The Role of in ’s Effects on the Brain

David M. Lovinger, Ph.D. Serotonin is an important brain chemical that acts as a Department of Molecular to communicate information among nerve cells. Serotonin’s actions have Physiology and Biophysics been linked to alcohol’s effects on the brain and to alcohol abuse. Vanderbilt University School of Medicine Alcoholics and experimental animals that consume large quantities of Nashville, TN 37232-0615 alcohol show evidence of differences in brain serotonin levels compared with nonalcoholics. Both short- and long-term alcohol exposures also affect the serotonin receptors that convert the chemical signal produced by serotonin into functional changes in the signal-receiving cell. that act on these receptors alter alcohol consumption in both humans and animals. Serotonin, along with other , also may contribute to alcohol’s intoxicating and rewarding effects, and abnormalities in the brain’s serotonin system appear to play an important role in the brain processes underlying alcohol abuse.

Neurotransmitters are chemicals This article reviews serotonin’s plays an important role in the control that allow signal transmission, and function in the brain and the conse- of emotions, and the nucleus accum- thus communication, among nerve quences of acute and chronic alcohol bens, a brain area involved in con- cells (i.e., neurons). One neurotrans- consumption on serotonin-mediated trolling the motivation to perform mitter used by many neurons (i.e., serotonergic) signal transmis- certain behaviors, including the throughout the brain is serotonin, sion. In addition, the article summa- abuse of alcohol and other drugs. In also known as 5-hydroxytryptamine rizes recent findings indicating that these brain regions, the axon endings (5-HT). Serotonin released by the serotonin may play a pivotal role in of the serotonergic neurons secrete signal-emitting neuron subtly alters the development of alcohol abuse. serotonin when activated. The the function of the signal-receiving neurotransmitter then traverses the neurons in a process called neuro- Serotonin’s Functions small space separating the neurons modulation. For example, in some in the Brain from each other (i.e., the synaptic neurons serotonin alters the rate at cleft) and binds to specialized dock- which the cells produce the electrical Serotonin is produced in and re- ing molecules (i.e., receptors) on the signals (i.e., action potentials) used leased from neurons that originate recipient cell. for relaying information within the within discrete regions, or nuclei, in The binding of serotonin to its cells, whereas in other neurons it the brain (1). Many serotonergic receptors initiates a series of bio- modulates the release of other neuro- neurons are located at the base of the chemical events that converts the ex- transmitters. Although serotonin’s brain in an area known as the raphe tracellular, chemical signal into an effect on individual neurons can be nucleus, which influences brain intracellular signal in the recipient rather modest, its overall effect on functions related to attention, emo- cell. For example, the interaction of the neurons in a given brain area can tion, and motivation. The axons of serotonin with one type of substantially influence brain func- the neurons in the raphe nucleus ex- stimulates the formation of small tions such as learning and memory, tend, or project, throughout the molecules (i.e., second messengers) perception of the environment, brain to numerous regions with di- within the cell. Second messengers mood states, and responses to alco- verse functions. These brain regions interact with other proteins to acti- hol and other drugs of abuse. include the amygdala, an area that vate various cellular functions, such

23 Current Separations 18:1 (1999) F1 products generated after the neuro- Activation of serotonin transmitter has been removed from receptors (5-HTR) produces multiple effects the (i.e., serotonin metabo- on neurons. Serotonin 5-HT + lites). The concentrations of these (5-HT) can bind to receptors that activate metabolites, which can be deter- proteins within the cell + 5-HT3 R mined from samples of blood, urine, called G proteins. 5-HT Activation of these Ion or the fluid that bathes the brain and proteins, in turn, affects channel spinal cord (i.e., cerebrospinal fluid ion channels in the cell membranes and [CSF]) (3,4,5), provide an indirect induces the formation Direct measure of changes in the overall of signaling molecules 5-HTR G protein activation serotonin level in the brain. (i.e., second-messenger of neuron molecules). Second messengers also can act Second-messenger molecules on ion channels or travel Acute Alcohol Effects on the to the nucleus to alter Brain’s Serotonin Systems gene expression. Other Cell serotonin-activated nucleus receptors (i.e., the 5-HT Alcohol interacts with serotoner- receptors) double as ion3 channels. Their activation gic synaptic transmission in the brain directly excites neurons. in several ways. Even single-episode (i.e., acute) alcohol exposure alters various aspects of serotonin’s synap- T1 functions. In humans, for exam- Serotonin receptor Receptor Potential Role in the ple, the levels of serotonin subtypes and their Subtypes Development of Alcohol Abuse potential roles in the metabolites in the urine and blood development of May control consummatory behavior, including alcohol increase after a single drinking ses- alcohol abuse. 