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GABA and the GABA a Receptor

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GABA and the GABA a Receptor NEUROTRANSMITTER REVIEW campus. Journal of Neurochemistry 62:1635–1638, 1994. their receptors reduce neuronal excitability. For optimal TRUJILLO, K.A., AND AKIL, H. Excitatory amino acids and drugs of abuse: A functioning, the brain must balance the excitatory and role for N-methyl-D-aspartate receptors in drug tolerance, sensitization and inhibitory influences: Excessive excitation can lead to physical dependence. Drug and Alcohol Dependence 38:139–154, 1995. seizures, whereas excessive neuronal inhibition can result TSAI, G.; GASTFRIEND, D.R.; AND COYLE, J.T. The glutamatergic basis of in incoordination, sedation, and anesthesia. human alcoholism. American Journal of Psychiatry 152:332–340, 1995. Gamma-aminobutyric acid (GABA) is the primary in- hibitory neurotransmitter in the central nervous system. WOODWARD, J.J., AND GONZALES, R.A. Ethanol inhibition of N-methyl-D- aspartate-stimulated endogenous dopamine release from rat striatal slices: Because alcohol intoxication is accompanied by the incoor- Reversal by glycine. Journal of Neurochemistry 54:712–715, 1990. dination and sedation indicative of neuronal inhibition, re- searchers have investigated alcohol’s effects on GABA and its receptors. This article summarizes findings that alcohol significantly alters GABA-mediated neurotransmission and GABA AND THE GABAA RECEPTOR presents some evidence that the primary GABA receptor (called the GABAA receptor) may play a crucial role in the S. John Mihic, Ph.D., and R. Adron Harris, Ph.D. development of tolerance to and dependence on alcohol as well as contribute to the predisposition to alcoholism. The neurotransmitter gamma-aminobutyric acid (GABA) inhibits the activity of signal-receiving neurons THE GABAA RECEPTOR by interacting with the GABAA receptor on these cells. The GABAA receptor is a channel-forming protein that 1 GABAA receptors are large proteins embedded in the cell allows the passage of chloride ions into the cells. membranes of neurons (see figure). Each receptor consists Excessive GABAA activation may play a role in mediat- of five protein molecules, or subunits, that assemble so that ing the sedative effects of alcohol and other sedating a channel is formed at the center of the complex. When and anesthetic agents. For example, alcohol enhances GABA molecules or GABA-like compounds bind to the the GABAA-mediated chloride flow into cells and may receptor and activate it, this channel temporarily opens and thereby enhance neuronal inhibition. Alcohol’s effects allows the passage of negatively charged molecules (i.e., - on the GABAA-receptor function likely involve other ions), such as chloride ions (Cl ), to pass from the cell’s molecules (e.g., other neurotransmitters and proteins exterior to its interior. This ion flow decreases the cell’s that add phosphate groups to the receptor [i.e., pro- excitability. The cumulative neuronal inhibition caused by tein kinases]). Several experimental approaches also GABA’s binding to many neurons results in sedation and have suggested that changes in GABA -receptor func- intoxication (Whiting et al. 1995). In laboratory animals, A these effects manifest themselves as loss of the righting tion contribute to the tolerance to and dependence on reflex—that is, the animals can not get up when placed on alcohol. Finally, individual differences in the GABA their backs. Compounds that enhance the GABA recep- system may play a role in determining a person’s sus- A tor’s activity cause increased neuronal inhibition. In con- ceptibility to developing alcohol dependence. KEY trast, compounds that reduce GABAA receptor activity WORDS: GABA; GABA receptors; neurotransmission; result in the excitation of the signal-receiving neurons. brain; sedative hypnotics; receptor proteins; chloride The subunits that constitute the GABAA receptor each channel; ion; protein kinases; AOD dependence; AOD consist of a large extracellular region located on the out- tolerance; AOD intoxication; AOD use susceptibility; side of the cell membrane, four segments spanning the cell animal model; literature review membrane, and several intracellular regions that are ex- posed to the neuron’s interior. Whereas the extracellular protein region is responsible for GABA binding, the intra- erve cells, or neurons, in the brain communicate through chemical messengers called neurotransmit- S. JOHN MIHIC, PH.D., is an assistant professor in the Nters. These molecules are released by the signal- Department of Physiology and Pharmacology, Bowman emitting neuron and bind to specific proteins (i.e., Grey School of Medicine, Winston-Salem, North Carolina. receptors) on the signal-receiving neuron. (For more infor- mation on signal transmission within and among