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and Interactions

C. FERNANDO VALENZUELA, M.D., PH.D.

Evidence suggests that alcohol affects function by interacting with multiple neurotransmitter systems, thereby disrupting the delicate balance between inhibitory and excitatory . Short-term alcohol exposure tilts this balance in favor of inhibitory influences. After long-term alcohol exposure, however, the brain attempts to compensate by tilting the balance back toward equilibrium. These neurological changes occur as the development of tolerance to alcohol’s effects. When alcohol consumption is abruptly discontinued or reduced, these compensatory changes are no longer opposed by the presence of alcohol, thereby leading to the excitation of neurotransmitter systems and the development of alcohol withdrawal syndrome. Long- term alcohol intake also induces changes in many neurotransmitter systems that ultimately to the development of craving and alcohol-seeking behavior. KEY WORDS: neurotransmitter receptors; ; AODE (alcohol and other effects); AOD use behavior; AOD tolerance; AOD withdrawal syndrome; AOD craving; biological inhibition; ; ; biochemical mechanism; literature review

cientists have long sought the which they bind have provided data neurotransmitter systems to influence mechanisms by which alcohol on both the structure and the mecha- behavior. Sacts on the brain to modify be- nism of action of these as havior. An important finding is the well as clues to their role in behavior. demonstration that alcohol can However, the function of individual NEUROTRANSMITTER SYSTEMS the function of specific neurotransmit- neurotransmitters and their receptors WORK TOGETHER ters1 (Lovinger et al. 1989). Studies of cannot entirely explain a syndrome as Communication among is neurotransmitters and the receptors to complex as . organized in interacting levels. The Neurotransmitter systems do not most basic level of complexity is the function in isolation. Therefore, scien- C. FERNANDO VALENZUELA, M.D., arrangement of connections (i.e., PH.D., is an instructor in the tists are paying increasing to ) between individual neurons. Department of , the integration of communication University of Colorado, Health systems in the brain. Although the 1Nerve cells (i.e., neurons) communicate by Sciences Center, Denver, Colorado. study of neural integration is in its releasing chemical messengers called neuro- infancy, enough has been learned to transmitters, which bind to on help guide future research. This article the surface of other neurons. This process is Support for this work was provided by called neurotransmission. For definitions of National Institute on Alcohol Abuse suggests mechanisms by which alco- technical terms used in this article, see central and Alcoholism grant AA00227. hol consumption may affect multiple glossary, pp. 177Ð179.

144 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and NeurotransmitterRunning Interactions

