NEUROTRANSMITTER REVIEW campus. Journal of Neurochemistry 62:1635Ð1638, 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 38:139Ð154, 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 152:332Ð340, 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 54:712Ð715, 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. 177Ð179.

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 at balance of excitatory and inhibitory influences in the brain specific sites. In one experiment, for example, mice lack- toward inhibition, thereby causing the incoordination, ing a certain PKC subtype in the brain displayed reduced sedation, and even anesthesia that accompany their use. sensitivity to alcohol on several behavioral tests. More- Because alcohol produces similar effects, it also likely over, alcohol no longer enhanced the GABA-induced flow - promotes neuronal inhibition through the GABAA receptor of Cl into brain microsacs prepared from these PKC (Tabakoff and Hoffman 1996). “knock-out” mice (Mihic and Harris 1996). This observa- Using several different approaches, researchers have tion further strengthens the hypothesis that alcohol-induced attempted to determine which of alcohol’s behavioral ef- enhancement of GABAA receptor activity not only in- fects are mediated by changes in GABAA receptor func- volves proteins other than the receptor proteins but also tion. One strategy has been to administer alcohol together requires protein phosphorylation. with other compounds that interact with the GABAA recep- Other studies have used electrophysiological techniques to tor and then determine whether alcohol enhances or im- assess alcohol’s effects on GABAA receptor function. These pedes the effects of these compounds. For example, studies have employed different experimental systems: (1) injections of GABA or GABA-like compounds into the neurons that are still in an intact brain, (2) neurons in thin brains of rats increased alcohol’s incoordinating and hyp- slices of isolated brain tissue, (3) isolated brain cells that have notic effects (Deitrich et al. 1989). Similarly, rats that were been grown in tissue culture, and (4) nonneuronal cells that

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normally do not produce GABAA receptors but which can be induced artificially to manufacture receptors composed of specific subunits. Like the experiments described previously, GABA these electrophysiological analyses indicate that the mecha- ? nisms underlying alcohol-induced enhancement of GABA- ? β mediated signal transmission are complex and may involve neurotransmitter receptors other than the GABAA receptor. For example, one study found that alcohol enhanced the activity of the GABAA receptor on certain cells in the cere- γ α bellum of rats only in the presence of the neurotransmitter β GABA norepinephrine, which acts through another receptor, the - Barbiturates adrenergic receptor (Freund and Palmer 1997). These find- Benzodiazepines ings suggest that alcohol-dependent enhancement of GABA Exterior Alcohol activity in the cerebellum requires the activation of the β- adrenergic receptor. This receptor is located on the same cells in the cerebellum as the GABAA receptor. Both receptors also interact in the absence of alcohol, but this interaction Membrane may be enhanced in the presence of alcohol. At least three plausible mechanisms could explain the interactions among the β-adrenergic receptor, the GABAA receptor, and alcohol, as follows:

¥ Norepinephrine could increase the GABAA receptor’s sensitivity to alcohol. Interior Alcohol P ¥ Alcohol could interact with the β-adrenergic receptor, P P thereby increasing that receptor’s ability to modulate GABAA receptor function. ¥ Alcohol may further increase β-adrenergic enhancement Schematic representation of the gamma-aminobutyric acid (GABAA) receptor. The functional receptor consists of five of GABAA receptor function by inhibiting the removal α β of norepinephrine from the synapses. proteins, or subunits—most likely two subunits, one subunit, and two γ subunits. (Question marks indicate that the identity β-adrenergic signal transmission results in increased pro- of these subunits has not been confirmed.) The proposed binding sites for GABA (α and β subunits), benzodiazepines tein phosphorylation. Thus, whatever the exact mechanism (adjacent α and γ subunits), barbiturates (unidentified subunit), may be, the association between the activities of the and alcohol (α, β, and γ subunits) are indicated. P’s GABAA and β-adrenergic receptors supports the conclu- represent phosphate groups attached to the receptor that - sions from the C1 -flow analyses described above that regulate the receptor’s activity and sensitivity to alcohol. alcohol’s effect on the GABAA receptor may require acti- vation of phosphorylating proteins, such as PKC (for a detailed discussion, see Weiner et al. 1997). be performed in cultured cells or other artificial systems, The link between protein phosphorylation and the sensi- not in intact brains. Therefore, one cannot conclude un- tivity to alcohol of the GABA receptor also has been con- A equivocally from these studies whether the GABAA recep- firmed in studies analyzing alcohol’s effects on GABAA tor’s sensitivity to alcohol in an intact organism is receptors with known subunit composition. For example, determined by differences in receptor subunits, phosphory- γ the 2 subunit of the GABAA receptor exists in two forms— lating enzymes, or other unknown factors (see Weiner et al. γ γ a short variant ( 2S) and a long variant ( 2L)—which differ 1997; Harris et al. 1997; Mihic and Harris 1996). in size by eight amino acids. Analyses in cultured cells γ found that receptors containing the 2L subunit showed alcohol-induced enhancement of their activity, whereas THE GABA RECEPTOR AND ALCOHOL TOLERANCE γ A receptors containing the 2S subunit generally were insensi- AND DEPENDENCE tive to intoxicating alcohol concentrations (Wafford and Whiting 1992; Whitten et al. 1996; Harris et al. 1997). The After continuous alcohol consumption, both humans γ additional eight amino acids present in 2L contain a site and laboratory animals develop tolerance to alcohol’s that can be phosphorylated by PKC, indicating that phos- effects—that is, they require larger amounts of alcohol phorylation is a prerequisite for the GABAA receptor’s to achieve the same effects. Moreover, continuous sensitivity to alcohol. However, these experiments only can alcohol consumption leads to the development of de-

