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, the Brain, and Beh a v i o r

Mechanisms of

The actions of alcohol that cause intoxication, initiate and maintain excessive drinking behavior, and promote relapse during abstinence occur primarily in the brain. A thorough understanding of alcohol’s effects on the mechanisms underlying brain function is essential to develop and improve alcoholism prevention and treatment strategies. This article is not an exhaustive overview of alcoholism neurobiology, but a sampling of the more significant recent advances in the field. KEY WORDS: neurobehavioral theory of AODU (AOD [alcohol or other ] use, abuse, and dependence); brain; ; neuron; signaling; intracellular messengers; kinases; ; AOD tolerance; AOD withdrawal syndrome.

he specific mental proc e s s e s Information is transferred by chemical ter gamma-aminobutyric acid (GABA) thought to underlie the devel o p - me s sengers called , which at the GABAA (Diamond and Tment of alcoholism and its mani- ar e released by one neuron and then bound Gor don 1997). These actions are among festations invol v e functions such as learn- by specialized called rec e p t o r s the reasons that alcohol is often thought of ing, attention, emotion, and cognition. embedded in the outer membrane of as a depressant. The normal brain must orchestrate these another neuron. The tiny gap betwee n The NMDA and GABAA rec e p t o r s functions simultaneously to perce i v e the communicating neurons is called a synapse. ar e linked to channels; that is, they en v i r onment, assess the significance of Th e r e are many neurotransmitters, each of function by opening a pore th r ough the en v i r onmental stimuli in terms of sur- which binds to a particular rec e p t o r . to allow specific vi v al, and initiate behavioral rea c t i o n s . Howev er a given receptor may exist in mul- (electrically charged atoms) to enter the These activities req u i r e efficient commu- tiple subtypes. Each subtype may produce a cell and affect the cell’s electrical ba l a n c e nication among different regions of the di f f e r ent response to the same neurot r a n s - (H arris 1999). Other neurotr a n s m i t t e r s brain and at multiple levels within those mi t t e r , accounting for multiple effects of the of interest to alcohol res e a r chers include regions. This article considers alcohol’s same in differen t dopamine, (5–HT), and a effects on three levels of communication brain regions or even in different locations family of substances called opioid pe p - within the brain: (1) the synaptic level , on the same neuron (Weiner et al. 1997). tides. These neurotransmitters interac t in v olving information transfer betwee n Although a given neuron can release only with their receptors to modulate the ac t i v - individual nerve cells (neurons); (2) the one or two neurotransmitters it may possess ity of the neuron on which they res i d e . systems level, rep r esenting the integrated d i f f e rent receptors. Thus, a neuro n’s Dop a m i n e ’s role in coordinating the activity of different brain regions; and (3) response to information from other neu- ex ecution of complex motor activities has the intracellular level, comprising signal- rons depends on complex interactions long been rec o g n i z ed. Dopamine also ing processes that occur within neuron s . of potentially conflicting messages arriv- appears to play a major role in motiva- ing simultaneously (Charness 1990). tional behavior (i.e., the pursuit of One of the most power ful effects of rewa r ding stimuli). Alcohol administra- ALCOHOL AT THE SYNAPSE: alcohol is to reduce the pace of brain tion causes release of dopamine in a brain MODIFYING COMMUNICATION activity in part by (1) decreasing the region (the nucleus accumbens) that is a BETWEEN NEURONS exc i t a t o r y actions of the neurot r a n s m i t - key member of a group of linked struc - ter glutamate at the NMDA subtype of 1 Within the brain, each neuron may glutamate rec e p t o r and (2) boosting the 1So called because the synthetic chemical N-methyl-D- communicate with many other neuron s . in h i b i t o r y actions of the neurot r a n s m i t - aspartate (NMDA) also can activate this receptor subtype.

