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144 ALCOHOL HEALTH & RESEARCH WORLD
Scientists have long sought themechanisms by which alcoholacts on the brain to modify be- havior. An important finding is the demonstration that alcohol can affect the function of specific neurotransmit- ters1 (Lovinger et al. 1989). Studies of neurotransmitters and the receptors to
which they bind have provided data on both the structure and the mecha- nism of action of these molecules as well as clues to their role in behavior. However, the function of individual neurotransmitters and their receptors cannot entirely explain a syndrome as complex as alcoholism.
Neurotransmitter systems do not function in isolation. Therefore, scien- tists are paying increasing attention to the integration of communication systems in the brain. Although the study of neural integration is in its infancy, enough has been learned to help guide future research. This article suggests mechanisms by which alco- hol consumption may affect multiple
neurotransmitter systems to influence behavior.
NEUROTRANSMITTER SYSTEMS WORK TOGETHER
Communication among neurons is organized in interacting levels. The most basic level of complexity is the arrangement of connections (i.e., synapses) between individual neurons.
Alcohol and Neurotransmitter
Interactions C. FERNANDO VALENZUELA, M.D., PH.D.
Evidence suggests that alcohol affects brain function by interacting with multiple neurotransmitter systems, thereby disrupting the delicate balance between inhibitory and excitatory neurotransmitters. 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 lead to the development of craving and alcohol-seeking behavior. KEY WORDS: neurotransmitter receptors; neurotransmission; AODE (alcohol and other drug effects); AOD use behavior; AOD tolerance; AOD withdrawal syndrome; AOD craving; biological inhibition; memory; reinforcement; biochemical mechanism; literature review
C. FERNANDO VALENZUELA, M.D., PH.D., is an instructor in the Department of Pharmacology, University of Colorado, Health Sciences Center, Denver, Colorado.
Support for this work was provided by National Institute on Alcohol Abuse and Alcoholism grant AA00227.
1Nerve cells (i.e., neurons) communicate by releasing chemical messengers called neuro- transmitters, which bind to receptor proteins on the surface of other neurons. This process is called neurotransmission. For definitions of technical terms used in this article, see central glossary, pp. 177–179.
One neuron may connect with up to hundreds or thousands of adjacent neurons (Shepherd 1994). Each neu- ron releases one or a few different types of neurotransmitters. Each re- ceptor type responds preferentially to one type of neurotransmitter. How- 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 receptor is located. Inhibitory neuro- transmitters transiently decrease the responsiveness of other neurons to further stimuli, whereas excitatory neurotransmitters produce the oppo- site effect. Some neurotransmitters produce longer lasting changes, con- tributing to processes such as learning and memory. Chemical messengers called neuromodulators modify the effects of neurotransmitters.
Successively higher levels of orga- nization integrate the various func- tions of adjacent groups of neurons. At the highest level of complexity are neural pathways, sequences of neu- rons communicating through several brain regions (Shepherd 1994).
EFFECTS OF SHORT-TERM ALCOHOL CONSUMPTION
Short-term alcohol consumption de- presses brain function by altering the balance between inhibitory and exci- tatory neurotransmission (see figure). Specifically, alcohol can act as a de- pressant by increasing inhibitory neu- rotransmission, by decreasing excitatory neurotransmission, or through a combination of both. Alcohol’s depressant effect on neu- rons may be associated with some of the behavioral manifestations of in- toxication: Alcohol consumption is initially accompanied by decreased attention, alterations in memory, mood changes, and drowsiness. Continued acute consumption may result in lethargy, confusion, amnesia, loss of sensation, difficulty in breath- ing, and death (Draski and Deitrich 1995). Alcohol’s excitatory actions (e.g., reduction of social inhibitions) appear to be caused, at least in part,
by suppression of inhibitory neuro- transmitter systems (Pohorecky 1977).
