วารสารสมาคมจิตแพทย์แห่งประเทศไทย
Journal of the Psychiatrist Association of Thailand
ISSN: 0125-6985
บรรณาธิการ มาโนช หล่อตระกูล
Editor: Manote Lotrakul, M.D.

Amporn Benjaponpitak M.D.*

Abstract

แอลกอฮอล์: ความก้าวหน้าของงานวิจัย

 อัมพร เบญจพลพิทักษ์ พ.บ.

 บทคัดย่อ

แอลกอฮอล์เป็นสารกดประสาทที่มีการใช้เพื่อเสพติดมากที่สุด การตระหนักถึงปัญหาการติดแอลกอฮอล์ได้นำไปสู่การวิจัยเพื่อสร้างความเข้าใจกลไกการออกฤทธ์ของแอลกอฮอล์ในระดับต่างๆ จากความก้าวหน้าของวงการวิทยาศาสตรการแพทย์ทำให้การวิจัยเกี่ยวกับแอลกอฮอล์มีความก้าวหน้าสูงมาก และบ่งชี้ถึงความเป็นไปได้ของแนวทางป้องกันแก้ไขภาวะการเสพติดแอลกอฮอล์อย่างเหมาะสมในอนาคตอันใกล้

ผู้เขียนได้เรียบเรียงข้อมูลความก้าวหน้าของผลงานวิจัยเหล่านี้ เพื่อเป็นแนวทางในการติดตามการเปลี่ยนแปลงของข้อมูลใหม่ต่อไป

วารสารสมาคมจิตแพทย์แห่งประเทศไทย 2541; 43(2): 159-66.

In most cultures, alcohol is the most frequently used brain depressant. At some time in their lives, as many as 90% of adults in the United States have had some experiences with alcohol, and a substantial number (60% of males and 30% of females) have had one or more alcohol related adverse life events(1). Excessive consumption of alcohol is a major public health concern worldwide. Tremendous insights in alcohol research largely developed in recent years. These advances which have had enormous impact on medical scientific field include:

• advance in genetic work;
• the application of neuroscience to understanding drinking and the phenomena of addiction;
• how alcohol damages organs, and
• the development of new approaches to treatment and prevention.

Advance in genetic work

Research on the genetics of alcoholism is still in the formative stage; nevertheless, a tremendous amount of work has been accomplished, and many tentative conclusions appear not only possible but reasonable.

Familial studies have demonstrated that the incidence of alcoholism is higher in families of alcoholic than in the general population. Sons of alcoholics are approximately 3-5 times more likely to become alcoholic than are sons of non alcoholics(2). The significance of this proportion has led to the possibility that the etiology for alcoholism to run in families is genetically determined(3,4,5). Twin studies for the most part have shown concordance for alcoholism to be greater in identical (monozygotic) twin-pairs than the concordance for alcoholism in fraternal (dizygotic) twin-pairs(6,7,8,9). In order to assess the relative contribution of genetic and environmental factors to the development of alcoholism, investigators have analyzed drinking patterns in adopted children of alcoholics and non-alcoholics. Sons of alcoholics, adopted by non-alcoholic families in early life, are 3 times more likely to become alcoholic than are similarly adopted sons of non-alcoholics (10,11,12).

The combination of family, twin, and adoption studies offers enough support for genetic factors to justify a search for what might be inherited to increase the risk for this disorder. As a result, a number of laboratories have begun to look for trait or phenotypic markers of a vulnerability toward alcoholism.

Phenotypic markers can be defined as molecular, biochemical, physiological or behavioral patterns of response to alcohol that can be shown to genetically associated with alcoholism. In the current use of animal models and the approaches of Qualitative Trait Loci (QTL) mapping to find locations in the mouse genome that may have synonymy with the human genome, it is interesting that a number of candidate loci are located in the 4q, 9q, and 13q chromosomal regions (Table 1) (13,14,15,16).

Table 1. Relationship between candidate loci and phenotypic markers.