5-HT1A consumption. sion, indicating increased serotonin May contribute to alcohol’s intoxicating effects. May play release in the (3). 5-HT 1B a role in development of tolerance to alcohol’s effects. This increase may reflect enhanced signal transmission at serotonergic May contribute to development of alcohol withdrawal 5-HT 2 symptoms. May play a role in alcohol’s rewarding effects. . Animal studies also have found that acute alcohol exposure May regulate alcohol consumption. May contribute to 5-HT3 elevates serotonin levels within the alcohol’s rewarding effects. brain (6,7), suggesting either that more serotonin is released from the serotonergic axons or that the neuro- as changes in the cell’s electrical ac- cells’ exposure to serotonin, thereby transmitter is cleared more slowly tivity or in the activity of certain disrupting the exquisite timing of from the synapses. For example, in- genes (see F1). These changes can nerve signals within the brain. The creased serotonin release after acute result either in the inhibition or the net result of such disruptions is ab- alcohol exposure has been observed excitation of the signal-receiving normal brain activity, which can lead in brain regions that control the con- neuron, depending on the cell af- to psychological problems or mental sumption or use of numerous sub- fected. Through these mechanisms, illness. One prominent example of stances, including many drugs of serotonin can influence mood states; psychological disorder that appears abuse (7). Researchers currently are thinking patterns; and even behav- to involve inappropriate serotonin trying to determine the exact mecha- iors, such as alcohol drinking. use in the brain is depression (2); nisms underlying the alcohol-in- Serotonin’s actions at the syn- some of the most effective antide- duced changes. For example, they apses normally are tightly regulated pressant act on the sero- are investigating whether the net in- by proteins called serotonin trans- tonin transporters to prolong the crease in synaptic serotonin levels porters, which remove the neuro- neurotransmitter’s activity. results from alcohol’s direct actions transmitter from the synaptic cleft Researchers currently cannot di- on molecules involved in serotonin after a short period of time by trans- rectly measure serotonin concentra- release and uptake or from more in- porting it back into the signal-emit- tions in the human brain or within the direct alcohol effects. ting cell. Consequently, serotonin synapses in laboratory animals. To Alcohol also interferes with the can affect neighboring neurons only gain information about serotonin function of serotonin receptors. Sev- for a short period of time. Any inter- levels in the brain, physicians and eral types of these receptors exist, ference with serotonin transporter researchers have measured the con- including the 5-HT1A, 5-HT1B,5- function extends or diminishes the centrations of serotonin breakdown HT2 and 5-HT3 receptors (see T1).

Current Separations 18:1 (1999) 24 When activated by serotonin bind- process, also called tolerance devel- ciated with impulsive violence and ing, the 5-HT3 receptor rapidly in- opment, presumably is a mechanism other behavioral disorders (5). creases neuron activity by to re-establish normal cell function, generating electrical signals (8). or homeostasis, in response to con- Serotonin’s Role in the Acute alcohol exposure enhances the tinuous alcohol-induced alterations. Development of Alcohol electrical signals generated by the For example, if alcohol exposure in- Abuse 5-HT3 receptor. This change in re- hibits the function of a neurotrans- ceptor function likely results from mitter receptor, the cells may Two lines of evidence suggest alcohol’s direct action on the recep- attempt to compensate for continu- that serotonin may be a key contribu- tor protein or molecules closely as- ous inhibition by increasing the re- tor to the brain dysfunction that leads sociated with the receptor in the cell ceptor numbers or by altering the to alcohol abuse: [1] analyses of se- membrane (8,9). Increased 5-HT3 molecular makeup of receptors or rotonin levels in alcoholics and non- receptor function probably causes cell membranes so that alcohol no alcoholics and [2] studies of drugs excessive stimulation of neurons in longer inhibits receptor function. that block serotonin receptors and brain regions receiving information The 5-HT2 receptor appears to