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Serotonin's Role in Alcohol's Effects on the Brain

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Serotonin's Role in Alcohol's Effects on the Brain NEUROTRANSMITTER REVIEW IMPERATO, A., AND DI CHIARA, G. Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. Journal SEROTONIN’S ROLE IN ALCOHOL’S of Pharmacology and Experimental Therapeutics 239:219–228, 1986. EFFECTS ON THE BRAIN KITAI, S.T., AND SURMEIER, D.J. Cholinergic and dopaminergic modula- tion of potassium conductances in neostriatal neurons. Advances in David M. Lovinger, Ph.D. Neurology 60:40–52, 1993. LE MOINE, C.; NORMAND, E.; GUITTENY, A.F.; FOUQUE, B.; TEOULE, R.; AND BLOCH, B. Dopamine receptor gene expression by enkephalin Serotonin is an important brain chemical that acts as a neurons in rat forebrain. Proceedings of the National Academy of Sciences neurotransmitter to communicate information among USA 87:230–234, 1990. nerve cells. Serotonin’s actions have been linked to al- LE MOINE, C.; NORMAND, E.; AND BLOCH, B. Phenotypical character- cohol’s effects on the brain and to alcohol abuse. ization of the rat striatal neurons expressing the D1 dopamine receptor Alcoholics and experimental animals that consume gene. Proceedings of the National Academy of Sciences USA 88: large quantities of alcohol show evidence of differences 4205–4209, 1991. in brain serotonin levels compared with nonalcoholics. LYNESS, W.H., AND SMITH F.L. Influence of dopaminergic and sero- Both short- and long-term alcohol exposure also affect tonergic neurons on intravenous ethanol self-administration in the rat. the serotonin receptors that convert the chemical sig- Pharmacology and Biochemistry of Behavior 42:187–192, 1992. nal produced by serotonin into functional changes in the signal-receiving cell. Drugs that act on these recep- MARTIN, L.P., AND WASZCZAK, B. D1 agonist-induced excitation of substantia nigra pars reticulata neurons: Mediation by D1 receptors on tors alter alcohol consumption in both humans and an- striatonigral terminals via a pertussis toxin-sensitive coupling pathways. imals. Serotonin, along with other neurotransmitters, Neuroscience 14:4494–4506, 1994. also may contribute to alcohol’s intoxicating and re- PONTIERI, F.E.; TANDA, G.; AND DI CHIARA, G. Intravenous cocaine, warding effects, and abnormalities in the brain’s sero- morphine and amphetamine preferentially increase extracellular tonin system appear to play an important role in the dopamine in the “shell” as compared with the “core” of the rat nucleus brain processes underlying alcohol abuse. KEY WORDS: accumbens. Proceedings of the National Academy of Sciences USA acute AODE (alcohol and other drug effects); chronic 92:12304–12308, 1995. AODE; serotonin receptors; brain; AODU (alcohol and PONTIERI, F.E.; TANDA, G.; ORZI, F.; AND DI CHIARA, G. Effects of other drug use) development; neurotransmission; nicotine on the nucleus accumbens and similarity to those of addictive synapse; neurotransmitters; serotonin uptake inhibitors; drugs. Nature 382:255–257, 1996. GABA; dopamine; receptor proteins; AOD abuse; AOD ROBBINS, T.W.; CADOR, M.; TAYLOR, J.R.; AND EVERITT, B.J. Limbic intoxication; AOD dependence; reinforcement; animal striatal interactions in reward-related processes. Neuroscience and model; literature review Biobehavioral Reviews 13:155–162, 1989. SPANO, P.F.; TRABUCCHI, M.; AND DI CHIARA, G. Localization of nigral eurotransmitters are chemicals that allow signal dopamine-sensitive adenylate cyclase on neurons originating from corpus transmission, and thus communication, among striatum. Science 196:1343–1345, 1977. Nnerve cells (i.e., neurons). One neurotransmitter used by many neurons throughout the brain is serotonin, STARKE, K. Presynaptic receptors. Annual Review in Pharmacology and Toxicology 21:7, 1981. also known as 5-hydroxytryptamine (5-HT). Serotonin released by the signal-emitting neuron subtly alters the TANDA, G.; PONTIERI, F.E.; AND DI CHIARA, G. Cannabinoid and heroin function of the signal-receiving neurons in a process called activation of mesolimbic dopamine transmission by a common m1 opioid neuromodulation. For example, in some neurons serotonin receptor mechanism. Science 276:2048–2050, 1997. alters the rate at which the cells produce the electrical signals (i.e., action potentials) used for relaying informa- THIERRY, A.M.; BLANC, G.; SOBEL, A.; STINUS, L.; AND GLOWINSKI, J. Dopaminergic terminals in the rat cortex. Science 182:499–501, 1973. tion within the cells, whereas in other neurons it modulates the release of other neurotransmitters. (For more informa- UNGERSTEDT, U. Stereotaxic mapping of the monoamine pathways in the tion on the mechanisms underlying signal transmission rat brain. Acta Physiologica Scandinavica 367(Suppl.):1–48, 1971. within and among neurons, see the article “The Principles of Nerve Cell Communication,” pp. 107-108.) Although WEISS, F.; LORANG, M.T.; BLOOM, F.E.; AND KOOB, G.F. Oral alcohol serotonin’s effect on individual neurons can be rather mod- self-administration stimulates dopamine release in the rat nucleus accumbens: Genetic and motivational determinants. Journal of AVID OVINGER H Pharmacology and Experimental Therapeutics 267:250–258, 1995. D M. L , P .D., is an associate professor in the Department of Molecular Physiology and Bio- WISE, R.A. Neuroleptics and operant behavior: The anhedonia hypothesis. physics, Vanderbilt University School of Medicine, Behavioral and Brain Science 5:39-87, 1982. Nashville, Tennessee. 