12 Alcohol Research & Health Mechanisms of Addiction

tu r es associated with the development of cannot be attributed to a limited num- citability characteristic of the acute addiction (Rassnick et al. 1992; Brod i e ber of specific chemical interactions. withdrawal syndrome (Littleton 1998). and Pesold 1999). This realization sparked a closer look at Some brain damage occurs during Opioid peptides are a class of neuro- al c o h o l ’s effects on pathways of neu- acute alcohol withdrawal, and the transmitters that produce physiological ronal communication that integrate the se v erity of symptoms increases after effects similar to those of morphine and activities of multiple brain reg i o n s . repeated withdrawal episodes (Bec k e r he r oin. In humans, opioid peptides inter- 1998). Withdrawal triggers the body’s act with other neurotransmitters to influ- Reinforcement and st r ess response, leading to elevated lev- ence a broad range of physiological func- Neuroadaptation els in the blood of the stress tions, including the control of . Hig h co r tisol. Exce s s i v e cortisol levels can kill blood levels of certain opioid peptides Two major processes that contribute to ne u r ons in the hippocampus, increa s e ha v e been correlated with feelings of de v elopment of addiction are rei n f o rc e - the risk of infectious diseases, alter euphoria. Alcohol consumption affects ment and neuroadaptation. Rei n f o rc e - energy , and promote disor- the activity of opioid peptides, which in ment is when a rewa r ding stimulus (e.g. ders of mood and intellect (Adinoff et turn appears to increase the rewa rd i n g alcohol and other drug [AOD] induced al. 1998). effects of alcohol (Rob e r ts et al. 2000). euphoria) or relief of an unpleasant state Neu r oadaptation is usually thought The medication naloxone, which inhibits (e.g., anxiety) increases the prob a b i l i t y of in terms of counteradaptation—pro- the function of opioid receptors, blocks of a behavioral response (e.g., AOD cesses such as tolerance that are initiated the release of dopamine in the nucleus use). Neu r oadapt-ation refers to com- to oppose the acute effects of drug s . accumbens and has been shown to sup- pe n s a t o r y adjustments whereb y the Howeve r , neuroadaptation also includes pr ess alcohol consumption by laboratory brain attempts to continue normal func- sensitization, an in c re a s e d response to a animals (Benjamin et al. 1993). tion despite the presence of alcohol. dr ug effect following repeated drug Ser otonin is invol v ed in the reg u l a t i o n Occurring essentially simultaneously, administration. If sensitization induces of mood, sleep, body temperature, rei n f o r cement and neuroa d a p t a t i o n in c r eased AOD consumption (as in the appetite, and a host of other physiological appear to underlie both the initial, mo t i v ational state called “wa n t i n g ” or functions. Experiments in which mice sh o r t-term (acute) response to a drug craving, discussed later), it may con- ha v e been genetically altered to lack spe- and the establishment of the long-term tribute to addiction. Sensitization may be cific serotonin receptor subtypes have (c h r onic) craving that characterizes mo r e likely to occur with intermittent, suggested a role of serotonin on drinking addiction. Some neuroa d a p t i v e changes repeated exposure to AODs, whereas tol- le v els. Alcohol-induced activation of spe- may be permanent, producing the per- erance is more likely to occur with con- cific serot o n i n - r eceptor subtypes can sistent of discomfort that may tinuous exposure (Robinson and stimulate activity in the to relapse long after a person stops Berridge 1993). nucleus accumbens, potentially con- drinking (Koob et al. 1993). Acute alcohol withdrawal includes tributing to alcohol’s rewa r ding effects. A common manifestation of neu- mo t i v ational effects (Koob and LeMoa l Other serotonin receptors have potential roadaptation is the occurrence of an 1997). The neurological struc t u r es associ- roles in tolerance,2 wi t h d r a w a l , 3 an d acute withdrawal syndrome followi n g ated with the rei n f o r cing actions of alcohol in t o xication (Valenzuela 1997). the abrupt cessation of a bout of heavy and other may invol v e a common drinking. In response to the continued neural circu i t r y that forms a separate entity pr esence of alcohol, compensatory within the basal forebrain, the extended Alcohol and Neuronal mechanisms attempt to over come alco- amygdala (Alheid and Heimer 1988). The Circuits: Detours on the ho l ’s inhibition of NMDA receptors by term extended amygdala refers to a com- Information Highway in c r easing overall NMDA function plex of several small struc t u r es near the (u p r egulation). When alcohol leaves base of the front of the brain that are simi- Since the discover y in the late 1980s the synapse, the combination of lar in cell struc t u r e, function, and neural that alcohol at concentrations capable up r egulated exci t a t o r y transmission co n n e c t i v i t y . This system has extensive of producing intoxication in humans and down r egulated inhibitory trans- connections to brain regions that play cen- can inhibit the exci t a t o r y effects of the mission results in the brain hyperex - tral roles in rei n f o r cement and rewa r d NMDA receptor and enhance the (D iamond and Gor don 1997). in h i b i t o r y function of the GABA rec e p - Rats trained to self-administer alcohol 2Tolerance, or the reduction in a drug effect after repeated to r , much alcohol res e a r ch has focused use, may stimulate a user to take increasing doses of the during withdrawal show neuroc h e m i c a l on identifying other specific rec e p t o r s drug in an attempt to reexperience its initial effect. and neuropharmacologic changes indica- and ion channels that may be affected ti v e of alterations in GABAergic, dopa- 3Acute withdrawal syndrome begins from 6 to 48 hours by alcohol. Howeve r , unlike most illicit after the last drink and may include tremors, elevated minergic, and function in dr ugs of abuse, alcohol does not have a blood pressure, increased rate, and . specific components of the extended specific neurotransmitter binding site in Alcohol and other drug (AOD) withdrawal also includes amygdala. One key struc t u r e encom- changes in mental state (anxiety, depression, and craving) the brain. More o ver , the complex that may outlast the physiological symptoms and motivate passed by the extended amygdala is the behaviors associated with alcohol use renewed AOD consumption. nucleus accumbens, which has long been