The application of neuroscience to understanding the phenomena of alcohol addiction

Remarkable application of technologies and techniques of neuroscience has been brought to bear on understanding the consumption of alcohol and related behavioral phenomena of addiction, that is, tolerance; withdrawal; impair control over drinking ; and craving.

Ethanol diffuses into cell membranes and increase membrane fluidity. After chronic exposure to ethanol, cellular membranes become resistant to the fluidizing effect(17). In addition, there are also acute and chronic ethanol-induced changes in many membrane component and functions; membrane lipids and phosphatidylinositol, receptors, second messengers, GTP binding proteins, neuromodulators, ion channels, transporters, and protein whose gene expression is altered by ethanol. Many of these membrane components are acutely affected by ethanol and later exhibit tolerance when rechallenged (18,19,20,21,22,23,24).

Research has found many effects of different receptor system, such as NMDA; of nitric oxide; and especially of the cytokine network that has now been shown to be involved in the action of alcohol. The excitatory NMDA receptor in the hippocampus appears to play a role in learning and memory, and is exquisitely sensitive to ethanol. The voltage-dependent calcium channel is also a major target for the acute and chronic effects of ethanol. The increased number of voltage-dependent calcium channels found after chronic exposure to ethanol involves regulation by protein kinase C and may play a role in alcohol withdrawal seizures. Indeed, mice genetically prone to develop ethanol withdrawal seizures exhibit an increase in voltage-dependent calcium channels. Abnormal sensitivity to ethanol or altered regulation of these membrane-dependent events by ethanol could play a role in a genetic predisposition to alcoholism(25,26,27,28,29).

cAMP signal transduction is a second messenger system that undergoes acute and chronic adaptive responses to ethanol. Adenosine is an inhibitory modulator that appears to mediate many acute and chronic effects of ethanol in the nervous system(30).

Recent investigations indicated the potential involvement of several neurotransmitter and neuromodulator systems, such as serotonin, dopamine, and g aminobutyric acid (GABA), in abnormal alcohol drinking behavior. The benzodiazepine/GABA receptor complex appears to be a major target for ethanol, exhibiting cross-tolerance with BZD and barbiturates. Differences in GABA_A-activated Cl^- channel function have recently been found in animal with differential genetic sensitivity to the hypnotic effect of ethanol(31).

Also, attention has focused on the endogenous opioid system as a possible mediator of alcohol drinking. There are at least three possible mechanisms by which alcohol can enhance opioid receptor activity. First, the alcohol metabolite, acetaldehyde, can combine with catecholamines to form the alkaloid tetrahydropapaveroline(THP). THP can convert to tetrahydroisoquinoline alkaloids(TIQ_S), which are opioid receptor agonists and directly lead to morphine-like effects. Second, Alcohol can stimulate the release of b endorphin or enkephalins, and thus indirectly stimulate opioid receptor activity. However, this action may be specific to only people at risk for alcohol dependence because of a positive family of alcoholism. Third, alcohol can directly enhance the sensitivity of the opioid receptors to endogenous opioids by altering membrane fluidity(32).

Another interest is focused on Arginine vasopressin(AVP), a mammalian antidiuretic hormone. It was shown that in animal studies the administration of AVP will maintain (reduce the rate of loss of) functional ethanol tolerance, once that tolerance has been acquired, even in the absence of further ethanol intake by the animals. This action may be related to the effect of AVP on c-fos expression in the lateral septum(33,34).

How alcohol affects organs

Many discoveries have been made about the toxicology of alcohol in the brain, heart, liver, gastrointestinal tract, marrow, breast tissue and especially in the developing fetus(35,36,37,38,39). Recently, acetaldehyde, the first metabolite of ethanol is recognizing as an animal carcinogen and is suspected to be the key chemical in alcohol-related cancer(40). Another aspect of toxicology is its converse, the fact that while alcohol harms body tissues. It also has protective effects on coronary circulation, and possibly prevent osteoporosis in postmenopausal women. These diverse and sometimes conflicting findings have served to stimulate further scientific study of how much drinking either endangers or benefits the health of both men and women(41,42).

