Alcohol abuse represents a significant problem in our society. Chronic intermittent ethanol (CIE) treatment of rats (60 doses of intermittent intoxication and withdrawal), encompasses all of the major characteristics of human alcoholism, including anxiety, lowered seizure thresholds, and enhanced alcohol preference after withdrawal. At least some of these symptoms may be explained by the measured reduction in the function of the 3-aminobutyric acid (A) receptor (GABAAR) and altered sensitivity to its allosteric modulators. GABAARs mediating synaptic (phasic) and extrasynaptic (tonic) inhibition appear to be altered differently. Thus, tolerance develops to acute ethanol (EtOH) potentiation of hippocampal extrasynaptic GABAARs, while synaptic GABAARs develop high sensitivity to EtOH. Such paradoxical changes in EtOH sensitivity are proposed to underlie both the development and persistence of alcoholism. Preliminary studies suggest that altered subunit composition and localization of GABAARs may account for the observed alterations in GABAAR function within the hippocampus. However, it is unknown whether other key brain areas implicated in symptoms of alcohol withdrawal and dependence experience similar neuroadaptations. It is also unknown whether EtOH-induced neurodegeneration may account for these neuroadaptations. Underscoring the persistence of CIE-induced changes is a new observation of fundamental importance: a single intoxicating dose of EtOH results in GABAAR changes similar to those seen after CIE treatment, but recovery is seen by 1-2 weeks after this single dose.
The specific aims of this proposal were designed to address key hypotheses regarding GABAAR involvement in mechanisms of alcohol withdrawal and dependence by: 1) determining the dose-, duration-, and frequency-dependence of CIE treatment to produce long-lasting symptoms of EtOH dependence;2) studying changes in GABAAR subunit composition and function within nucleus accumbens and basolateral nucleus of the amygdala (brain areas known to be of major importance for the mechanisms of reward and dependence) and relating them to the behavioral measures of withdrawal from single or multiple EtOH treatments;and 3) determining whether neurodegeneration plays a role in altered GABAergic inhibition after EtOH intoxication through the use of histochemical and stereological techniques. The knowledge acquired from the proposed experiments will increase our understanding of the alcohol-induced alterations in GABAAR function, which has profound effects on various emotional and intellectual aspects of brain activity. This knowledge will also be useful to the development of therapeutics targeting the GABAergic system for the treatment of alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Dentistry
Los Angeles
United States
Zip Code
Lindemeyer, A Kerstin; Shen, Yi; Yazdani, Ferin et al. (2017) ?2 Subunit-Containing GABAA Receptor Subtypes Are Upregulated and Contribute to Alcohol-Induced Functional Plasticity in the Rat Hippocampus. Mol Pharmacol 92:101-112
Suryanarayanan, A; Carter, J M; Landin, J D et al. (2016) Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol. Neuropharmacology 107:181-188
Liang, Jing; Lindemeyer, A Kerstin; Suryanarayanan, Asha et al. (2014) Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats. J Neurophysiol 112:39-50
Lindemeyer, A Kerstin; Liang, Jing; Marty, Vincent N et al. (2014) Ethanol-induced plasticity of GABAA receptors in the basolateral amygdala. Neurochem Res 39:1162-70
Liang, Jing; Marty, Vincent N; Mulpuri, Yatendra et al. (2014) Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats. J Neurophysiol 112:51-60
Meyer, Edward M; Long, Virginia; Fanselow, Michael S et al. (2013) Stress increases voluntary alcohol intake, but does not alter established drinking habits in a rat model of posttraumatic stress disorder. Alcohol Clin Exp Res 37:566-74
Shen, Yi; Lindemeyer, A Kerstin; Gonzalez, Claudia et al. (2012) Dihydromyricetin as a novel anti-alcohol intoxication medication. J Neurosci 32:390-401
Marty, Vincent N; Spigelman, Igor (2012) Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens. Alcohol 46:317-27
Shen, Yi; Lindemeyer, A Kerstin; Spigelman, Igor et al. (2011) Plasticity of GABAA receptors after ethanol pre-exposure in cultured hippocampal neurons. Mol Pharmacol 79:432-42
Ribak, Charles E; Shapiro, Lee A; Perez, Zachary D et al. (2009) Microglia-associated granule cell death in the normal adult dentate gyrus. Brain Struct Funct 214:25-35

Showing the most recent 10 out of 12 publications