Vol. 24, No. 1, 2000 13 implicated in the rewa r ding prop e r ties of factors that initiate the expression of specific (Schuckit 1998). Knockout of a specific

AODs. Other investigations have (Diamond and Gor don 1997). kinase that interacts with GABAA rec e p - demonstrated selective activation of Many signaling pathways invol v e tors in mice produces results consistent dopaminergic transmission in the shell of molecules called second messengers. with Schuckit’s observations in humans the nucleus accumbens in response to These molecules may regulate short- t e r m (Weiner et al. 1997). acute administration of virtually all major ev ents (e.g., ion channel activity and neu- Knockout of a different kinase in dr ugs of abuse (Tanda et al. 1997). rotransmitter release) as well as longer- mice inhibits the function of hippocam- pal NMDA receptors, impairs the devel - opment of acute tolerance to alcohol, Alcohol and Molecules: The me c h a n i s m s in c r eases sensitivity to alcohol-induced Sabotaging the sedation, and impairs spatial learning. Communications un d e r lying alcohol’s Some evidence indicates that this kinase Infrastructure ch ro n i c effects invol v e may modulate the activities of both NMDA and GABAA receptors to deter- Co o r dinated interneuronal communica- pr ocesses called mine alcohol sensitivity (Yagi 1999). ■ tion can help account for rel a t i v ely tran- sient features of alcoholism, such as acute in t r acellular signaling. tolerance, physical withdrawal symptoms, References and the initiation of rei n f o r cement, which can lead to dependence. Howeve r , study- term processes (e.g., , Selected references are presented. For a full list of ing these processes alone does not provi d e me m o r y, and learning). Some G prot e i n s research cited, see the related article in the Te n t h Special Report to the United States Congress on a complete understanding of longer-term may influence shifts in alcohol sensitivity Alcohol and Health. manifestations of alcoholism, such as the fo l l o wing chronic alcohol exposure by un c o n t r olled craving that may contribute affecting the function of calcium-specific ADI N O F F , B.; IRA N M A N E S H , A.; VEL D H U I S , J.; AN D FIS H E R , L. Disturbances of the stress response: The to relapse years after cessation of drinking. ion channels. Calcium itself can be a sec- role of the hypothalamic-pituitary-adrenal axis dur- The mechanisms underlying alcohol’s ond messenger, and is req u i r ed to stimu- ing alcohol withdrawal and abstinence. Al c o h o l ch r onic effects invol v e processes called late many neuronal activities, including Health & Research World 22(1):67–71, 1998. intracellular signaling, the cell’s internal the release of neurot r a n s m i t t e r s . ALH E I D , G.F., AN D HEI M E R , L. New perspectives in biochemical response to receptor activa- basal forebrain organization of special relevance for tion by extracellular chemical messengers. Alcohol’s Effects on Protein neuropsychiatric disorders: The striatopallidal, amyg- daloid, and corticopetal components of substantia Phosphorylation innominata. Ne u r o s c i e n c e 27(1):11–39, 1988. Some Aspects of Normal