The development of new approach to treatment

The search for new pharmacological adjuncts for the treatment of alcohol dependence is motivated by the limited effectiveness of current psychosocial and pharmacological treatments. Psychosocial treatments are associated with only modest success rates(43). Combining pharmacological and psychosocial treatments has limited clinical usefulness because the medications either are ineffective or have low level of patient compliance. The recent focus in alcoholism treatment research is the development of new pharmacotherapy. Naltrexone, an opiate antagonist, in the United States and acamprosate (calcium bisacetylchromotaurinate), a GABA agonist, in Europe are the most interesting examples(44,45,46). Many studies suggest that either naltrexone or acamprosate effectively reduces the rate of alcoholic relapse and the level of craving for alcohol. Naltrexone apparently exerts its beneficial effects by reducing the ’high’ that is associated with alcohol consumption. In addition, both of these drugs appear to be safe in the alcohol-dependent population, and they are associated with only few side effects. If the efficacy suggested by these data is replicated in additional studies, it may be concluded that these drugs demonstrate many of the qualities hoped for in an ideal pharmacological treatment for alcoholism.

Another growing interest in treatment area has been focused on objective markers of heavy alcohol consumption since individuals do not always report accurately on the amount that they drink. Several biochemical markers are used clinically to indicate if a patient has a drinking problem. Among those in current use are blood ethanol, mean erythrocyte volume, high-density lipoprotein cholesterol,?g -glutamyltranspeptidase, and carbohydrate-deficient transferrin(47,48). Recently, all of these have drawbacks in diagnostic sensitivity and/or specificity. Phosphotidylethanol (PEth) is being investigated as another new biochemical marker of excess alcohol intake.

PEth is a unique phospholipid that is formed in cell membranes only in the presence of ethanol. In humans, basal PEth formation has been observed in neutrophil granulocytes of alcoholic patients up to 24 hours after the latest alcohol intake, when blood ethanol concentration was 0 (49). Investigators are now exploring ways of utilizing this test to better detect hidden heavy alcohol use and to monitor alcoholics during treatment and recovery(50).

SUMMARY

Alcohol abuse and alcoholism are serious social problems with both biological and behavioral elements. Investigating how the brain affects behavior is the one of greater challenges facing alcohol research over the next decade. All the new techniques of neuroscience are being used to further our understanding of the fundamental phenomena of alcohol use and abuse. How alcohol influences the variable expression of receptor subunits and how the initial pattern of subunits affects sensitivity to alcohol both under study. The toxic effects of alcohol on the structure and function of various organs are being explained. Subtle aspects of cognitive impairment are being studied with sophisticated tests combined with imaging. Important insight into the specificity of ethanol action at various receptors have revolutionized thinking. This contemporary work presents indicative of both the success of science in understanding brain, behavior and biology, and the future promise of neuroscience research to solve many questions concerning how alcoholism develops, and how it can be successfully prevented and treated. To formulate rational social policy in the future, it is necessary to know all details of its actions, not just one side of it.

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistic Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press, 1994.

2. Goodwin DW. Alcoholism and genetics: The sins of the fathers. Arch Gen Psychiatry 1985; 42: 171-4.

3. Devor EJ, Cloninger CR. Genetics of alcoholism. Annu Rev Genet 1989; 23: 19-36.

4. Merikangas KR. The genetic epidemiology of alcoholism. Psychol Med 1990; 20: 11-22.

5. Ball DM, Murray RM. Genetics of alcohol misuse. Br Med Bull 1994; 50: 18-35.

6. Romanov K, Kaprio J, Rose RJ, Koskenvuo M. Genetics of alcoholism: Effect of migration on concordance rates among male twins. Alcohol 1991; 1 (Suppl): 137-40.

7. Pickens RW, Svikis DS, Mc Gue M, Lykken DT, Heston LL, Clayton PJ. Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Arch Gen Psychiatry 1991; 48: 19-28.

