National Institute on Alcohol Abuse and Alcoholism No. 33 PH 366 July 1996

Neuroscience Research and Medications Development

Research suggests that the processes leading to the development of alcoholism reside largely in the brain. This has led to the concept of developing medications that act on specific brain chemicals to interfere with these processes. In 1995, the U.S. Food and Drug Administration approved the use of one such medication--naltrexone, under the brand name ReVia(TM)--to help prevent relapse in recovering alcoholics. By combining results of clinical and neuroscience research, this advance signals a new era in alcoholism treatment. This Alcohol Alert shows how brain chemistry research may lead to further breakthroughs in the medical treatment of alcoholism and its effects.

Phenomena of Addiction

Reinforcement. It may seem self-evident that a person will repeat an action that brings pleasure, or reward. The process by which such an action becomes repetitive is called positive reinforcement. Normally, this process functions to sustain motivation for behaviors essential to the individual or species, such as eating, drinking, or reproductive behavior (1,2). Evidence suggests that alcohol and other drugs of abuse (AOD's) are chemical surrogates of such natural reinforcers (3). AOD's that cause a rewarding mental state (e.g., euphoria) function as positive reinforcers upon initial exposure (3). These drugs may be more powerfully and persistently rewarding than the natural reinforcers to which the human brain is accustomed (4). Thus, continued exposure to AOD's can initiate increased drug-seeking behavior and set the stage for addiction. Although the remainder of this discussion concentrates on alcoholism, the principles described are generally valid for other addictions as well.

After alcohol-seeking behavior has been established, the brain undergoes certain adaptive changes to continue functioning despite the presence of alcohol. As a consequence of this adaptation, however, certain abnormalities occur in the brain when alcohol is removed. Thus, periods of abstinence are marked by feelings of discomfort and craving, motivating continued alcohol consumption. This kind of motivation--based not on reward but on avoidance of painful stimuli--is called negative reinforcement. Both positive and negative reinforcement are involved in the maintenance of alcoholism (5,6).

Dependence. Physical dependence in alcoholism is the need for continued alcohol consumption to avoid a withdrawal syndrome that generally occurs from 6 to 48 hours after the last drink. Withdrawal symptoms include anxiety, agitation, tremor, elevated blood pressure, and, in severe cases, seizures. The withdrawal syndrome is distinct from the ongoing process of negative reinforcement described above, although both phenomena result from adaptation of the nervous system (7,8).

Alcohol and the Brain

All brain functions, including addiction, involve communication among nerve cells (neurons) in the brain. Each of the brain's neurons connects with hundreds or thousands of adjacent neurons. The points of connection between neurons are generally separated by microscopic gaps called synapses. Messages are carried across synapses by chemicals called neurotransmitters. Although there are approximately 100 different neurotransmitters, each neuron releases only one or a few different types. After its release, a neurotransmitter crosses the synapse and activates a receptor protein in the outer membrane of the "receiving" neuron.

Each receptor type responds preferentially to one type of neurotransmitter. However, most neurotransmitters can activate different subtypes of the same receptor, producing different responses in different brain cells or in different parts of the brain (9). Determining the specific neurotransmitters and receptor subtypes that may be involved in the development and effects of alcoholism is the first step in developing medications to treat alcoholism (10,11).

Receptor activation causes a change in the receiving neuron. This change may consist of a transient increase or decrease in the neuron's responsiveness to further messages (12). Alternatively, some receptors promote long-term changes that support functions such as growth; learning; or adaptation to changes in the neuron's environment, such as the presence of alcohol. The process of converting messages from other neurons into changes within the receiving neuron is called signal transduction (9). Alcohol may produce some of its effects by interfering with signal transduction (13,14).

Pharmacological treatment for alcoholism has focused on the processes described above. Other elements of message proce ssing, described below, may provide additional targets for medications development.

The brain's long-lasting adaptations to alcohol may result in part from changes in gene function (15). Genes direct the synthesis of proteins, such as receptors. By influencing gene function, alcohol may alter the structure and function of specific receptors that have roles in intoxication, reinforcement, and physical dependence (16-19). Alcohol's effects on genes may also alter proteins involved in signal transduction (14). Additional research is needed in this area before practical benefits, in the form of medications, can be realized.