VOL. 21, NO. 2, 1997 129 NEUROTRANSMITTER REVIEW pendence, which is manifested by certain behavioral the DNA levels in each cell remain constant, mRNA levels and physiological withdrawal responses that occur when fluctuate. Thus, mRNA levels increase when the gene is alcohol is withheld (e.g., anxiety, excitability, and “turned on” and much protein is produced. Conversely, seizures). Changes in GABAA receptor function may mRNA levels decrease when the gene is “turned off” and help explain both tolerance and dependence. For exam- only little protein is produced. ple, changes in the GABAA receptor that would reduce Several recent studies have investigated the effects of its susceptibility to alcohol’s effects could produce chronic alcohol administration on the levels of mRNA for tolerance. Similarly, inhibition of GABAA receptor various GABAA receptor subunits. For example, analyses function may occur during alcohol withdrawal, because in rats found that chronic alcohol treatment leads to re- α α medications that inhibit the receptors’ activity (i.e., duced mRNA levels for one of the subunits (i.e., the 1 α receptor antagonists) produce symptoms similar to subunit) as well as to decreased 1 protein levels (Morrow those observed in alcoholics during withdrawal. 1995). These findings support the hypothesis that tolerance Several experimental approaches have been used to development involves reduced GABAA receptor numbers. investigate the role of the GABAA receptor in alcohol The levels of other GABAA receptor subunits, however, tolerance and dependence. These approaches include appear to be elevated. Furthermore, studies in humans α studies of receptor antagonists, biochemical and elec- produced conflicting results regarding the levels of 1 trophysiological analyses, and genetic analyses. mRNA, possibly because analyses in humans often cannot The effects of GABAA receptor antagonists were stud- be controlled as accurately as in animals. Additional stud- α ied in animals that underwent a regimen of chronic alcohol ies found that the 1 mRNA levels were reduced most administration followed by alcohol withdrawal to induce significantly in animals that were genetically predisposed seizures in the animals. The alcohol-treated animals were to severe withdrawal symptoms. These findings suggest more susceptible to the seizure-inducing effects of a that when alcohol is withheld, the reduced GABAA subunit GABAA receptor antagonist called bicuculline and of a levels prevent GABA-induced signal transmission, thereby compound called picrotoxin, which inhibits chloride chan- contributing to withdrawal symptoms, such as seizures. nels (including the GABAA receptor), than were animals that had not received alcohol (Buck and Harris 1991; GABA AND ALCOHOL ABUSE AND DEPENDENCE Morrow 1995). These findings indicate that chronic alco- hol administration had reduced GABAA receptor function, Recent research findings suggest that the GABA system so that lower levels of the GABAA receptor antagonists also may play a role in determining a person’s suscepti- were required to induce seizures. bility to developing alcohol abuse or alcohol dependence. The effects of chronic alcohol treatment on GABAA For example, one study compared the effects of the ben- receptor function also have been examined biochemically zodiazepine lorazepam on the brain’s use of glucose (i.e., and electrophysiologically. Several studies found that glucose metabolism) in nonalcoholic subjects with a fam- whereas one-time alcohol administration enhanced GABA- ily history of alcoholism (FP subjects) and subjects with- induced Cl- flow into mouse brain microsacs, no such out such a family history (FN subjects) (Volkow et al. effect occurred after chronic alcohol administration (Buck 1995). By measuring the glucose metabolism in various and Harris 1991; Morrow 1995). This resistance to alco- brain regions, researchers can determine whether these hol’s chronic effects may represent a mechanism for alco- regions are active at the time of measurement (i.e., whether hol tolerance. Similarly, the ability of benzodiazepines to signal transmission is occurring). The study analyzed enhance GABA-induced Cl- uptake into brain microsacs lorazepam’s effects in the cerebellum, an area at the base was reduced in microsacs obtained from mice that had of the brain that is responsible for motor coordination. received chronic alcohol treatment, suggesting that chronic The FP subjects exhibited lower cerebellar glucose alcohol administration induced tolerance not only to alco- metabolism than did the FN subjects. Moreover, hol but also to other substances affecting the GABAA re- lorazepam reduced the cerebellar glucose metabolism to a ceptor (Buck and Harris 1991). lesser extent in FP subjects than in FN subjects. These One potential mechanism underlying alcohol tolerance findings suggest that the activity of the GABAA receptors at the cellular level is a decrease in the number of GABAA in the cerebellum was disrupted in the FP subjects, mak- receptors on each neuron to compensate for the continuous ing these people less vulnerable to the actions of agents alcohol-induced increase in GABAA receptor activity. To such as lorazepam or alcohol and thereby possibly pro- investigate this hypothesis, researchers have monitored moting increased alcohol consumption. changes in GABAA receptor subunit levels after chronic Other studies found that alcoholics had fewer GABAA alcohol administration by determining the messenger receptors in various brain regions than did nonalcoholic ribonucleic acid (mRNA) levels for these subunits. mRNA control subjects (Freund and Ballinger 1988a,b). It is un- is an intermediate molecule produced during the conver- clear, however, whether these reduced receptor levels were a sion of the genetic information encoded in the DNA into a cause or a consequence of chronic alcohol consumption. protein product (e.g., a GABAA receptor subunit). Whereas Researchers also found that some abstinent alcoholics had