8. Mc Gue M, Pickens RW, Svikis DS. Sex and age effects on the inheritance of alcohol problems. A twin study. J Abnorm Psychol 1992; 101: 3-17.

9. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ. A population-based twin study of alcoholism in women. JAMA 1992; 268: 1877-82.

10. Goodwin DW. Schulsinger F, Moller N, et al. Drinking problems in adopted and non-adopted sons of alcoholics. Arch Gen Psychiatry 1974; 31: 164-9.

11. Cloninger CR, Bohman M, Sigvardsson S. Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch Gen Psychiatry 1981; 38: 861-8.

12. Goodwin DW , Schulsinger F, Hermansen L, et al. Alcohol problems in adoptees raised apart from alcoholic biological parents. Arch Gen Psychiatry 1973; 28:238-43.

13. Keat BJB, Ott J, Conneally PM. Report of the committee on linkage and gene order. Cytogenet. Cell Genet 1989; 51:459-502.

14. Coming DE, Muhleman D, Dietz Jr. GW, Donlon T, Human Tryptophan oxygenase localized to 4q31: Possible implication for alcoholism and other behavioral disorders. Genomics 1991;9:301-8.

15. Craig SP, Buckle VJ, Lamouroux A, et al. Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. Cytogenet. Cell. Genet 1988; 48:48-50.

16. Sparkes RS, Lan N, Klisak I, et al. Assignment of a serotonin 5HT-2 receptor gene to human chromosome 13q14-q21 and mouse chromosome 14. Genomics 1991; 9:461-5.

17. Goldstein DB. Ethanol-induced adaptation in biological membranes. Ann NY Acad Sci 1986;492:103-11.

18. Lowinson JH, Ruiz P, Millman RB, et al. eds. Substance abuse. A comprehensive textbook. 3rd ed. Baltimore: Williams&Wilkins, 997.

19. Begleiter H, Kissin B, eds. The Genetics of Alcoholism. Oxford University Press:. New York, 1995.

20. Reynolds JN, Wu PH, Khanna JM, et al. Ethanol tolerance in hippocampal neurons: Adaptive changes in cellular responses to ethanol measure in vitro. J Pharmacol Exp Ther 1990; 252: 265-71.

21. Diamond I, Wrubel B, Estrin E, et al. Basal and adenosine-receptor stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients. Proc Natl Acad Sci (USA)1987;84:1413-6.

22. Charness ME, Querimit LA, Henteleff M. Ethanol differentially regulates G proteins in neural cells. Biochem Biophys. Res. Commun 1988;155:138-43.

23. Nagy LE, Diamond I, Casso DJ, et al. Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the neucleotide transporter. J Biol Chem 1990; 265: 1946-51.

24. Miles MF, Diaz JE, DE Guzman VS. Mechanisms of neuronal adaptation to ethanol. J Biol Chem 1991; 266: 409-14.

25. Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science. 1989; 243:1721-4.

26.Dolin S, Little H, Hudspith M, et al. Increased dihydropyridine sensitive calcium channels in rat brain may underlie ethanol physical dependence. Neuropharmacology 1987;26:275-9.

27. Messing RO, Sneade AB, Saridge B. Proteinkinase C participates in up-regulation of dihydropyridine-sensitive calcium channels by ethanol. J Neurochem 1990; 55: 1385-9.

28. Koppi S, Eberhardt G, Haller R, et al. Calcium-chaael-blocking agent in the treatment of acute alcohol withdrawal-caroverine versus meprobamate in the randomized double-blind study. Neuropsychobiology 1987; 17: 49-52.

29. Brennan CH, Crabb J, Littleton JM. Genetic regulation of dihydropyridine sensitive calcium channels in brain may determine susceptibility to physical dependence on alcohol. Neuropharmacology 1990; 29:429-32.

