all the studies, and P=8 × 10(-6) (OR=1.25 (1.13, 1.38)) in subjects of European ancestry and for rs279858, P=5 × 10(-6) (OR=1.18 (1.1, 1.26)) in subjects of European ancestry. Findings from this extensive meta-analysis of five GABAA receptor genes and substance abuse support their involvement (with the best evidence for GABRA2) in the pathogenesis of AD. Further replications with larger samples are warranted.

Dataset Information

Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence.

Publications

Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence.

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