un- serotonin transporters. from serotonergic neurons. As a re- dergo such adaptive changes (11). sult of this stimulation, the release of Thus, the number of 5-HT2 receptor Serotonin Levels other neurotransmitters that play key molecules and the chemical signals in Alcoholics roles in alcohol intoxication may be produced by the activation of this The first line of evidence impli- increased. The contribution of the receptor increase in laboratory ani- cating serotonin in the development 5-HT3 receptor to the effects of acute mals that receive alcohol for several of alcohol abuse was the discovery and chronic alcohol consumption is weeks. of a relationship between alcoholism discussed later in this article. Increased serotonin activity at and the levels of serotonin metabo- The effects of acute alcohol con- the 5-HT2 receptor caused by lites in the urine and CSF of human sumption on serotonin receptors chronic alcohol exposure also may alcoholics. For example, the concen- also have been investigated in so- contribute to the alcohol withdrawal trations of the first serotonin degra- called knockout mice, in whom cer- syndrome — the pattern of behaviors dation product, 5-hydroxyindole- tain genes (e.g., those coding for occurring when alcohol is withheld acetic acid, were lower in the CSF of different serotonin receptors) have after chronic use. For example, alco- alcoholics than in nonalcoholics of been experimentally inactivated so holics frequently experience in- the same age and general health that the animals cannot produce the creased anxiety levels after cessation status (3,4,5), an observation sug- protein encoded by those genes. By of drinking. This withdrawal symp- gesting that alcoholics may have re- studying knockout mice that lack a tom may involve enhanced serotonin duced serotonin levels in the brain. particular receptor, researchers can activity at the 5-HT2 receptors; in Several mechanisms could account assess that receptor’s role in specific animal models of alcohol with- for such a decrease in brain serotonin aspects of brain functioning and be- drawal, drugs that blocked the acti- levels. For example, the brain cells havior, including responses to alco- vation of this receptor (i.e., 5-HT2 could produce less serotonin, release hol and alcohol consummatory antagonists) prevented behavior in- less serotonin into the synapse, or behavior. For example, scientists dicative of increased anxiety (12). take more serotonin back up into the have studied a strain of knockout The effects of chronic alcohol cells. Alternatively, the serotonin mice lacking the 5-HT1B receptor consumption also were investigated metabolite levels in alcoholics could with respect to the effects of acute in the 5-HT1B receptor knockout be reduced, because less serotonin is alcohol exposure (10). These ani- mice discussed in the previous sec- broken down in the brain. To date, mals exhibited reduced intoxication tion. Compared with normal mice, the exact mechanisms underlying the in response to a single dose of alco- the knockout mice showed less evi- changes in serotonin-metabolite lev- hol compared with normal mice, in- dence of tolerance to alcohol’s ef- els are still unknown. dicating that 5-HT1B receptor fects (10). Interestingly, the Researchers currently are trying activity produces some of alcohol’s knockout mice also demonstrated in- to determine whether alcoholics intoxicating effects. creased aggressive behavior, even in with abnormal serotonin metabolite the absence of alcohol consumption. levels have specific variations in the Effects of Chronic Alcohol A similar association between alco- gene that codes for the tryp- Exposure on Serotonergic holism and aggression exists in some tophan hydroxylase, which produces Synaptic Transmission alcoholics. Consequently, the 5- serotonin from other molecules in HT1B receptor knockout mice may the cells. Several variants of the tryp- Long-term, or chronic, alcohol serve as a model for the alcoholism tophan hydroxylase gene exist; one exposure can lead to adaptive subtype that is characterized by an variant appears to be particularly changes within brain cells. This early age at onset and often is asso- common in alcoholics with histories