One may connect with up to hundreds or thousands of adjacent neurons (Shepherd 1994). Each neu- A C ron releases one or a few different types of neurotransmitters. Each re- ceptor type responds preferentially to Inhibition Excitation Excitation one type of neurotransmitter. How- Inhibition ever, subtypes of the same receptor may respond differently from one another depending on the neuron or on the part of the brain in which the Under normal conditions, a balance Research suggests that after long-term receptor is located. Inhibitory neuro- exists between excitatory and inhibitory alcohol exposure, the brain attempts transmitters transiently decrease the neurotransmission in the brain. to restore equilibrium by compensating responsiveness of other neurons to for the effects of alcohol; further stimuli, whereas excitatory thus, the brain decreases inhibitory neurotransmitters produce the oppo- neurotransmission and enhances site effect. Some neurotransmitters excitatory neurotransmission. produce longer lasting changes, con- tributing to processes such as B D and memory. Chemical messengers Inhibition called neuromodulators modify the Excitation effects of neurotransmitters. Excitation Successively higher levels of orga- Inhibition nization integrate the various func- tions of adjacent groups of neurons. At the highest level of complexity are Short-term alcohol exposure tilts the During alcohol withdrawal, these neural pathways, sequences of neu- balance toward inhibition by both compensatory changes are no longer rons communicating through several enhancing the function of inhibitory opposed by the presence of alcohol brain regions (Shepherd 1994). neurotransmitters and neuromodulators and the balance shifts toward a state (i.e., GABA, , and ) of excessive excitation. This state of and decreasing the function of excitatory hyperexcitation is characterized by EFFECTS OF SHORT-TERM neurotransmitters (i.e., glutamate and , delirium, and . aspartate). ALCOHOL CONSUMPTION Short-term alcohol consumption de- Schematic representation of alcohol’s effects on the balance of inhibitory and presses brain function by altering the excitatory neurotransmission in the brain. balance between inhibitory and exci- tatory neurotransmission (see figure). Specifically, alcohol can act as a de- by suppression of inhibitory neuro- research, however, shows that alcohol pressant by increasing inhibitory neu- transmitter systems (Pohorecky 1977). does not increase GABA receptor rotransmission, by decreasing A function in some brain regions and excitatory neurotransmission, or under certain experimental conditions. through a combination of both. Alcohol Increases Inhibitory Many factors probably determine Alcohol’s depressant effect on neu- Neurotransmission whether GABAA receptors respond to rons may be associated with some of The main inhibitory neurotransmitter the behavioral manifestations of in- short-term alcohol exposure (Mihic in the brain is gamma-aminobutyric toxication: Alcohol consumption is and Harris 1995). Determining the (GABA). Acting through a recep- initially accompanied by decreased mechanisms by which these factors attention, alterations in memory, tor subtype called GABAA, GABA modulate the receptor’s sensitivity to mood changes, and drowsiness. to a state of and de- alcohol is a major focus of research. Continued acute consumption may creased anxiety. Researchers are focusing much of result in lethargy, confusion, , such as the (e.g., their attention on other inhibitory ¨ loss of sensation, difficulty in breath- Valium ) also act at the GABAA neurotransmitters. Glycine is the major ing, and death (Draski and Deitrich receptor. Some reports suggest that inhibitory neurotransmitter in the 1995). Alcohol’s excitatory actions short-term alcohol exposure increases and brain stem. Alcohol (e.g., reduction of social inhibitions) the inhibitory effect of GABAA recep- has been shown to increase the func- appear to be caused, at least in part, tors (Mihic and Harris 1995). Other tion of glycine receptors in laboratory