130 ALCOHOL HEALTH & RESEARCH WORLD NEUROTRANSMITTER REVIEW lower GABA levels in the blood, a finding that likely re- COWLEY, D.S.; ROY-BYRNE, P.P.; GREENBLATT, D.J.; KRAMER, G.L.; AND flects reduced GABA levels in the brain (Adinoff et al. PETTY, F. Effect of diazepam on plasma gamma-aminobutyric acid in sons 1995). However, these low GABA concentrations apparent- of alcoholic fathers. Alcoholism: Clinical and Experimental Research 20:343Ð347, 1996. ly were not associated with an increased genetic predisposi- tion for alcohol dependence. Finally, sons of alcoholics, who DEITRICH, R.A.; DUNWIDDIE, T.V.; HARRIS, R.A.; AND ERWIN, V.G. are at an increased risk of becoming alcoholics themselves, Mechanism of action of ethanol: Initial central nervous system actions. were more likely than control subjects to report feelings of Pharmacological Reviews 41:491Ð537, 1989. intoxication following benzodiazepine consumption FREUND, G., AND BALLINGER, W.E. Decrease of benzodiazepine receptors (Cowley et al. 1992, 1996). Together, these results suggest in frontal cortex of alcoholics. Alcohol 5:275Ð282, 1988a. that some alcoholics may exhibit abnormal GABA metabolism. Moreover, GABA receptor function—as mea- FREUND, G., AND BALLINGER, W.E., JR. Loss of muscarinic and benzo- A diazepine neuroreceptors from hippocampus of alcohol abusers. Alcohol sured by benzodiazepine’s effects on brain metabolism and 6:23Ð31, 1988b. behavior—is disrupted less prominently in people with a family history of alcoholism and therefore may be related to FREUND, R.K., AND PALMER, M.R. Beta adrenergic sensitization of these people’s genetic liability for alcoholism. gamma-aminobutyric acid receptors to ethanol involves a cyclic AMP protein kinase A second-messenger mechanism. Journal of Pharmacology and Experimental Therapeutics 280:1192Ð1200, 1997.