25 Current Separations 18:1 (1999) of aggression and suicidal tenden- depression (2). Experimental ani- gest that may help reduce cies (5). mals treated with this and related anxiety in alcoholics with anxiety The relationship between sero- compounds exhibited reduced alco- disorders, thereby possibly improv- tonin levels and alcohol consump- hol consumption (4,6). Similarly, al- ing their compliance with therapeu- tion also has been investigated in coholics taking drank less tic regimens. animal models of alcohol abuse. frequently and reduced their alcohol SSRIs also are useful in treat- Some of the most intriguing findings consumption during drinking ses- ing anxiety, depression, and other have come from work on rats that sions (3,4,16,17). The alcoholics mood disorders that result at least were selectively bred for alcohol also reported less desire to drink and in part from dysfunctional seroton- preference (P rats) or non-preference fewer pleasurable feeling after ergic signal transmission in the (NP rats), based on the amounts of drinking. Fluoxetine reduces alcohol brain (2). Many alcoholics suffer alcohol that they would drink when consumption in humans only moder- from these mood disorders. Ac- given a choice between alcoholic or ately, however, and does not affect all cordingly, drugs that target sero- nonalcoholic solutions. alcoholics (16). Moreover, although tonergic signal transmission may When the concentrations of dif- increased serotonin levels at the syn- reduce alcohol consumption partly ferent neurotransmitters were deter- apses in the brain can moderate alco- by improving the co-occurring psy- mined in various brain regions of hol consumption, additional factors chiatric problems and thus elimi- these animals, the levels of serotonin contribute to continued alcohol nating the need for self- and its metabolites were lower in P abuse. Consequently, SSRIs cannot with alcohol. To some extent, how- rat brains than in NP rat brains. The be recommended as the sole treat- ever, the effects of SSRIs on alco- differences were particularly pro- ment for alcoholism. hol consumption appear to be nounced in the nucleus accumbens, Other drugs that affect serotoner- unrelated to the medications’ anti- a brain area thought to be involved in gic signal transmission also alter al- depressant or anxiolytic effects the rewarding effects of ethanol cohol consumption in animals (6). (20). The effects of SSRIs and other (6,13). Moreover, the P rats had For example, antagonists of the 5- serotonergic medications on alcohol fewer serotonergic neurons in the ra- HT3 and 5-HT1A receptors reduced abuse will be difficult to disentangle phe nucleus compared with the NP alcohol ingestion in rodents from their effects on co-occurring rats (14), a finding that could explain (4,15,16). However, the 5-HT1A re- mental disorders. Nevertheless, the the reduced serotonin and serotonin- ceptor antagonists also altered food information currently available metabolite levels. The observation and water intake, suggesting that this clearly indicates that serotonergic that P rats naturally have low sero- receptor may modulate general con- signal transmission plays an impor- tonin levels supports the hypothesis summatory behavior rather than spe- tant role in alcohol abuse and there- that heavy drinking may partly rep- cifically reduce the desire to drink fore may yet be a target for therapies resent an attempt to normalize sero- alcohol. In humans, the 5-HT3 recep- to reduce alcohol consumption. tonin levels in certain key brain tor antagonist reduced regions, because acute alcohol con- total alcohol consumption and the Interactions Between sumption can elevate serotonin lev- desire to drink in alcoholics; as with Serotonin and Other els. Recent studies also have the SSRIs, however, this effect was Neurotransmitters evaluated the numbers and proper- relatively modest (4,18,19). ties of different serotonin receptors More research is needed to deter- Serotonin does not act alone in P and NP rats. These studies found mine how and under what drinking within the brain. Instead, serotoner- that P rats have fewer 5-HT1A recep- conditions alcohol consumption is gic neurons are parts of larger cir- tor molecules than do NP rats (15). affected by different serotonin re- cuits of interconnected neurons that ceptor antagonists. In addition, re- transmit information within and Effects of Serotonin searchers must investigate whether among brain regions. Many neurons Uptake Inhibitors the effects of these drugs vary within these circuits release neuro- The second line of evidence im- among subgroups of alcoholics transmitters other than serotonin. plicating serotonin in the develop- (e.g., alcoholics with different Accordingly, some of the serotonin- ment of alcohol abuse stems from drinking patterns or with co-occur- mediated neuronal responses to alco- studies of compounds that interfere ring mental disorders). For example, hol may arise from interactions with the functions of the transporters recent evidence indicates that buspi- between serotonin and other neuro- that remove serotonin from the syn- rone — an agent that binds to the transmitters. These neurotransmit- apse. These agents also are called 5-HT1A receptor and which is used ters also may be affected by alcohol. selective serotonin re-uptake inhibi- as an anxiety-reducing (i.e., anx- Two key neurotransmitters that in- tors (SSRIs). One of these agents, iolytic) medication — also increases teract with the serotonergic system  fluoxetine (Prozac ), is used widely the time of abstinence from heavy are gamma-aminobutyric acid for treating mood disorders, such as drinking (4,16). These findings sug- (GABA) and .