Alcohol Increases Inhibitory Neurotransmission The main inhibitory neurotransmitter in the brain is gamma-aminobutyric acid (GABA). Acting through a recep- tor subtype called GABAA, GABA leads to a state of sedation and de- creased anxiety. Sedative medications such as the benzodiazepines (e.g., Valium®) also act at the GABAA receptor. Some reports suggest that short-term alcohol exposure increases the inhibitory effect of GABAA recep- tors (Mihic and Harris 1995). Other
research, however, shows that alcohol does not increase GABAA receptor function in some brain regions and under certain experimental conditions. Many factors probably determine whether GABAA receptors respond to short-term alcohol exposure (Mihic and Harris 1995). Determining the mechanisms by which these factors modulate the receptor’s sensitivity to alcohol is a major focus of research.
Researchers are focusing much of their attention on other inhibitory neurotransmitters. Glycine is the major inhibitory neurotransmitter in the spinal cord and brain stem. Alcohol has been shown to increase the func- tion of glycine receptors in laboratory
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Running HeadsAlcohol and Neurotransmitter Interactions
Inhibition Excitation
Inhib ition
Exci tatio
n Inhibition
Excitation
Inhibition Excitation
A
B
C
D
Schematic representation of alcohol’s effects on the balance of inhibitory and excitatory neurotransmission in the brain.
Under normal conditions, a balance exists between excitatory and inhibitory neurotransmission in the brain.
Short-term alcohol exposure tilts the balance toward inhibition by both enhancing the function of inhibitory neurotransmitters and neuromodulators (i.e., GABA, glycine, and adenosine) and decreasing the function of excitatory neurotransmitters (i.e., glutamate and aspartate).
Research suggests that after long-term alcohol exposure, the brain attempts to restore equilibrium by compensating for the depressant effects of alcohol; thus, the brain decreases inhibitory neurotransmission and enhances excitatory neurotransmission.
During alcohol withdrawal, these compensatory changes are no longer opposed by the presence of alcohol and the balance shifts toward a state of excessive excitation. This state of hyperexcitation is characterized by seizures, delirium, and anxiety.
preparations (Valenzuela and Harris 1997). Alcohol’s actions on inhibitory neurotransmission in this lower area of the central nervous system may cause some of alcohol’s behavioral effects.
Alcohol might also increase in- hibitory neurotransmission by increas- ing the activity of inhibitory neuro- modulators, such as adenosine. Activation of the adenosine system causes sedation, whereas inhibition of this system causes stimulation. Stimu- lants that inhibit the actions of adeno- sine include caffeine as well as theophylline, a chemical found in tea. Animal studies have shown that caf- feine and theophylline reduce the sedative and motor-incoordinating effects of alcohol (Dunwiddie 1995), although these substances do not alleviate symptoms of intoxication in humans. Biochemical evidence indi- cates that short-term exposure to alco- hol of nerve cell cultures in the laboratory increases the levels of adenosine that can interact with adeno- sine receptors. Thus, an alcohol-in- duced increase in adenosine levels might be responsible for part of alco- hol’s sedative actions.
Neurotransmitter systems may interact to produce the sedative effects of alcohol. An example of such inter- action occurs in Purkinje cells, a type of neuron found in the cerebellum. In these cells, the increased activation of the GABAA receptor induced by alco- hol occurs only with concurrent acti- vation of certain receptors for norepinephrine, a neurotransmitter with many regulatory functions (Lin et al. 1993). Interestingly, alcohol also acts on some receptors for norepine- phrine (LeMarquand et al. 1994; Tabakoff and Hoffman 1996; Valen- zuela and Harris 1997).
Alcohol Inhibits Excitatory Neurotransmission Alcohol might induce sedative effects by reducing excitatory neurotransmis- sion. The major excitatory neurotrans- mitters in the brain are the amino acids aspartate and glutamate, which act through both NMDA receptors— so named because they respond to the
synthetic chemical N-methyl-D-aspar- tate—and non-NMDA receptors. Short-term exposure to intoxicating concentrations of alcohol appears to inhibit both NMDA and non-NMDA receptor activity, potentially resulting in sedation (Valenzuela and Harris 1997). As in the case of GABAA re- ceptors, however, these excitatory receptors are relatively insensitive to intoxicating concentrations of alcohol under some experimental conditions (Wright et al. 1996), underscoring the need for more research in this area.