30. Gordon AS, Nagy LE, Mochly-Rosen D, et al. Chronic ethanol-induced heterologous desensitization is mediated by changes in adenosine transport. In: G proteins and signal transduction, Symposium No. 56, G. Milligan, M.J. o. Wakelam and J. Kay, eds. London: London Biochemical Society, 1990.

31. Allan AM, Harris RA. Neurochemical studies of genetic differences in alcohol action. In: Crabbe JC Jr, Harris RA, eds. The genetic basis of alcohol and drug addictions. Plenum Press: New York, 1991: 105-52.

32. Ulm RR, Volpiccelli LA. Opiates and alcohol self-administration in animals. J Clin Psychiatry 1995; 56 (suppl7): 5-14.

33. Wu PH, Liu JF, Wu WL, et al. Development of alcohol tolerance in the rat after a single exposure to combined treatment with arginine(8)-vasopressin and ethanol. J Pharmacol Exp Ther 1996;276:1283-91.

34. Rathna GP, Dave JR, Tabakoff B, et al. Arginine vasopressin induces the expression of c-fos in the mouse septum and hippocampus. Mol Brain Res 1990;7:131-7.

35. Myers WD, Ng KT, Singer G, et al. Dopamine and salsolonol levels in rat hypothalami and striatum after schedule-induced self-injection(SISI) of ethanol and acetaldehyde. Brain Res 1985; 358: 122-8.

36. Collins MA, Ung-Chhun N, Cheng BY, et al. Brain and plasma tetrahydroisoquinolines in rats: effects of chronic ethanol intake and diet. J Neurochem. 1990; 55: 1507-14.

37. Kato I. The extent of the problems and the epidemiological aspects of alcoholdrinking. In: Preedy VR, Watson RR, eds. Alcohol and the Gastrointestinal tract. Florida: CRC Press, 1996: 1-17.

38. Longnecker M. Alcohol beverage consumption in relation to risk of breast cancer:meta-analysis and review. Cancer Causes Control 1994; 5: 73-82.

39. Conry J. Neuropsychological details in fetal alcohol syndrome and fetal alcohol effects. Alcohol Clin Exp Res 1990; 14: 650-61.

40. Blot WJ. Alcohol and cancer. Cancer Res 1992; 52: 2119s-2123s.

41. Hanna EZ, Chou SP, Grant BF. The relationship between drinking and heart disease morbidity in the United States; Results from the National Health Interview Survey. Alcohol Clin Exp Res 1997; 21(1): 111-8..

42. Galanter M. Recent developments in alcoholism. Vol 12, Alcoholism and women. Plenum Press: New York, 1995.

43. Nathan PE. Outcomes of treatment for alcoholism: current data. Ann Behav Med 1986: 40-6.

44. Volpicelli JR, Clay KL, Watson NT , O’Brien CP. Naltrexon in the treatment of alcoholism: Predicting response to naltrexone. J Clin Psychiatry 1995;56(suppl7):39-44.

45. Sass H, Soyka M, Mann K, et al. Relapse prevention by acamprosate: result from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry 1996;53:673-80.

46. Benjaponpitak A. Acamprosate as an alternative in the treatment of alcohol addiction. Journal of the Psychiatric Association of Thailand 1997; 42: 107-12.

47. Rosman AS, Basu P, Galvin K, Lieber CS. Utility of carbohydrate deficient transferrin. Improvement with individualized reference levels during long-term monitoring. Alcohol Clin Exp Res 1995; 961-3.

48. Kelly W, ed. Textbook of Internal Medicine. Philadelphia: JB Lippincott, 1989.

49. Lundqvist C, Alling C, Aradottir S, et al. Aronist-stimulated phospholipase D activity and phosphotidylethanol accumulation in neutrophils from alcoholics. Alcohol Clin Exp Res 1994; 18:580-6.

50.Hansson P, Caron M, Johnson G, et al. Blood Phosphatidylethanol as a marker of alcohol abuse: Levels in alcoholic males during withdrawal. Alcohol Clin Exp Res 1997;21:108-10.