Current Separations 18:1 (1999) 26 Interactions with GABA neurons) reside at the results of studies in animal models GABA is the major inhibitory base of the brain and communicate (23,27,28), which also found that 5- neurotransmitter in the brain (1) — signals to brain regions involved in HT3 receptor antagonists interfered that is, it tends to reduce the activity the rewarding effects of many drugs with the serotonin-induced of the signal-receiving neuron. of abuse, including alcohol (24). For dopamine release in the brain’s re- Many drugs that enhance GABA’s example, alcohol consumption in- ward systems. These findings may actions in the brain (e.g., the ben- duces a dopamine surge in the brain, help explain the antagonists’ ability  zodiazepine Valium ) cause seda- which is thought to signal to the to reduce drinking behavior. tion and intoxication that resemble brain the importance of this action, These examples demonstrate that the effects of alcohol. In fact, alcohol thereby indicating that alcohol con- serotonin interacts with other neuro- may produce some of its sedative and sumption is an action that should be transmitters in several ways to pro- intoxicating effects by enhancing continued. Such a response to alco- mote alcohol’s intoxicating and GABA’s inhibitory function (21). hol ingestion easily could contribute rewarding effects. Serotonin also may Serotonin may interact with to the development of an addiction to interact with additional neurotrans- GABA-mediated signal transmission alcohol, because these brain re- mitters that have been found to con- by exciting the neurons that produce sponses would tend to reinforce al- tribute to alcohol’s effects on the brain. and secrete GABA (i.e., GABAergic cohol drinking and thus increase neurons). For example, serotonin can consumption. Summary increase the activity of GABAergic Serotonin can alter dopaminer- neurons in the hippocampal forma- gic signal transmission in several Serotonin plays an important tion (22), a part of the brain that is ways. For example, by interacting role in mediating alcohol’s effects on important for memory formation and with the 5-HT2 receptor, serotonin the brain. Alcohol exposure alters other cognitive functions. Conse- stimulates the activity of dopaminer- several aspects of serotonergic signal quently, alcohol’s effects on sero- gic neurons in a brain region called transmission in the brain. For exam- tonin may alter the activity of the ventral tegmental area (VTA), ple, alcohol modulates the serotonin GABAergic neurons in the hippo- thereby enhancing an alcohol-in- levels in the synapses and modifies campal formation. These changes duced increase in the activity of these the activities of specific serotonin may disrupt cognition and possibly neurons (25) and causing increased receptor proteins. Abnormal sero- contribute to alcohol-induced mem- dopamine release (26). The tonin levels within synapses may ory loss and impaired judgment. dopaminergic neurons in the VTA contribute to the development of al- To activate hippocampal are connected to the brain areas cohol abuse, because some studies GABAergic neurons, serotonin thought to mediate rewarding ef- have found that the levels of chemi- binds to the 5-HT3 receptor. This fects. Thus, the serotonin-dependent cal markers representing serotonin receptor is present in many brain re- activation of these neurons could re- levels in the brain are reduced in gions (23) and may reside on inforce alcohol-drinking behavior. alcoholic humans and chronically al- GABAergic neurons. As discussed This scenario suggests that sero- cohol-consuming animals. More- previously, alcohol increases the ac- tonin, through its interaction with the over; SSRI’s and receptor tivity of this receptor. Increased 5- dopaminergic system, may play a antagonists can reduce consumption HT3 activity results in enhanced pivotal role in producing alcohol’s in humans and animals, although GABAergic activity, which, in turn, rewarding effects. these agents are only moderately ef- causes increased inhibition of neu- Serotonin also interacts with fective in treating alcohol abuse. rons that receive signals from the dopaminergic signal transmission Serotonin is not the only neuro- GABAergic neurons. Other sero- through the 5-HT3 receptor, which transmitter whose actions are af- tonin receptor types might act simi- helps control dopamine release in the fected by alcohol, however, and larly on GABAergic neurons. areas reached by VTA neurons, most many of alcohol’s effects on the Consequently, alcohol’s effects on notably the nucleus accumbens. Se- brain probably arise from changes in these receptor subtypes also might rotonin release in these brain regions the interactions between serotonin influence GABAergic signal trans- can stimulate dopamine release, pre- and other important neurotransmit- mission in the brain. sumably by activating 5-HT3 recep- ters. Thus, one approach researchers tors located on the endings of currently are pursuing to develop Interactions with Dopamine dopaminergic neurons (23,27). Con- better therapeutic strategies for re- The activation of serotonin re- sequently, an alcohol-induced in- ducing alcohol consumption focuses ceptors also modifies the activity of crease in 5-HT3 receptor activity on altering key components of the the neurotransmitter dopamine, would enhance dopamine release in brain’s serotonin system. which, like serotonin, modulates these brain regions, thereby, contrib- Editor’s Note: This article originally neuronal activity. The neurons that uting to alcohol’s rewarding effects. appeared in Alcohol Health & Res. produce and secrete dopamine (i.e., This hypothesis is supported by the World 21(2) (1997) 114-120.

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