The objectives of this study are to determine whether persistent alterations in the GABAA receptor complex (GABAR) can provide a molecular explanation for the development of physical dependence on ethanol in an animal model of alcoholism. Chronic intermittent ethanol (CIE) administration to rats has many features resembling human alcohol abuse behavior, including long-lasting susceptibility to readdiction. The numerous episodes of ethanol (EtOH)-induced depression of the nervous system and the following rebound hyperexcitability (withdrawal) have been shown to exert a kindling-like effect, i.e., a persistent increased severity of the hyperexcitable withdrawal symptoms. Rats treated in this manner become EtOH-dependent, one measure being a decreased seizure threshold to the convulsant drug pentylenetetrazol (PTZ), a blocker of the GABAR. The hyperexcitability to PTZ (kindling) lasts at least 40 days after cessation of EtOH. The CIE rats exhibit elevated anxiety, show tolerance to the sedative action of EtOH and cross-tolerance to other sedatives, and impaired hippocampal memory. Neurochemical and electrophysiological studies have been focused on whether this ethanol withdrawal syndrome can be associated with alterations in GABAR, and have demonstrated a significant reduction, specifically in the hippocampal formation, in GABAR function, as well as multiple alterations in the molecular properties of GABAR. We showed a restructuring of GABAR subunit composition consistent with changes in electropharmacology of GABAR-mediated synaptic and extrasynaptic tonic currents. These biochemical and physiological changes appear relevant to the altered behaviors. The same persistent alterations seen in CIE are also observed transiently after a single administration of an intoxicating dose of EtOH. In future we propose to study the molecular and cellular mechanisms whereby this GABAR plasticity develops and how it becomes persistent. In addition to acute and chronically EtOH-treated rats we will extend the model to mice to allow studies on genetically engineered animals with altered GABAR to help determine their role in developing dependence. We suggest that reduced GABAR function in ethanol-dependent individuals has profound effects on various emotional and intellectual aspects of brain activity. Finding the molecular mechanisms responsible may help in treatment of withdrawal symptoms and hopefully in reduction of ethanol dependence. This type of mammalian animal model seems to have great potential for uncovering important insights into abuse mechanisms. In addition, our studies on animal models of alcoholism will allow families and health professionals'better understanding of what environmental and genetic factors contribute to the susceptibility for alcohol abuse, of the behavioral changes of the alcohol abuser, and of possible behavioral modification and medications to consider in treating the disorder.
This project studies the cellular and molecular mechanisms of alcohol dependence in a rodent model in hopes of developing therapeutics for prevention and treatment of alcoholism. Rats and mice are given chronic intermittent ethanol (CIE) and studied for changes in inhibitory neurotransmission in brain involving receptors for the neurotransmitter 3-aminobutyric acid (GABA). The amounts, locations, and functions of the GABA receptors are related to the behavioral changes seen in alcohol dependence such as hyperexcitability, increased anxiety, sleep disturbances, and seizure susceptibility.
|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|
|Peng, Zechun; Zhang, Nianhui; Chandra, Dave et al. (2014) Altered localization of the ? subunit of the GABAA receptor in the thalamus of ?4 subunit knockout mice. Neurochem Res 39:1104-17|
|Wallner, M; Hanchar, H J; Olsen, R W (2014) Alcohol selectivity of ?3-containing GABAA receptors: evidence for a unique extracellular alcohol/imidazobenzodiazepine Ro15-4513 binding site at the ?+?- subunit interface in ??3? GABAA receptors. Neurochem Res 39:1118-26|
|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|
|Cushman, Jesse D; Moore, Mellissa D; Olsen, Richard W et al. (2014) The role of the ? GABA(A) receptor in ovarian cycle-linked changes in hippocampus-dependent learning and memory. Neurochem Res 39:1140-6|
|Olsen, Richard W; Li, Guo-Dong; Wallner, Martin et al. (2014) Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol. Alcohol Clin Exp Res 38:595-603|
|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|
|Davies, Daryl L; Bortolato, Marco; Finn, Deborah A et al. (2013) Recent advances in the discovery and preclinical testing of novel compounds for the prevention and/or treatment of alcohol use disorders. Alcohol Clin Exp Res 37:8-15|
|Gonzalez, Claudia; Moss, Stephen J; Olsen, Richard W (2012) Ethanol promotes clathrin adaptor-mediated endocytosis via the intracellular domain of ?-containing GABAA receptors. J Neurosci 32:17874-81|
|Shen, Yi; Lindemeyer, A Kerstin; Gonzalez, Claudia et al. (2012) Dihydromyricetin as a novel anti-alcohol intoxication medication. J Neurosci 32:390-401|
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