Medid Hypotheses (1990) 32.5&O @ Longman Group UK Ltd 1990
Do Alcoholics Receptors?
have Abnormal
Benzodiazepine
S. S. MISSAK P.O. Box 2B97, Wilkes-Barre,
PA 18703, USA
Abstract - The behavioral effects of a given amount of ethanol vary greatly between alcoholic and nonalcoholic subjects. A blood alcohol level of more than 150 mg/dL without gross evidence of intoxication is a definitive diagnostic laboratory test for alcoholism (1). In a previous paper, I have proposed that the human body produces a substance similar to caffeine (2). In the present paper, my new concept is used to explain the intriguing ability of alcoholics to tolerate the effects of ethanol. Understanding why alcoholics differ from normal individuals in, their response to ethanol is an important step that will pave the way for the prevention of the transmission of alcoholism to future generations.
Introduction (A) Ethanol produces central nervous system depression similar to the one produced by the sedative-hypnotics including short-acting barbiturates and benzodiazepines (3). (B) It is believed that ethanol exerts its incoordinating and anxiolytic effects through modulation of the function of the benzodiazepine receptor (4). (C) The benzodiazepine receptor has been shown to mediate the pharmacological actions of benzodiazepines and barbiturates (5) (D) Caffeine inhibits the binding of benzodiazepines to specific sites in brain tissue (6). Keeping the above mentioned information in mind, it is reasonable to propose that caffeine is Date Date
received accepted
29 May 1989 18 August 1989
a competitive antagonist of ethanol and benzodiazepines at the level of the benzodiazepine receptors. In a previous paper, I have proposed that the human body produces a substance similar to caffeine and that this substance plays a physiologic role in every human being (2). This caffeine-like substance is likely to be similar to caffeine in its ability to compete with ethanol and benzodiazepines for the benzodiazepine receptors.
Discussion In nonalcoholic subjects, a blood alcohol level of loo-150 mg/dL produces gross motor incoordination (7). Alcoholics have a remarkable ability to tolerate the effects of ethanol. A blood alcohol level of more than 150 mg/dL without gross
60 evidence of intoxication is a definitive diagnostic laboratory test for alcoholism (1). Some studies suggest that children of alcoholics become significantly less intoxicated at a given blood alcohol concentration than do controls, even before alcoholism develops. After modest alcohol doses, the sons of alcoholics report less intense subjective feelings of intoxication and show less alcohol-related impairment in cognitive and psychomotor tests than do controls. However, after heavy alcohol intake the differences between the two groups are less marked (8). In order to explain the peculiar ability of alcoholics to tolerate the effects of ethanol, I propose that alcoholics have abnormal benzodiazepine receptors that preferentially bind an endogenous caffeine-like substance which acts as an ethano@enzodiazepine antagonist. An unusually high blood alcohol concentration has to be achieved before ethanol can displace this endogenous ethanol/benzodiazepine antagonist from the benzodiazepine receptors. This explains why, after heavy alcohol intake, the differences between sons of alcoholics and controls are less marked. Conclusion
MEDICAL HYPOTHESES
zodiazepine receptors of alcoholics is genetically controlled. The identification of the responsible genes will pave the way for the prevention of the transmission of alcoholism to future generations through proper genetic counseling.
References 1. Criteria committee, National Council on alcoholism, New York, New York (Kaim S C, committee chairman). Criteria for the diagnosis of alcoholism. Annals of Internal Medicine 77: 249-258, 1972. 2. Missak S S. Does the human body produce a substance similar to caffeine? Medical Hypotheses 24: 161-165, 1987. 3. Meyers F H, Jawetz E, Goldfien A. Alcohols. p 244 in Review of Medical Pharmacologv. Seventh edition. (F H Meyers, E; Jawetz, A Goldfien,~ids) Lange Medical PubI lications, Los Altos, California, 1980. 4. Hoffman P L, et al. Effect of an imidazobenzodiazepine, Ro 15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital. Life Sciences 41: 611-619,1987. modification of 5. Trullas R, et al. Environmentally-induced the benzodiazepine/GABA receptor coupled chloride ionophore. Psychopharmacology 91: 384-390,1987. 6. Rall T W. Central nervous system stimulants. p 590 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Seventh edition. (A G Gilman, L S Goodman, eds) Macmillan Publishing Company, New York, 1985.
The concept of an endogenous caffeine-like substance which acts as an ethanol/betizodiazepine antagonist is very helpful in understanding the peculiar ability of alcoholics to tc$erate the effects of ethanol. The isolation of this caffeine-like substance will be helpful in the characterization of the abnormal benzodiazepine receptors of alcoholics. Since their is strong evidence that alcoholism has a genetic component (8, 9), I propose that the synthesis of the abnormal ben-
Meyers F H, Jawetz E, Goldfien A. Alcohols. p 246 in Review of Medical Pharmacology. Seventh edition. (F H Meyers, E Jawetz. A Goldfien, eds) Lange Medical plhlicaiions, Los Altos, California, 19b. Schuckit M A. Alcohol and alcoholism. v 2109 in ... Harrison’s Principles of Internal Medicine. Elkventh ediI__ tion. (E Braunwald, K J Isselbacher, eds) McGraw-Hill Book Company, New York, 1987. Kim T F. - Research increasingly focuses on possible genetic factors in complex problem of alcohol abuse. The Journal of the American Medical Association 261, No. 15: 2170-2171,1989. -1
Do Alcoholics Receptors?
have Abnormal
Benzodiazepine
S. S. MISSAK P.O. Box 2B97, Wilkes-Barre,
PA 18703, USA
Abstract - The behavioral effects of a given amount of ethanol vary greatly between alcoholic and nonalcoholic subjects. A blood alcohol level of more than 150 mg/dL without gross evidence of intoxication is a definitive diagnostic laboratory test for alcoholism (1). In a previous paper, I have proposed that the human body produces a substance similar to caffeine (2). In the present paper, my new concept is used to explain the intriguing ability of alcoholics to tolerate the effects of ethanol. Understanding why alcoholics differ from normal individuals in, their response to ethanol is an important step that will pave the way for the prevention of the transmission of alcoholism to future generations.