Groups of neurons with similar functions extend from one brain region to another, forming neural circuits. Circuits interact with one another to integrate the functions of the brain. One important part of a circuit that has been studied for its role in reward is the nucleus accumbens, located near the front of the brain (3,20). Other circuits are involved in various aspects of alcoholism. For example, circuits involved in physical withdrawal have long been targets of medications development.

Medications Development

Any alteration in the function of message reception or transduction systems may have significant effects on the progression of alcoholism after drinking has started. An understanding of how specific changes in the function of these systems affect susceptibility to alcohol provides a starting point for medications development (21-23). Medications can theoretically be developed to block receptors or enhance their function; to increase or decrease the synthesis, release, or synaptic concentration of neurotransmitters; or to modulate signal transduction.

Medications development for alcoholism focuses mainly on two goals: treatment of withdrawal and the maintenance of abstinence (relapse prevention). Many withdrawal symptoms appear to result in part from overactivity of the sympathetic ("fight or flight") nervous system (24), which normally functions to prepare the body for stressful situations. The preferred medications for withdrawal are benzodiazepines, such as Valium®, which "brake" the racing sympathetic nervous system while helping prevent seizures (25,26).

Medications to interrupt the process of reinforcement are being investigated. The key neurotransmitters involved in reinforcement include the endogenous opioids and dopamine. The endogenous opioids are a group of brain chemicals similar in action to morphine. They appear to amplify the pleasurable effects of rewarding activities (27,28) and have been shown to help maintain drinking behavior (29,30). Naltrexone helps prevent relapse and reduce craving by blocking certain opioid receptors, presumably reducing the pleasurable effect of alcohol (31-33).

Dopamine is involved in aspects of motivation and has been implicated in addiction to several drugs (34). Alcohol has been shown to increase levels of dopamine in the nucleus accumbens (35), although dopamine's precise role in the development of alcoholism remains unclear (34,36). Bromocriptine, a medication that activates dopamine receptors, has been thought to reduce craving in alcoholics; however, it has not been found to maintain abstinence (37).

A significant impetus to medications development has been the recognition that alcoholism and some psychiatric disorders appear to involve some of the same neurotransmitter systems (38). This presumed similarity in neural mechanisms may also be related to the substantial co-occurrence of AOD and psychiatric disorders in the same patients (39-41). For both of these reasons, researchers have investigated current and experimental psychiatric medications to treat alcoholism occurring either alone or in the presence of psychiatric symptoms. An example is buspirone, an antianxiety medication that activates certain serotonin receptors. Seroton in, a neurotransmitter that helps regulate many mental and bodily functions, helps modulate reinforcement (42,43). Extensive research has demonstrated a limited effect of buspirone on alcohol craving and consumption among anxious alcoholics (44,45). Similarly, the antidepressants imipramine (46) and desipramine (47) were found to decrease alcohol consumption among alcoholics whose co-occurring depression improved in response to the medication.

The antidepressants that have stimulated the most alcohol-related research activity include fluoxetine (Prozac®) and related medications that increase serotonin concentrations in synapses (48,49). Clinical trials of these medications to date have not shown effectiveness in treating alcoholism (23).

In summary, medications that treat psychiatric disorders may in some cases be effective in treating co-occurring alcoholism as well. Further research is needed to determine whether such medications can improve treatment outcome in the absence of co-occurring psychopathology.

Neuroscience Research and Medications Development-- A Commentary by NIAAA Director Enoch Gordis, M.D.

Developing effective pharmacotherapies for alcoholism treatment is a top priority of alcohol research. Doing so depends on neuroscientists' continued elucidation of how alcohol acts on the brain to produce the fundamental phenomena of alcoholism--tolerance, withdrawal, impaired control over drinking, and craving--and how these phenomena can be interrupted or controlled. It also depends on clinical researchers' testing the efficacy of medications through carefully controlled clinical trials. The development of naltrexone in the United States and acamprosate in Europe is based on just such an important convergence of neurosciences and clinical research.

