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 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 molecules as havior. An important finding is the well as clues to their role in behavior. demonstration that alcohol can affect 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 neurons is neurotransmitters and the receptors to complex as alcoholism. 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 attention to synapses) between individual neurons. Department of Pharmacology, 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 receptor proteins 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. 177–179. 144 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and NeurotransmitterRunning Interactions Heads One neuron 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 depressant 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 learning 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, glycine, and adenosine) 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 seizures, delirium, and anxiety. 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 acid (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. leads to a state of sedation and de- alcohol is a major focus of research. Continued acute consumption may creased anxiety. Sedative medications Researchers are focusing much of result in lethargy, confusion, amnesia, such as the benzodiazepines (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 spinal cord 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 nervous system 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 stimulation. 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 caffeine as well as need for more research in this area. theophylline, a chemical found in tea. 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, consciousness, alertness, 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