Alcohol abuse represents a major clinical condition in the Unites States and worldwide. Despite the prevalence of alcohol dependence and the well-known adverse effects of chronic alcohol exposure, the neurobiological mechanisms mediating alcohol's effects in the brain are still not fully understood. The challenge of current and future studies is to understand the neurobiological changes that influence tolerance and dependence in motivational systems that lead to chronic drinking. The central amygdala (CeA) is a major component of the brain involved in the motivational effects of drugs of abuse and alcohol in particular (Alheid and Heimer, 1988). The inhibitory neurotransmitter GABA is a key element of the CeA circuitry and is a critical component of the behavioral effects of acute and chronic ethanol consumption (Hyytia &Koob, 1995;Roberts et al., 1996). To date, studies in the CeA have predominantly focused on alterations in the presynaptic GABA system (Roberto et al., 2003, 2004). Importantly, no studies have examined a specific form of GABAA receptor signaling characterized by persistent inhibitory currents mediated by GABAA receptors with a distinct subunit composition. Denoted tonic inhibition, this form of GABAA receptor signaling has been shown to have high sensitivity to ethanol (Wallner et al., 2003) and has been implicated in the effects of alcohol in several brain regions (Wei et al., 2004;Liang et al., 2007;Jia et al., 2008). However, no studies have been performed on this type of GABAA receptor signaling in the CeA. Therefore, the goal of this proposal is to characterize tonic GABAA receptor signaling in the CeA and to investigate the effects of acute and chronic ethanol exposure on this signaling. Applying electrophysiological and molecular techniques to elucidate alterations in tonic GABAA receptor expression and function in the CeA will provide important information as to the cellular changes that contribute to the transition from recreational alcohol consumption to dependence. This information could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics.

Public Health Relevance

This proposal utilizes electrophysiological and molecular techniques to characterize a novel cellular neuroadaptation to ethanol exposure in the CeA. The overarching hypothesis is that changes in tonic GABAA receptor signaling in the CeA are a major contributing factor in the development of alcohol dependence. The results of these studies will provide important information as to one of the underlying mechanisms related to the development of alcohol dependence and could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AA020430-03
Application #
8507116
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Liu, Qi-Ying
Project Start
2011-08-16
Project End
2014-08-15
Budget Start
2013-08-16
Budget End
2014-08-15
Support Year
3
Fiscal Year
2013
Total Cost
$53,942
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91
Herman, Melissa Ann; Roberto, Marisa (2016) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol 21:72-86
Herman, Melissa A; Sidhu, Harpreet; Stouffer, David G et al. (2015) GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Proc Natl Acad Sci U S A 112:7091-6
Repunte-Canonigo, Vez; Herman, Melissa A; Kawamura, Tomoya et al. (2015) Nf1 regulates alcohol dependence-associated excessive drinking and gamma-aminobutyric acid release in the central amygdala in mice and is associated with alcohol dependence in humans. Biol Psychiatry 77:870-9
Gilpin, Nicholas W; Herman, Melissa A; Roberto, Marisa (2015) The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol Psychiatry 77:859-69
Grieder, Taryn E; Herman, Melissa A; Contet, Candice et al. (2014) VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci 17:1751-8
Herman, Melissa A; Contet, Candice; Justice, Nicholas J et al. (2013) Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice. J Neurosci 33:3284-98
Herman, Melissa A; Kallupi, Marsida; Luu, George et al. (2013) Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects. Neuropharmacology 67:337-48