CONCLUSIONS HARRIS, R.A.; MIHIC, S.J.; BROZOWSKI, S.J.; HADINGHAM, K.L.; AND

WHITING, P.J. Comparison of drug effects on recombinant GABAA Over the past decade, researchers have learned much about receptors expressed in mammalian cells and Xenopus oocytes. alcohol’s effects on GABAA receptors. Evidence exists Alcoholism: Clinical and Experimental Research 21:444Ð452, 1997. that both acute and chronic alcohol exposure alter GABAA MCKERNAN, R.M., AND WHITING, P.J. Which GABA -receptor subtypes receptor function. Furthermore, these receptors may play A really occur in the brain? Trends in Neuroscience 19:139Ð143, 1996. important roles in the development of tolerance to and dependence on alcohol and may underlie some of the MIHIC, S.J.; AND HARRIS, R.A. Alcohol actions at the GABAA receptor/ genetic differences in the susceptibility to alcohol’s ac- chloride channel complex. In: Deitrich, R.A., and Erwin, V.G., eds. tions. Understanding the molecular basis for alcohol’s Pharmacological Effects of Ethanol on the Nervous System. Boca Raton, effects on these receptors provides a fascinating research FL: CRC Press, 1996. pp. 51Ð72. challenge. Perhaps the most perplexing question currently MORROW, A.L. Regulation of GABAA receptor function and gene expres- facing investigators who study alcohol’s interactions with sion in the central nervous system. International Review of Neurobiology GABAA receptors is, Which factors determine whether a 38:1Ð41, 1995. particular GABAA receptor will respond to acute alcohol TABAKOFF, B., AND HOFFMAN, P.L. Alcohol addiction: An enigma among exposure? By answering this question, researchers will be us. Neuron 16:909Ð912, 1996. able to elucidate the mechanism of alcohol’s actions not VOLKOW, N.D.; WANG, G.J.; BEGLEITER, H.; HITZEMANN, R.; PAPPAS, N.; only on the GABAA receptor but also on other neurotrans- mitter receptors in the brain that help mediate alcohol’s BURR, G.; PASCANI, K.; WONG, C.; FOWLER, J.S.; AND WOLF, A.P. Regional brain metabolic response to lorazepam in subjects at risk for alcoholism. effects. Another pivotal question regards the mechanisms Alcoholism: Clinical and Experimental Research 19:510Ð516, 1995. by which chronic alcohol consumption alters GABAA receptor function. Knowledge of these processes should WAFFORD, K.A., AND WHITING, P.J. Ethanol potentiation of GABAA lead to new strategies for identifying people at risk for receptors requires phosphorylation of the alternatively spliced variant of γ alcoholism and for treating the disease. the 2 subunit. FEBS Letters 313:113Ð117, 1992. WEINER, J.L.; VALENZUELA, C.F.; WATSON, P.L.; FRAZIER, C.J.; AND DUNWIDDIE, T.V. Elevation of basal protein kinase C activity increases

REFERENCES ethanol sensitivity of GABAA receptors in rat hippocampal CA1 pyramidal neurons. Journal of Neurochemistry 68:1949Ð1959, 1997. ADINOFF, B.; KRAMER, G.L.; AND PETTY, F. Levels of gamma-amino- butyric acid in cerebrospinal fluid and plasma during alcohol withdrawal. WHITING, P.J.; MCKERNAN, R.M.; AND WAFFORD, K.A. Structure and Psychiatry Research 59:137Ð144, 1995. pharmacology of vertebrate GABAA receptor subtypes. In: Bradley, R.J., and Harris, R.A., eds. International Review of Neurobiology. San Diego: BUCK, K.J., AND HARRIS, R.A. Neuroadaptive responses to chronic ethanol. Alcoholism 15:460Ð470, 1991. Academic Press, 1995. p. 95.

COWLEY, D.S.; ROY-BYRNE, P.P.; GODON, C.; GREENBLATT, D.J.; RIES, R.; WHITTEN, R.J.; MAITRA, R.; AND REYNOLDS, J.N. Modulation of GABAA WALKER, R.D.; SAMSON, H.H.; AND HOMMER, D.W. Response to receptor function by alcohols: Effects of subunit composition and dif- diazepam in sons of alcoholics. Alcoholism: Clinical and Experimental ferential effects of ethanol. Alcoholism: Clinical and Experimental Research 16:1057Ð1063, 1992. Research 20:1313Ð1319, 1996.