At the present time, clinical research indicates that the best treatment results are achieved with a combination of pharmacotherapy and skilled counseling. Research is underway to determine how alcoholism treatment medications work (the mechanism of action), the potential therapeutic value of using pharmacotherapy over a longer period of time, and which subsets of patients are most likely to benefit from new pharmacological treatments. The prospects for improved alcoholism treatment have never been better.

References

(1) Koob, G.F. Plenary address: Neural mechanisms of drug reinforcement. In: Kalivas, P.W., and Samson, H.H., eds. The Neurobiology of Drug and Alcohol Addiction. Annals of the New York Academy of Sciences 654:171-191, 1992. (2) Koob, G.F., and Bloom, F.E. Cellular and molecular mechanisms of drug dependence. Science 242(4879):715-723, 1988. (3) Di Chiara, G.; Acquas, E.; and Tanda, G. Ethanol as a neurochemical surrogate of conventional reinforcers: The dopamine-opioid link. Alcohol 13(1):13-17, 1996. (4) Hyman, S.E., and Nestler, E.J. Initiation and adaptation: A paradigm for understanding psychotropic drug action. American Journal of Psychiatry 153(2):151-162, 1996. (5) Gardner, E.L., and Lowinson, J.H. Drug craving and positive/negative hedonic brain substrates activated by addicting drugs. Seminars in the Neurosciences 5(5):359-368, 1993. (6) Koob, G.F.; Markou, A.; Weiss, F.; and Schultheis, G. Opponent process and drug dependence: Neurobiological mechanisms. Seminars in the Neurosciences 5(5):351-358, 1993. (7) Linnoila, M. Alcohol withdrawal and noradrenergic function. Annals of Internal Medicine 107(6):875-889, 1987. (8) Morrow, A.L.; Suzdak, P.D.; Karanian, J.W.; and Paul, S.M. Chronic ethanol administration alters *-aminobutyric acid, pentobarbitol and ethanol-induced 36Cl* uptake in cerebral cortical synaptoneurosomes. Journal of Pharmacology and Experimental Therapeutics 246(1):158-164, 1988. (9) Shepherd, G.M. Neurobiology . 3rd ed. New York: Oxford University Press, 1994. (10) Hunt, W.A. Neuroscience research: How has it contributed to our understanding of alcohol abuse and alcoholism? A review. Alcoholism: Clinical and Experimental Research 17(5):1055-1065, 1993. (11) Deitrich, R.A., and Erwin, V.G., eds. Pharmacological Effects of Ethanol on the Nervous System. Boca Raton, FL: CRC Press, 1996. (12) Grant, K.A. Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behavioural Pharmacology 5:383-404, 1994. (13) Alling, C.; Diamond, I.; Leslie, S.W.; Sun, G.Y.; and Wood, W.G., eds. Alcohol, Cell Membranes, and Signal Transduction in Brain. New York: Plenum Press, 1993. (14) Davis-Cox, M.I.; Fletcher, T.L.; Turner, J.N.; Szarowski, D.; and Shain, W. Three-day exposure to low-dose ethanol alters guanine nucleotide binding protein expression in the developing rat hippocampus. Journal of Pharmacology and Experimental Therapeutics 276(2):758-764, 1996. (15) Miles, M.F. Alcohol's effects on gene expression. Alcohol Health & Research World 19(3):237-243, 1995. (16) Snell, L.D.; Tabakoff, B.; and Hoffman, P.L. Radioligand binding to the N-methyl-d-aspartate receptor/ionophore complex: Alterations by ethanol in vitro and by chronic in vivo ethanol ingestion. Brain Research 602(1):91-98, 1993. (17) Charness, M.E.; Hu, G.; Edwards, R.H.; and Querimit, L.A. Ethanol increases *-opioid receptor gene expression in neuronal cell lines. Molecular Pharmacology 44(6):1119-1127, 1993. (18) Ortiz, J.; Fitzgerald, L.W.; Charlton, M.; Lane, S.; Trevisan, L.; Guitart, X.; Shoemaker, W.; Duman, R.S.; and Nestler, E.J. Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse 21(4):289-298, 1995. (19) Hu, G.; Querimit, L.A.; Downing, L.A.; and Charness, M.E. Ethanol differentially increases *2-adrenergic and muscarinic acetylcholine receptor gene expression in NG108-15 cells. Journal of Biological Chemistry 268(31):23441-23447, 1993. (20) Koob, G.F.; Rassnick, S.; Heinrichs, S.; and Weiss, F. Alcohol, the reward system and dependence. In: Jansson, B.; Jörnvall, H.; Rydberg, U.; Terenius, L.; and Vallee, B.L, eds. Toward a Molecular Basis of Alcohol Use and Abuse. Basel, Switzerland: Birkhaüser-Verlag, 1994. pp. 103-114. (21) Kranzler, H.R., and Orrok, B. The pharmacotherapy of alcoholism. In: Tasman, A.; Hales, R.E.; and Frances, A.J., eds. American Psychiatric Association Review of Psychiatry. Vol. 8. Washington, DC: American Psychiatric Press, 1989. pp. 359-379. (22) Litten, R.Z., and Allen, J.P. Pharmacotherapies for alcoholism: Promising agents and clinical issues. Alcoholism: Clinical and Experimental Research 15(4):620-633, 1991. (23) Litten, R.Z., and Allen, J.P. Pharmacological therapies of alcohol addiction. In: Miller, N.S., and Gold, M.S., eds. Pharmacological Therapies for Drug & Alcohol Addictions. New York: Marcel Dekker, 1995. pp. 127-141. (24) Linnoila, M. Alcohol withdrawal syndrome and sympathetic nervous system function. Alcohol Health & Research World 13(4):355-357, 1989. (25) Treiman, D.M. Treatment of alcohol withdrawal seizures with benzodiazepines: Clinical applications. In: Porter, R.J.; Mattson, R.H.; Cramer, J.A.; Diamond, I.; and Schoenberg, D.G., eds. Alcohol and Seizures: Basic Mechanisms and Clinical Concepts. Philadelphia: F.A. Davis, 1990. pp. 283-289. (26) Anton, R.F., and Becker, H.C. Pharmacotherapy and pathophysiology of alcohol withdrawal. In: Kranzler, H.R., ed. The Pharmacology of Alcohol Abuse. New York: Springer-Verlag, 1995. pp. 315-367. (27) Terenius, L. Alcohol addiction (alcoholism) and the opioid system. Alcohol 13(1):31-34, 1996. (28) Reid, L.D. Endogenous opioids and alcohol dependence: Opioid alkaloids and the propensity to drink alcoholic beverages. Alcoh ol 13(1):5-11, 1996. (29) Froehlich, J.C.; Zweifel, M.; Harts, J.; Lumeng, L.; and Li, T.-K. Importance of delta opioid receptors in maintaining high alcohol drinking. Psychopharmacology 103(4):467-472, 1991. (30) Gianoulakis, C.; De Waele, J.-P.; and Thavundayil, J. Implication of the endogenous opioid system in excessive ethanol consumption. Alcohol 13(1):19-23, 1996. (31) Volpicelli, J.R.; Alterman, A.I.; Hayashida, M.; and O'Brien, C.P. Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49:876-880, 1992. (32) Volpicelli, J.R.; Watson, N.T.; King, A.C.; Sherman, C.E.; and O'Brien, C.P. Effect of naltrexone on alcohol "high" in alcoholics. American Journal of Psychiatry 152(4):613-615, 1995. (33) O'Malley, S.S.; Jaffe, A.J.; Chang, G.; Rode, S.; Schottenfeld, R.; Meyer, R.E.; and Rounsaville, B. Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Archives of General Psychiatry 53(3):217-224, 1996. (34) Di Chiara, G. The role of dopamine in drug abuse viewed from the perspective of its role in motivation. Drug and Alcohol Dependence 38:95-137, 1995. (35) Wozniak, K.M.; Pert, A.; Mele, A.; and Linnoila, L. Focal application of alcohols elevates extracellular dopamine in rat brain: A microdialysis study. Brain Research 540(1-2):31-40, 1991. (36) Rassnick, S.; D'Amico, E.; Riley, E.; and Koob, G.F. GABA antagonist and benzodiazepine partial inverse agonist reduce