VOL. 21, NO. 2, 1997 145 preparations (Valenzuela and Harris synthetic chemical N-methyl-D-aspar- (Weiner et al. 1997; Valenzuela and 1997). Alcohol’s actions on inhibitory tate—and non-NMDA receptors. Harris 1997). neurotransmission in this lower area of Short-term exposure to intoxicating the central may cause concentrations of alcohol appears to some of alcohol’s behavioral effects. inhibit both NMDA and non-NMDA LONG-TERM ALCOHOL Alcohol might also increase in- receptor activity, potentially resulting CONSUMPTION hibitory neurotransmission by increas- in sedation (Valenzuela and Harris Evidence suggests that the brain at- ing the activity of inhibitory neuro- 1997). As in the case of GABA re- A tempts to restore equilibrium after long- modulators, such as adenosine. ceptors, however, these excitatory term alcohol ingestion (see figure). For Activation of the adenosine system receptors are relatively insensitive to causes sedation, whereas inhibition of example, although short-term alcohol intoxicating concentrations of alcohol consumption may increase GABA this system causes . Stimu- under some experimental conditions A lants that inhibit the actions of adeno- receptor function, prolonged drinking (Wright et al. 1996), underscoring the has the opposite effect (Mihic and sine include as well as need for more research in this area. , a chemical found in . Harris 1995; Valenzuela and Harris 1997). This decrease in GABAA func- Animal studies have shown that caf- Investigating Alcohol’s Effects feine and theophylline reduce the tion may result from a decrease in sedative and motor-incoordinating on Memory receptor levels or a change in the pro- effects of alcohol (Dunwiddie 1995), Complex brain functions such as tein composition of the receptor, lead- although these substances do not memory, , , and ing to decreased sensitivity to neuro- alleviate symptoms of intoxication in learning are controlled by multiple transmission. Similarly, glutamate humans. Biochemical evidence indi- neurotransmitter and neuromodulatory receptors appear to adapt to the inhib- cates that short-term exposure to alco- systems acting in concert. In the case itory effects of alcohol by increasing their excitatory activity (Tabakoff and hol of cell cultures in the of memory, researchers have postulat- Hoffman 1996; Valenzuela and Harris laboratory increases the levels of ed that information is stored in the 1997). Additional studies show a com- adenosine that can interact with adeno- brain as a change in the level of com- pensatory decrease in adenosine activi- sine receptors. Thus, an alcohol-in- munication across synapses produced ty following long-term alcohol duced increase in adenosine levels by an external event such as a sight or exposure (Valenzuela and Harris 1997). might be responsible for part of alco- (Bliss and Collingridge 1993). hol’s sedative actions. A phenomenon called long-term po- Neurotransmitter systems may tentiation (LTP) appears to be funda- Tolerance interact to produce the sedative effects mental for memory formation (Bliss of alcohol. An example of such inter- The compensatory changes previously and Collingridge 1993). LTP is a described might be involved in the action occurs in Purkinje cells, a type sudden but lasting increase in the of neuron found in the . In development of alcohol-related behav- overall level of excitatory neurotrans- ior. An example of such behavior is these cells, the increased activation of mission in the , a brain the GABA receptor induced by alco- tolerance (i.e., a person must drink A region involved in memory. In gener- hol occurs only with concurrent acti- progressively more alcohol to obtain a al, LTP seems to require activation of vation of certain receptors for given effect on brain function). For glutamate receptors and inhibition of , a neurotransmitter example, in animals exposed for several GABA receptors. Some studies have with many regulatory functions (Lin A days to alcohol, many neurotransmitter shown that short-term alcohol expo- et al. 1993). Interestingly, alcohol also receptors appear resistant to the short- acts on some receptors for norepine- sure inhibits func- term actions of alcohol on glutamate phrine (LeMarquand et al. 1994; tion (Lovinger et al. 1990) and and GABAA receptors compared with Tabakoff and Hoffman 1996; Valen- stimulates GABAA receptor function animals that have not been exposed to zuela and Harris 1997). in the hippocampus (Weiner et al. alcohol (Valenzuela and Harris 1997). 1994). Therefore, it appears that alco- Investigators have postulated that hol might inhibit LTP. Indeed, Alcohol Inhibits Excitatory tolerance is regulated by connections Morrisett and Swartzwelder (1993) between neurons that produce multi- Neurotransmission reported that short-term alcohol expo- ple neurotransmitters or neuromodula- Alcohol might induce sedative effects sure decreased LTP in the hippocam- tors (Kalant 1993). For example, by reducing excitatory neurotransmis- pus (Bliss and Collingridge 1993). evidence indicates that (a sion. The major excitatory neurotrans- Thus, if LTP does play a role in mem- pituitary with effects on mitters in the brain are the amino ory storage processes, alcohol’s gen- body fluid equilibrium) plays an im- aspartate and glutamate, which eral inhibitory effect on memory portant role in maintaining tolerance act through both NMDA receptors— could be related in part to its effects to alcohol (Tabakoff and Hoffman so named because they respond to the on glutamate and GABA systems 1996). Remarkably, a single exposure

146 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and NeurotransmitterRunning Interactions Heads

