The Role of Serotonin in Alcohol’s Effects on the Brain David M. Lovinger, Ph.D. Serotonin is an important brain chemical that acts as a neurotransmitter 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. Drugs that act on these receptors alter alcohol consumption in both humans and animals. Serotonin, along with other neurotransmitters, 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 receptor 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 synapse (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 tic 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 nervous system (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. synapses. 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 medications 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