motivated responding for ethanol. Alcoholism: Clinical and Experimental Research 17(1):124-130, 1993. (37) Powell, B.J.; Campbell, J.L.; Landon, J.F.; Liskow, B.I.; Thomas, H.M.; Nickel, E.J.; Dale, T.M.; Penick, E.C.; Samuelson, S.D.; and Lacoursiere, R.B. A double-blind, placebo-controlled study of nortriptyline and bromocriptine in male alcoholics subtyped by comorbid psychiatric disorders. Alcoholism: Clinical and Experimental Research 19(2):462-468, 1995. (38) Schatzberg, A.F., and Nemeroff, C.B., eds. The American Psychiatric Press Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press, 1995. (39) Helzer, J.D., and Pryzbeck, T.R. The co-occurrence of alcoholism with other psychiatric disorders in the general population and its impact on treatment. Journal of Studies on Alcohol 49(3):219-224, 1988. (40) Regier, D.A.; Farmer, M.E.; Rae, D.S.; Lake, B.Z.; Keith, S.J.; Judd, L.L.; and Goodwin, F.K. Comorbidity of mental disorders with alcohol and other drug abuse: Results from the Epidemiological Catchment Area (ECA) study. Journal of the American Medical Association 264(19):2511-2518, 1990. (41) Kessler, R.C.; Nelson, C.B.; McGonagle, K.A.; Edlund, M.J.; Frank, R.G.; and Leaf, P.J. The epidemiology of co-occurring addictive and mental disorders: Implications for prevention and service utilization. American Journal of Orthopsychiatry 66(1):17-31, 1996. (42) Grant, K.A. The role of 5-HT3 receptors in drug dependence. Drug and Alcohol Dependence 38(2):155-171, 1995. (43) Wozniak, K.M.; Pert, A.; and Linnoila, M. Antagonism of 5-HT3 receptors attenuates the effects of ethanol on extracellular dopamine. European Journal of Pharmacology 187(2):287-289, 1990. (44) Malec, E.; Malec, T.; Gagné, M.A.; and Dongier, M. Buspirone in the treatment of alcohol dependence: A placebo-controlled trial. Alcoholism: Clinical and Experimental Research 20(2):307-312, 1996. (45) Malcolm, R.; Anton, R.F.; Randall, C.L.; Johnston, A.; Brady, K.; and Thevos, A. A placebo-controlled trial of buspirone in anxious inpatient alcoholics. Alcoholism: Clinical and Experimental Research 16(6):1007-1013, 1992. (46) McGrath, P.J.; Nunes, E.V.; Stewart, J.W.; Goldman, D.; Agosti, V.; Ocepek-Welikson, K.; and Quitkin, F.M. Imipramine treatment of alcoholics with primary depression: A placebo-controlled clinical trial. Archives of General Psychiatry 53(3):232-240, 1996. (47) Mason, B.J.; Kocsis, J.H.; Ritvo, E.C.; and Cutler, R.B. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. Journal of the American Medical Association 275(10):761-767, 1996. (48) Naranjo, C.A.; Sellers, E.M.; and Lawrin, M.O. Modulation of ethanol intake by serotonin uptake inhibitors. Journal of Clinical Psychiatry 47(Suppl 4):16-22, 1986. (49) Gorelick, D.A. Serotonin uptake blockers and the treatment of alcoholism. In: Galanter, M., ed. Recent Developments in Alcoholism: Volume 7. Treatment Research. New York: Plenum Press, 1989. pp. 257-281.

All material contained in the Alcohol Alert is in the public domain and may be used or reproduced without permission from NIAAA. Citation of the source is appreciated.

Copies of the Alcohol Alert are available free of charge from the Scientific Communications Branch, Office of Scientific Affairs, NIAAA, Willco Building, Suite 409, 6000 Executive Boulevard, Bethesda, MD 20892-7003. Telephone: 301-443-3860

Full text of this publication is available on NIAAA's World Wide Web site at http://www.niaaa.nih.gov

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service * National Institutes of Health