Investigating Alcohol’s Effects on Memory Complex brain functions such as memory, consciousness, alertness, and learning are controlled by multiple neurotransmitter and neuromodulatory systems acting in concert. In the case of memory, researchers have postulat- ed that information is stored in the brain as a change in the level of com- munication across synapses produced by an external event such as a sight or sound (Bliss and Collingridge 1993). A phenomenon called long-term po- tentiation (LTP) appears to be funda- mental for memory formation (Bliss and Collingridge 1993). LTP is a sudden but lasting increase in the overall level of excitatory neurotrans- mission in the hippocampus, a brain region involved in memory. In gener- al, LTP seems to require activation of glutamate receptors and inhibition of GABAA receptors. Some studies have shown that short-term alcohol expo- sure inhibits glutamate receptor func- tion (Lovinger et al. 1990) and stimulates GABAA receptor function in the hippocampus (Weiner et al. 1994). Therefore, it appears that alco- hol might inhibit LTP. Indeed, Morrisett and Swartzwelder (1993) reported that short-term alcohol expo- sure decreased LTP in the hippocam- pus (Bliss and Collingridge 1993). Thus, if LTP does play a role in mem- ory storage processes, alcohol’s gen- eral inhibitory effect on memory could be related in part to its effects on glutamate and GABA systems
(Weiner et al. 1997; Valenzuela and Harris 1997).
LONG-TERM ALCOHOL CONSUMPTION
Evidence suggests that the brain at- tempts to restore equilibrium after long- term alcohol ingestion (see figure). For example, although short-term alcohol consumption may increase GABAA receptor function, prolonged drinking has the opposite effect (Mihic and Harris 1995; Valenzuela and Harris 1997). This decrease in GABAA func- tion may result from a decrease in receptor levels or a change in the pro- tein composition of the receptor, lead- ing to decreased sensitivity to neuro- transmission. Similarly, glutamate receptors appear to adapt to the inhib- itory effects of alcohol by increasing their excitatory activity (Tabakoff and Hoffman 1996; Valenzuela and Harris 1997). Additional studies show a com- pensatory decrease in adenosine activi- ty following long-term alcohol exposure (Valenzuela and Harris 1997).
Tolerance The compensatory changes previously described might be involved in the development of alcohol-related behav- ior. An example of such behavior is tolerance (i.e., a person must drink progressively more alcohol to obtain a given effect on brain function). For example, in animals exposed for several days to alcohol, many neurotransmitter receptors appear resistant to the short- term actions of alcohol on glutamate and GABAA receptors compared with animals that have not been exposed to alcohol (Valenzuela and Harris 1997).
Investigators have postulated that tolerance is regulated by connections between neurons that produce multi- ple neurotransmitters or neuromodula- tors (Kalant 1993). For example, evidence indicates that vasopressin (a pituitary hormone with effects on body fluid equilibrium) plays an im- portant role in maintaining tolerance to alcohol (Tabakoff and Hoffman 1996). Remarkably, a single exposure
146 ALCOHOL HEALTH & RESEARCH WORLD
to a vasopressinlike chemical while an animal is under the effects of alcohol is followed by long-lasting tolerance to alcohol (Kalant 1993). The devel- opment of this long-lasting tolerance depends not only on vasopressin but also on serotonin, norepinephrine, and dopamine—neurotransmitters with multiple regulatory functions (Taba- koff and Hoffman 1996; Valenzuela and Harris 1997).
Alcohol Withdrawal Syndrome When alcohol consumption is abrupt- ly reduced or discontinued, a with- drawal syndrome may follow, characterized by seizures, tremor, hallucinations, insomnia, agitation, and confusion (Metten and Crabbe 1995). Scientists postulate that this syndrome represents the hyperactivity of neural adaptive mechanisms no longer balanced by the inhibitory effects of alcohol (see figure).