Signaling Some protein kinases are located BEC K E R , H.C. Kindling in alcohol withdrawal. Intracellular signaling helps provide a link within the neuron, whereas others are Alcohol Health & Research World 22(1):25–33, 1998. be t w een the cell’s initial response to alco- attached to the inner surface of the BEN J A M I N , D.; GRA N T , E.R.; AN D POH O R E C K Y , L.A. hol and persistent alterations in neuron a l ne u r onal membrane, where they chem- Naltrexone reverses ethanol-induced dopamine function similar to the processes invol ve d ically modify the struc t u r e of rec e p t o r s release in the nucleus accumbens in awake, freely in memory. These processes may invol v e to help regulate their function. Certa i n moving rats. Brain Research 621(1):137–140, 1993. the activation of genes that direct the syn- kinases appear to influence alcohol’s BRO D I E , M.S., AN D PES O L D , C. Ethanol directly thesis of (i.e., express) specific prot e i n s effects on various NMDA and GABA excites dopaminergic ventral tegmental area reward such as components of receptors or struc - receptor functions (Diamond and neurons. Alcoholism: Clinical and Experimental tural elements of the outer neuron a l Gor don 1997). Re s e a r c h 23(11):1848–1852, 1999. membrane. Such changes can stren g t h e n The role of kinases in alcoholism CHA R N E S S , M.E. Alcohol and the brain. Al c o h o l information flow between neurons, help- has been studied using the techniques Health & Research World 14(2):85-89, 1990. ing close the loop between neurot r a n s m i t - of genetic engineering. Null mutant, or DIA M O N D , I., AN D GOR D O N , A.S. Cellular and ter activation and alcohol-related behavior. knockout (KO), mice are made by molecular neuroscience of alcoholism. Ph y s i o l o g i c a l Intracellular signaling comprises a com- replacing a normal with an inac- Re v i e w s 77(1):1–20, 1997. plex network of mutually interacting pro- ti v e gene. Transgenic mice are crea t e d HAR R I S , R.A. Ethanol actions on multiple ion chan- cesses. Among the common themes that by permanently adding a foreign gene nels: Which are important? Alcoholism: Clinical and emerge is the reg u l a t o r y role of prot e i n - that may function differently than the Experimental Research 23(10):1563–1570, 1999. o s p h o r ylating enzymes (e.g., prot e i n an i m a l ’s natural gene. KOO B , G.F., AN D LEMOA L , M. Drug abuse: kinases). Pho s p h o r ylation is the attachment Schuckit (1998) has suggested that Hedonic homeostatic dysregulation. Sc i e n c e of a phosphate group (a cluster of phospho- lo w initial sensitivity to alcohol’s behav- 278(5353):52–58, 1997. rus and oxygen atoms) to a molecule. ioral effects among sons of alcoholics is Pho s p h o r ylation can activate reg u l a t o r y associated with increased risk of future KOO B , G.F.; MAR K O U , A.; WEI S S , F.; AN D SCH U L T H E I S , G. Opponent process and drug enzymes (e.g., G proteins), modify the func- alcoholism, possibly mediated in part dependence: Neurobiological mechanisms. tion of ion channels, or activate transcription by more rapid development of tolerance Seminars in the Neurosciences 5:351-358, 1993.