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OPIOID PEPTIDES neurotransmitters. (For more information on these neuro- transmitters, see the related articles in this section.) Through these two mechanisms, endogenous opioid pep- Janice C. Froehlich, Ph.D. tides produce many effects, ranging from preventing diar- rhea to inducing euphoria and pain relief (i.e., analgesia). Opioid peptides produced in the body act as neuro- This article reviews the physiology of endogenous opi- oid peptides and their interactions with other neurotrans- modulators that modify the actions of other neuro- mitters. In addition, the article summarizes the interactions transmitters in the central nervous system. By altering between alcohol and the endogenous opioid system and the electrical properties of their target neurons, there- presents evidence that opioid peptides play a role in alco- by making these neurons more difficult to excite, opi- hol reinforcement. (For further information on alcohol and oid peptides can influence the release of various the opioid system, see Froehlich and Li 1993, 1994; neurotransmitters. As a result of this modulation, opi- Gianoulakis and colleagues 1996a; Herz 1997.) oid peptides can—among other functions—induce pain relief and euphoria as well as affect certain be- haviors, including alcohol consumption. Alcohol can PHYSIOLOGY OF OPIOID PEPTIDES activate the opioid peptide system. This mechanism Opioid Peptide Production may contribute to alcohol reinforcement and exces- sive alcohol consumption, because agents that inhibit Many peptides with opioidlike effects have been found in the opioid peptide system decrease alcohol self- the CNS and in peripheral tissues. Molecular biological approaches, such as recombinant DNA techniques, have administration in animals and reduce craving and al- demonstrated that these peptides fall into three categories— cohol consumption in human alcoholics. Moreover, a enkephalins, endorphins, and dynorphins—that are derived genetically determined, increased responsiveness of from three distinct precursor molecules. The active, func- the opioid system to alcohol may contribute to a pre- tional opioid peptides are generated from their precursors disposition for alcoholism in some people. KEY WORDS: by enzymes called peptidases, which cut these precursor endogenous opioids; peptides; drug interaction; neuro- molecules into smaller entities. The peptides are then modi- transmitters; opioid receptors; central nervous system; fied further during posttranslational processing, which can brain; neuron; biological activation; reinforcement; include the addition of various chemical groups to the pep- AOD use behavior; self administration of drugs; AOD tides (e.g., sugar molecules [i.e., glycosylation], acetyl craving; AOD sensitivity; AOD use susceptibility; eu- groups [i.e., acetylation], phosphate groups [i.e., phosphory- phoria; sense of pain; literature review lation], or methyl groups [i.e., methylation]). These modifi- cations can alter the peptides’ biological activities. Because the processing of opioid peptides from larger precursor ndogenous opioid peptides1 are small molecules that molecules is very selective, the opioid-peptide profiles can are naturally produced in the central nervous system vary among different tissue types. E(CNS) and in various glands throughout the body, So far, two of the enkephalins (i.e., leu-enkephalin and such as the pituitary and adrenal glands. These peptides met-enkephalin) and one of the endorphins (i.e., beta- produce the same effects as the chemicals known as classic endorphin) have been shown to be active in mediating alkaloid opiates, which include morphine and heroin. alcohol’s effects. Endogenous opioid peptides function both as hormones and as neuromodulators. Endogenous opioid peptides that Opioid Receptors serve as hormones are secreted into the circulation by the producing glands and are delivered to a variety of distant To affect the functions of their target cells, opioid peptides target tissues where they induce a response. Endogenous must bind to specific molecules, or receptors, on the sur- opioid peptides that serve as neuromodulators are produced faces of these cells. The body contains several receptors and secreted by nerve cells (i.e., neurons) and act in the that selectively recognize molecules with opioidlike struc- brain and spinal cord to modulate the actions of other tures. Three major categories of opioid receptors—mu, delta, and kappa—have been identified that differ both in their functions and in their binding characteristics. A given JANICE C. FROEHLICH, PH.D., is an associate professor in the opioid peptide can interact with more than one type of Departments of Medicine and Physiology/Biophysics, Indiana opioid receptor. The binding of opioid peptides to these University School of Medicine, Indianapolis, Indiana. receptors initiates a series of biochemical events that cul- minate in various effects, including analgesia and euphoria. Support for this work was provided by National Institute on Alcohol Abuse and Alcoholism grants AAÐ07611, 1For a definition of this and other technical terms used in this article, see AAÐ08312, and AAÐ10709. central glossary, pp. 177Ð179.

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