114 ALCOHOL HEALTH & RESEARCH WORLD NEUROTRANSMITTER REVIEW est, its overall effect on the neurons in a given brain area can substantially influence brain functions such as learning and memory, perception of the environment, mood states, 5-HT and responses to alcohol and other drugs of abuse. This article reviews serotonin’s functions in the brain 5-HT Ion and the consequences of acute and chronic alcohol con- 5-HT R sumption on serotonin-mediated (i.e., serotonergic) signal channel 3 transmission. In addition, the article summarizes recent 5-HTR G protein Direct activation findings indicating that serotonin may play a pivotal role in of neuron the development of alcohol abuse.1 Second-messenger molecules Cell nucleus SEROTONIN’S FUNCTIONS IN THE BRAIN Serotonin is produced in and released from neurons that originate within discrete regions, or nuclei, in the brain Activation of serotonin receptors (5-HTR) produces (Cooper et al. 1991). Many serotonergic neurons are locat- multiple effects on neurons. Serotonin (5-HT) can bind to ed at the base of the brain in an area known as the raphe receptors that activate proteins within the cell called G nucleus, which influences brain functions related to atten- proteins. Activation of these proteins, in turn, affects ion tion, emotion, and motivation. The axons of the neurons in channels in the cell membrane and induces the formation the raphe nucleus extend, or project, throughout the brain of signaling molecules (i.e., second-messenger molecules). to numerous regions with diverse functions. These brain Second messengers also can act on ion channels or travel to the nucleus to alter gene expression. Other serotonin- regions include the amygdala, an area that plays an impor- activated receptors (i.e., the 5-HT3 receptors) double as tant role in the control of emotions, and the nucleus accum- ion channels. Their activation directly excites neurons. bens, a brain area involved in controlling the motivation to perform certain behaviors, including the abuse of alcohol and other drugs. In these brain regions, the axon endings of ing neurons only for a short period of time. Any interfer- the serotonergic neurons secrete serotonin when activated. ence with serotonin transporter function extends or dimin- The neurotransmitter then traverses the small space sepa- ishes the cells’ exposure to serotonin, thereby disrupting the rating the neurons from each other (i.e., the synaptic cleft) exquisite timing of nerve signals within the brain. The net and binds to specialized docking molecules (i.e., receptors) result of such disruptions is abnormal brain activity, which on the recipient cell. can lead to psychological problems or mental illness. One The binding of serotonin to its receptors initiates a se- prominent example of a psychological disorder that appears ries of biochemical events that converts the extracellular, to involve inappropriate serotonin use in the brain is depres- chemical signal into an intracellular signal in the recipient sion (Baldessarini 1996); some of the most effective antide- cell. For example, the interaction of serotonin with one pressant medications act on the serotonin transporters to type of receptor stimulates the formation of small mole- prolong the neurotransmitter’s activity. cules (i.e., second messengers) within the cell. Second Researchers currently cannot directly measure serotonin messengers interact with other proteins to activate various concentrations in the human brain or within the synapses in cellular functions, such as changes in the cell’s electrical laboratory animals. To gain information about serotonin activity or in the activity of certain genes (see figure). levels in the brain, physicians and researchers have mea- These changes can result either in the inhibition or the sured the concentrations of serotonin breakdown products excitation of the signal-receiving neuron, depending on the generated after the neurotransmitter has been removed cell affected. Through these mechanisms, serotonin can from the synapse (i.e., serotonin metabolites). The concen- influence mood states; thinking patterns; and even behav- trations of these metabolites,
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