14 Alcohol Research & Health Mechanisms of Addiction

LIT T L E T O N , J. Neurochemical mechanisms under- ROB I N S O N T.E., AN D BER R I D G E , K.C. The neural VAL E N Z U E L A , C.F. Alcohol and neurotransmitter lying alcohol withdrawal. Alcohol Health & Research basis of drug craving: An incentive-sensitization interactions. Alcohol Health & Research World Wo r l d 22(1):13–24, 1998. theory of addiction. Brain Research Reviews 21 ( 1 ) : 1 9 9 7 . 18(3):247–291, 1993. RAS S N I C K , S.; PUL V I R E N T I , L.; AN D KOO B , G.F. WEI N E R , J.L.; VAL E N Z U E L A , C.F.; WAT S O N , P.L.; Oral ethanol self-administration in rats is reduced SCH U C K I T , M.S. Biological, psychological and envi- FRA Z I E R , D.J.; AN D DUN W I D D I E , T.V. Elevation of by the administration of dopamine and glutamate ronmental predictors of the alcoholism risk: A lon- basal protein kinase C increases ethanol sensitivity receptor antagonists into the nucleus accumbens. gitudinal study. Journal of Studies on Alcohol of GABA receptorsin rat hippocampal CA1 pyra- Ps y c h o p h a r m a c o l o g y 109(1–2):92–98, 1992. A 59(5):485–494, 1998. midal neurons. Journal of Neurochemistry ROB E R T S , A.J.; MCDON A L D , J.S.; HEY S E R , C.J.; 68(5):1949–1959, 1997. AN D A ON T I E R I AN D I HI A R A KIE F F E R , B.L.; MAT T H E S , H.W.D.; KOO B , G.F.; T , G.; P , F.E.; D C , G. AN D GOL D , L.H. m-Opioid receptor knockout mice and heroin activation of mesolimbic YAG I , T. Molecular mechanisms of Fyn-tyrosine do not self-administer alcohol. Journal of dopamine transmission by a common m1 opioid kinase for regulating mammalian behaviors and and Experimental Therapeutics receptor mechanism. Sc i e n c e 27 6 ( 5 2 3 1 ) : 2 0 4 8 – ethanol sensitivity. Biochemical Pharmacology 293(3):1002–1008, 2000. 2050, 1997. 57(8):845–850, 1999.

Brainwaves, gene scans, and street maps: What can they tell us about alcoholism?

he answer to this and other questions can be found in Alcohol Al e rt , the quarterly bulletin pub- lished by the National Institute on Alcohol Abuse and Alcoholism. Alcohol Alert provides timely Tinformation on alcohol res e a r ch and treatment. Each issue addresses a specific topic in alcohol res e a r ch and summarizes critical findings in a br i e f , four-page, easy-to-read format. Our most recent issue—From Genes to Geography— The Cutting Edge of Alcohol Research (No. 48)—demonstrates how computerized data analysis can integrate vast quantities of disparate data to support alcoholism prevention and treatment efforts.

For a free subscription to Alcohol Alert, write to: National Institute on Alcohol Abuse and Alcoholism, Attn.: Alcohol Alert, Publications Distribution Center, P.O. Box 10686, Rockville, MD 20849–0686. Fax: (202) 842–0418. Alcohol Alert is available on the World Wide Web at http://www.niaaa.nih.gov

Vol. 24, No. 1, 2000 15 Public Education Materials Ava i l a b l e

A variety of public education materials are available from NIAAA. All of these materials are free and may be obtained in English and Spanish ver s i o n s . Quantities also are available for school and other educational programs.

Alcoholism: Getting the Facts. A brief, research-based brochure to educate the general public about alcohol abuse and dependence. Provides answers to commonly asked questions; includes a list of resources for information and assistance.

Ho w to Cut Down on Your Drinking. The companion brochure to NIAAA’s The Physicians’ Guide to Helping Patients With Alcohol Problems. Presents tips for those who are acting on medical advice to reduce their alcohol consump- ti o n . Includes a list of resources for treatment and additional information.

Drinking and Your Pregnancy. A short pamphlet to answer common questions about alcohol consumption during pregnancy. Describes the consequences of drinking during pregnancy, focusing on fetal alcohol syndrome. Includes resources for help and additional information.

To order, write to: National Institute on Alcohol Abuse and Alcoholism, Publications Distribution Center, P.O. Box 10686, Rockville, MD 20849–0686. Fax: (202) 842–0418. Full text is available on the World Wide Web at http://www.niaaa.nih.gov

16 Alcohol Research & Health