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Kindling as a Model for Alcohol Withdrawal Syndromes

  • James C. Ballenger (a1) and Robert M. Post (a1)

Periodic brain stimulation, particularly in the limbic system, at stimulus intensities initially too low to produce any behavioural or EEG effects, progressively produces EEG changes, motor automatisms, and eventually convulsions, an effect called kindling. Data are presented and reviewed that suggest that the severity of alcohol withdrawal symptoms progressively increases over years of alcohol abuse in a stepwise fashion similar to the kindling process. The model is presented that the limbic system hyperirritability which accompanies each alcohol withdrawal serves over time to kindle increasingly widespread subcortical structures. These long-term changes in neuronal excitability might relate to the progression of alcohol withdrawal symptoms from tremor to seizures and delirium tremens, as well as the alcoholic personality changes between episodes of withdrawal.

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Reprints requests should be sent to: Robert M. Post, M.D., National Institutes of Health, Building 10, Room 3S239, 9000 Rockville Pike, Bethesda, Maryland 20014.
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Adamec, R. (1975) Behavioral and epileptic determinants of predatory attack behavior in the cat. Can. J. Neurol. Sci., 2, 457–66.
Arentsen, K. & Sindrum, E. (1963) Electroencephalographic investigation of alcoholics. Acta Psychiatr. Scand., 39, 371–83.
Arnold, P., Racine, R. & Wise, R. (1973) Effects of atropine, reserpine, 6-hydroxydopamine and handling on seizure development in the rat. Exp. Neurol., 40, 458–69.
Babington, R. & Wedeking, P. (1973) The pharmacology of seizures induced by sensitization with low intensity brain stimulation. Pharmacol. Biochem. Beh., 1, 461–7.
Ballenger, J. C., Goodwin, F. K., Major, F. & Brown, L. Alcohol and central serotonin metabolism in man. Arch. Gen. Psychiatry, in press.
Bear, D. & Fedio, P. (1977) Quantitative analysis of interictal behavior in temporal lobe epilepsy. Arch. Neurol., 34, 454–67.
Begleiter, H. & Platz, A. (1972) The effects of alcohol on the central nervous system in humans. In The Biology of Alcoholism: Physiology and Behavior, Volume II (eds Kissin, B. and Begleiter, H.). New York and London: Plenum Press.
Begleiter, H. Gross, M. M. & Porjesz, B. (1973) Recovery function and clinical symptomatology in acute alcoholization and withdrawal. In Alcohol Intoxication and Withdrawal: Experimental Studies (ed. Gross, M. M.). New York: Plenum Press.
Begleiter, H. Projesz, B. & Yerre-Grubstein, C. (1974) Excitability cycle of somatosensory evoked potentials during experimental alcoholization and withdrawal. Psychopharmacologia, 37, 1521.
Bjorkqvist, S. G., Isohanni, M., Makela, R. & Malinen, L. (1976) Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal multicentre double-blind comparison with placebo. Acta Psychiatr. Scand., 53, 333–42.
Blumer, D. (1970) Changes in sexual behavior related to temporal lobe disorder in man. J. Sex. Res., 6, 173–80.
Blumer, D. (1974) Organic personality disorder. In Personality Disorders: Diagnosis and Management (ed. Lion, J.). Baltimore: Williams and Williams Co.
Branchey, M., Rauscher, G. & Kissin, B. (1971) Modifications in the response to alcohol following the establishment of physical dependence. Psychopharmacologia, 22, 314–22.
Brune, F. (1966) Anhebung der krampfschwelle als therapeutisches prinzip bei der behandlung von alkolhol-delirien. Nervenarzt, 37, 415–18.
Brune, F. & Busch, H. (1971) Anticonvulsive-sedative treatment of delirium alcoholism. Q,. J. Stud. Alcohol, 32, 334–42.