Increased NMDA receptor activity significantly increases the amount of calcium that enters nerve cells. Although calcium is essential for nerve cell function, an excess of this substance within neurons has been reported to produce cell toxicity or death. In fact, repeated cycles of alco- hol consumption and abstinence (e.g., binge drinking) may cause calcium- related brain damage (Hunt 1993).
GABA’s role in withdrawal is relat- ed to decreased inhibitory function. As previously noted, long-term alcohol use may lead to a decrease in GABAA receptor function. In the absence of alcohol, the reduced activity of in- hibitory GABA neurotransmission might contribute to the anxiety and seizures of withdrawal. These symp- toms are treated, at least in part, using medications that increase GABAA receptor function, such as diazepam (Valium) and other sedatives.
The GABAA and NMDA receptor systems together could be responsible for a significant portion of the alcohol withdrawal syndrome. Changes in other neural systems might also be important in withdrawal, however. Voltage-sensitive calcium channels are pores in the cell membrane that
admit calcium into the neuron in re- sponse to changes in electrical cur- rents generated in the neuron.2 Short-term alcohol consumption in- hibits calcium flow through these channels. Long-term alcohol exposure results, however, in a compensatory increase in calcium flow, which be- comes excessive when alcohol con- sumption ceases. Evidence suggests that medications that inhibit calcium channel function (i.e., calcium chan- nel blockers such as nimodipine) can relieve the seizures accompanying alcohol withdrawal (Valenzuela and Harris 1997).
REINFORCEMENT AND ADDICTION Reinforcement is a key phenomenon in the development of addiction to alco- hol and other drugs. Positive reinforce- ment is the process by which an action that results in pleasure, or reward, becomes repetitive. Many people find the mental effects of alcohol consump- tion (e.g., euphoria) rewarding; this effect may lead to positive reinforce- ment and persistent alcohol-seeking behavior. The brain’s adaptive changes to the continued presence of alcohol result in feelings of discomfort and craving when alcohol consumption is abruptly reduced or discontinued. These feelings reinforce alcohol-seek- ing behavior during abstinence. The motivation of behavior based on avoid- ance of discomfort is called negative reinforcement. Both positive and nega- tive reinforcement play a role in alco- holism (Koob et al. 1994).
Reinforcement appears to be regu- lated by the interaction of multiple neurotransmitter and neuromodulatory systems. Among the neurotransmitter systems linked to the reinforcing effects of alcohol are dopamine, en- dogenous opiates (i.e., morphinelike neurotransmitters), GABA, serotonin, and glutamate acting at the NMDA receptor (Koob 1996). Complex inter- actions between these neurotransmit-
ter systems are likely to be important for the development and maintenance of alcohol-seeking behaviors. For example, alcohol has been shown to activate dopamine systems in certain areas of the brain (i.e., the limbic system) through an interaction with glutamate receptors (Koob 1996). Moreover, dopamine systems appear to be inhibited after alcohol withdraw- al, and this inhibition can be reversed by alcohol consumption (Koob 1996). Interestingly, endogenous opiate sys- tems could cause the decrease in the activity of dopamine systems that occurs during alcohol withdrawal (Koob 1996). Of particular impor- tance regarding the role of opiate systems in alcohol reinforcement is the recent finding that opiate receptor blockers (e.g., naltrexone) reduce craving and alcohol consumption (Valenzuela and Harris 1997).
CONCLUSION
Current research strongly suggests that alcohol affects multiple neuro- transmitter systems in the brain. Virtually all brain functions depend on a delicate balance between excita- tory and inhibitory neurotransmission. Research findings indicate that the consequences of short- and long-term brain exposure to alcohol result from alterations in this balance. However, many questions remain about the effects of alcohol on this delicate equilibrium. In addition, little is known about the molecular mecha- nisms of craving and addiction. Knowledge of the higher levels of neural integration is required to com- pletely determine how alcohol affects these processes. More important, a detailed understanding of alcohol’s mechanism of action in the brain is a prerequisite to discovering effective treatments for both alcohol abuse and alcoholism. ■
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2Although neurons communicate with one another chemically, signals travel through a neuron in the form of an electric current.
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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.
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