to a vasopressinlike chemical while an admit into the neuron in re- ter systems are likely to be important animal is under the effects of alcohol sponse to changes in electrical cur- for the development and maintenance is followed by long-lasting tolerance rents generated in the neuron.2 of alcohol-seeking behaviors. For to alcohol (Kalant 1993). The devel- Short-term alcohol consumption in- example, alcohol has been shown to opment of this long-lasting tolerance hibits calcium flow through these activate systems in certain depends not only on vasopressin but channels. Long-term alcohol exposure areas of the brain (i.e., the limbic also on , norepinephrine, and results, however, in a compensatory system) through an interaction with dopamine—neurotransmitters with increase in calcium flow, which be- glutamate receptors (Koob 1996). multiple regulatory functions (Taba- comes excessive when alcohol con- Moreover, dopamine systems appear koff and Hoffman 1996; Valenzuela sumption ceases. Evidence suggests to be inhibited after alcohol withdraw- and Harris 1997). that medications that inhibit calcium al, and this inhibition can be reversed channel function (i.e., calcium chan- by alcohol consumption (Koob 1996). Alcohol Withdrawal Syndrome nel blockers such as nimodipine) can Interestingly, endogenous sys- relieve the seizures accompanying tems could cause the decrease in the When alcohol consumption is abrupt- alcohol withdrawal (Valenzuela and activity of dopamine systems that ly reduced or discontinued, a with- Harris 1997). occurs during alcohol withdrawal drawal syndrome may follow, (Koob 1996). Of particular impor- characterized by seizures, , tance regarding the role of opiate , , agitation, REINFORCEMENT AND systems in alcohol reinforcement is and confusion (Metten and Crabbe Reinforcement is a key phenomenon in the recent finding that opiate receptor 1995). postulate that this blockers (e.g., ) reduce syndrome represents the hyperactivity the development of addiction to alco- hol and other . Positive reinforce- craving and alcohol consumption of neural adaptive mechanisms no (Valenzuela and Harris 1997). longer balanced by the inhibitory ment is the process by which an action effects of alcohol (see figure). that results in pleasure, or reward, becomes repetitive. Many people find Increased NMDA receptor activity CONCLUSION significantly increases the amount the mental effects of alcohol consump- of calcium that enters nerve cells. tion (e.g., ) rewarding; this Current research strongly suggests Although calcium is essential for effect may lead to positive reinforce- that alcohol affects multiple neuro- nerve cell function, an excess of this ment and persistent alcohol-seeking transmitter systems in the brain. substance within neurons has been behavior. The brain’s adaptive changes Virtually all brain functions depend reported to produce cell or to the continued presence of alcohol on a delicate balance between excita- death. In fact, repeated cycles of alco- result in feelings of discomfort and tory and inhibitory neurotransmission. hol consumption and (e.g., craving when alcohol consumption is Research findings indicate that the ) may cause calcium- abruptly reduced or discontinued. consequences of short- and long-term related (Hunt 1993). These feelings reinforce alcohol-seek- brain exposure to alcohol result from GABA’s role in withdrawal is relat- ing behavior during abstinence. The alterations in this balance. However, ed to decreased inhibitory function. As of behavior based on avoid- many questions remain about the previously noted, long-term alcohol ance of discomfort is called negative effects of alcohol on this delicate reinforcement. Both positive and nega- use may lead to a decrease in GABAA equilibrium. In addition, little is receptor function. In the absence of tive reinforcement play a role in alco- known about the molecular mecha- alcohol, the reduced activity of in- holism (Koob et al. 1994). nisms of craving and addiction. hibitory GABA neurotransmission Reinforcement appears to be regu- Knowledge of the higher levels of might contribute to the anxiety and lated by the interaction of multiple neural integration is required to com- seizures of withdrawal. These symp- neurotransmitter and neuromodulatory pletely determine how alcohol affects toms are treated, at least in part, using systems. Among the neurotransmitter these processes. More important, a systems linked to the reinforcing medications that increase GABAA detailed understanding of alcohol’s receptor function, such as effects of alcohol are dopamine, en- in the brain is a (Valium) and other . dogenous (i.e., morphinelike prerequisite to discovering effective neurotransmitters), GABA, serotonin, The GABAA and NMDA receptor treatments for both alcohol abuse and systems together could be responsible and glutamate acting at the NMDA alcoholism. ■ for a significant portion of the alcohol receptor (Koob 1996). Complex inter- withdrawal syndrome. Changes in actions between these neurotransmit- other neural systems might also be REFERENCES important in withdrawal, however. 2Although neurons communicate with one BLISS, T.V.P., AND COLLINGRIDGE, G.L. A syn- Voltage-sensitive calcium channels another chemically, signals travel through a aptic model of memory: Long-term potentiation are pores in the that neuron in the form of an electric current. in the hippocampus. 361:31Ð39, 1993.

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THE PHYSICIANS’ GUIDE TO HELPING PATIENTS

This easy-to-follow manual provides primary care physicians and other health care professionals with guidelines on the use of screening and brief intervention procedures for patients at risk for alcohol problems. The brief intervention procedures are designed for use in primary care settings during routine patient visits. Also available is the companion brochure for patients, “How to Cut Down on Your Drinking,” presenting tips for those whose doctors have advised them to reduce their alcohol consumption and are taking steps to follow that advice.

To order your free copies of the Physicians’ Guide and the patient brochure, write to: National Institute on Alcohol Abuse and Alcoholism, Publication Distribution Center, P.O. Box 10686, Rockville, MD 20849Ð0686. Fax: (202) 842Ð0418. Full text of both publications is available on NIAAA’s World Wide Web site at http://www.niaaa.nih.gov

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