nerve R. ADRON HARRIS, PH.D., is a professor in the Department cells, see the article “The Principles of Nerve Cell of Pharmacology and director of the Alcohol Research Communication,” pp. 107-108.) Two main types of neuro- Center, University of Colorado Health Sciences Center, transmitters and neurotransmitter receptors—excitatory and a research career scientist at the Denver Veterans and inhibitory—determine the response of the signal- Administration Medical Center, Denver, Colorado. receiving neuron. Excitatory neurotransmitters and their receptors increase the neuron’s intrinsic electrical activity 1For a definition of this and other technical terms used in this article, see and excitability, whereas inhibitory neurotransmitters and central glossary, pp. 177–179. VOL. 21, NO. 2, 1997 127 NEUROTRANSMITTER REVIEW cellular regions can be modified by the addition of phos- treated with a compound that inhibits GABA degradation phate groups (i.e., can become phosphorylated). As de- exhibited increased alcohol-induced incoordination scribed later in this article, this phosphorylation, which is (Deitrich et al. 1989). Finally, a compound called Ro 15- performed by enzymes such as protein kinase C (PKC) and 4513, which inhibits GABAA receptor function, has been occurs at specific sites of the GABA receptor subunits, shown to prevent some of alcohol’s behavioral effects. For regulates the receptor’s functioning. example, Ro 15-4513 reduced the severity of alcohol’s Many different GABAA receptor subunits have been hypnotic effects and decreased alcohol consumption in identified. These fall into three groups: α, β, and γ sub- animals (Mihic and Harris 1996). Such studies, however, units. Each of these groups contains several different sub- provide only indirect evidence of alcohol’s actions and γ γ units (e.g., 1 and 2). The exact subunit composition of therefore must be interpreted with caution. most GABAA receptors is not known. Most likely, each More direct evidence of alcohol’s interaction with the receptor consists of two α subunits, one β subunit, and two GABAA receptor derives from neurochemical analyses and γ subunits (see figure). Each subunit type only interacts from studies in mouse and rat strains bred to differ in their with specific molecules. Thus, the α sensitivities to some of alcohol’s be- and β subunits can interact with GABA, havioral effects. Neurochemical stud- whereas the α and γ subunits contain Some alcoholics may ies have analyzed alcohol’s effects on the binding site for benzodiazepines exhibit abnormal GABA-mediated Cl- uptake into brain (see below). Different subunits within “microsacs”—membranes isolated each of the three groups also differ in GABA metabolism from brain cells that form sealed their pharmacological properties (e.g., bags—and spinal-cord neurons grown the sensitivity to alcohol). Consequently, in tissue culture. Many of these studies the specific subunit composition of found that alcohol increased Cl- up- each GABAA receptor molecule determines that receptor’s take, suggesting that alcohol could enhance GABA-medi- overall characteristics. GABAA receptors in different ated inhibition of neurons (Mihic and Harris 1996). neurons or brain regions or at various developmental Researchers also have investigated alcohol’s effects on stages therefore can differ in their pharmacological proper- GABAA receptor function in mouse and rat strains specifi- ties (McKernan and Whiting 1996). cally bred to differ in their susceptibilities to alcohol- GABAA receptors are found throughout the brain. This induced incoordination or loss of righting reflex. For wide distribution likely is responsible for the plethora of example, so-called long-sleep (LS) mice exhibit a longer behaviors (e.g., sedation, relief of anxiety, and motor in- duration of the loss of righting reflex after an acute alcohol coordination) produced by agents that activate these injection than do short-sleep (SS) mice. Studies in these receptors, such as alcohol. mice found that alcohol enhanced GABA-mediated Cl- uptake into brain microsacs obtained from LS mice but not THE GABAA RECEPTOR’S ROLE IN ALCOHOL into microsacs obtained from SS mice (Mihic and Harris INTOXICATION 1996). These findings suggest that a biochemical differ- ence in alcohol’s effects on the GABAA receptor may Numerous clinically useful sedating medications (e.g., underlie the behavioral differences observed between the benzodiazepines, such as Valium®, and barbiturates, such two strains. as phenobarbital) and anesthetic agents (e.g., halothane) Alcohol’s effects on GABAA receptor function likely exert their effects at least in part by enhancing GABA’s involve the actions of other cellular proteins, such as the influence on GABAA receptors. Thus, these agents tilt the PKC enzymes that phosphorylate the GABAA receptor
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