Introduction (A) Ethanol produces central nervous system depression similar to the one produced by the sedative-hypnotics including short-acting barbiturates and benzodiazepines (3). (B) It is believed that ethanol exerts its incoordinating and anxiolytic effects through modulation of the function of the benzodiazepine receptor (4). (C) The benzodiazepine receptor has been shown to mediate the pharmacological actions of benzodiazepines and barbiturates (5) (D) Caffeine inhibits the binding of benzodiazepines to specific sites in brain tissue (6). Keeping the above mentioned information in mind, it is reasonable to propose that caffeine is Date Date
received accepted
29 May 1989 18 August 1989
a competitive antagonist of ethanol and benzodiazepines at the level of the benzodiazepine receptors. In a previous paper, I have proposed that the human body produces a substance similar to caffeine and that this substance plays a physiologic role in every human being (2). This caffeine-like substance is likely to be similar to caffeine in its ability to compete with ethanol and benzodiazepines for the benzodiazepine receptors.
Discussion In nonalcoholic subjects, a blood alcohol level of loo-150 mg/dL produces gross motor incoordination (7). Alcoholics have a remarkable ability to tolerate the effects of ethanol. A blood alcohol level of more than 150 mg/dL without gross
60 evidence of intoxication is a definitive diagnostic laboratory test for alcoholism (1). Some studies suggest that children of alcoholics become significantly less intoxicated at a given blood alcohol concentration than do controls, even before alcoholism develops. After modest alcohol doses, the sons of alcoholics report less intense subjective feelings of intoxication and show less alcohol-related impairment in cognitive and psychomotor tests than do controls. However, after heavy alcohol intake the differences between the two groups are less marked (8). In order to explain the peculiar ability of alcoholics to tolerate the effects of ethanol, I propose that alcoholics have abnormal benzodiazepine receptors that preferentially bind an endogenous caffeine-like substance which acts as an ethano@enzodiazepine antagonist. An unusually high blood alcohol concentration has to be achieved before ethanol can displace this endogenous ethanol/benzodiazepine antagonist from the benzodiazepine receptors. This explains why, after heavy alcohol intake, the differences between sons of alcoholics and controls are less marked. Conclusion
MEDICAL HYPOTHESES
zodiazepine receptors of alcoholics is genetically controlled. The identification of the responsible genes will pave the way for the prevention of the transmission of alcoholism to future generations through proper genetic counseling.
References 1. Criteria committee, National Council on alcoholism, New York, New York (Kaim S C, committee chairman). Criteria for the diagnosis of alcoholism. Annals of Internal Medicine 77: 249-258, 1972. 2. Missak S S. Does the human body produce a substance similar to caffeine? Medical Hypotheses 24: 161-165, 1987. 3. Meyers F H, Jawetz E, Goldfien A. Alcohols. p 244 in Review of Medical Pharmacologv. Seventh edition. (F H Meyers, E; Jawetz, A Goldfien,~ids) Lange Medical PubI lications, Los Altos, California, 1980. 4. Hoffman P L, et al. Effect of an imidazobenzodiazepine, Ro 15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital. Life Sciences 41: 611-619,1987. modification of 5. Trullas R, et al. Environmentally-induced the benzodiazepine/GABA receptor coupled chloride ionophore. Psychopharmacology 91: 384-390,1987. 6. Rall T W. Central nervous system stimulants. p 590 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Seventh edition. (A G Gilman, L S Goodman, eds) Macmillan Publishing Company, New York, 1985.
The concept of an endogenous caffeine-like substance which acts as an ethanol/betizodiazepine antagonist is very helpful in understanding the peculiar ability of alcoholics to tc$erate the effects of ethanol. The isolation of this caffeine-like substance will be helpful in the characterization of the abnormal benzodiazepine receptors of alcoholics. Since their is strong evidence that alcoholism has a genetic component (8, 9), I propose that the synthesis of the abnormal ben-
Meyers F H, Jawetz E, Goldfien A. Alcohols. p 246 in Review of Medical Pharmacology. Seventh edition. (F H Meyers, E Jawetz. A Goldfien, eds) Lange Medical plhlicaiions, Los Altos, California, 19b. Schuckit M A. Alcohol and alcoholism. v 2109 in ... Harrison’s Principles of Internal Medicine. Elkventh ediI__ tion. (E Braunwald, K J Isselbacher, eds) McGraw-Hill Book Company, New York, 1987. Kim T F. - Research increasingly focuses on possible genetic factors in complex problem of alcohol abuse. The Journal of the American Medical Association 261, No. 15: 2170-2171,1989. -1