Chambers, J. F. & Schultz, J. D. (1965) Double-blind study of three drugs in the treatment of acute alcoholic states. Q. J. Stud. Alcohol, 26, 1018.
Cole, J. A. & Ryback, R. S. (1976) Pharmacological therapy. In Alcoholism: Interdisciplinary Approaches to an Enduring Problem (eds Tarter, R. and Sugerman, A.). Reading, Massachusetts: Addison-Wesley Publishing Co.
Cutshall, B. J. (1965) The Saunders-Sutler syndrome: an analysis of delirium tremens. Q. J. Stud. Alcohol, 26, 423–48.
Davies, D. L., Shepherd, M. & Myers, E. (1956) The two year prognosis of fifty alcohol addicts after treatment in hospital. Q. J. Stud Alcohol, 17, 485502.
Deutsch, J. A. & Koopmans, H. S. (1973) Preference enhancement for alcohol by passive exposure. Science, 179, 1242–3.
Dewhurst, K. & Beard, A. W. (1970) Sudden religious conversions in temporal lobe epilepsy. Br. J. Psychiatry, 117, 497507.
Edmonds, H. L. & Bellin, S. I. (1976) Quantification of alcohol intoxication and withdrawal in the rat. Neuroscience Abstracts, Sixth Annual Meeting of the Society for Neuroscience, 7–11 November 1976, II, Abstract #1250.
Ellis, F. W. & Pick, J. R. (1970) Experimentally induced ethanol dependence in rhesus monkeys. J. Pharmacol. Exp. Ther., 175, 8893.
Essig, C. F. & Lam, R. C. (1971) The alcohol abstinence syndrome in dogs and its treatment with pentobarbital. In Recent Advances in Studies of Alcoholism: An Interdisciplinary Symposium, Washington, D.C., 1970 (eds Mello, N. K. and Mendelson, J.), Washington, D.C.: U.S. Government Printing Office, NIH Publ. No. (HSM) 71–9045.
Essig, C. F. Jones, E. & Lam, R. C. (1969) The effect of pentobarbital on alcohol withdrawal in dogs. Arch. Neurol., 20, 554–8.
Feldstein, A. (1971) Effect of ethanol on neurohumoral amine metabolism. In The Biology of Alcoholism: Biochemistry, Volume I (eds Kissin, B. and Begleiter, H.). New York: Plenum Press.
Feuerlein, W. (1967) Klinisch-statistische Untersuchengen Über die Entstehungsbedengungen und die Prognose des Alkoholdelirs. Nervenarzt, 38, 206–12.
Feuerlein, W. (1972) Zur frage des Alkohol-entzugssyndroms. Nervenarzt, 43, 247–53.
Feuerlein, W. (1974) The acute alcohol withdrawal syndrome: findings and problems. Br. J. Addict., 69, 141–8.
Flor-Henry, P. (1969) Schizophrenic-like reactions and affective psychoses associated with temporal lobe epilepsy: etiological factors. Am. J. Psychiatry, 126, 400–3.
Freund, G. (1969) Alcohol withdrawal syndrome in mice. Arch. Neurol., 21, 315–20.
Freund, G. & Walker, D. W. (1971) Sound-induced seizures during ethanol withdrawal in mice. Psychopharmacologia, 22, 2449.
Geschwind, N. (1973) Effects of temporal lobe surgery on behavior. N Engl. J. Med., 286, 480–1.
Gibbs, F. A. (1951) Ictal and nonictal psychiatric disorders in temporal lobe epilepsy. J. New. Ment. Dis., 113, 522–8.
Glatt, M. M. (1961) Drinking habits of English (middle class) alcoholics. Acta Psychiatr. Scand., 37, 88113.
Goddard, G. V. & Douglas, R. M. (1975) Does the engram of kindling model the engram of normal long term memory? Can. J. Neurol. Sci., 2, 385–94.
Goddard, G. V. McIntyre, D. C. & Leech, C. K. (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol., 25, 295330.
Goldstein, D. B. (1972a) Relationship of alcohol dose to intensity of withdrawal signs in mice. J. Pharmacol. Exp. Ther., 180, 203–15.
Goldstein, D. B. (1972b) An animal model for testing effects of drugs on alcohol withdrawal reactions. J. Pharmacol. Exp. Ther., 183, 1422.
Goldstein, D. B. (1974) Rates of onset and decay of alcohol physical dependence in mice. J. Pharmacol. Exp. Ther., 190, 377–83.
Goldstein, D. B. & Arnold, V. W. (1976) Drinking patterns as predictors of alcohol withdrawal reactions in DBA/2 J mice. J. Pharmacol. Exp. Ther., 199, 408–14.
Gross, M. M., Lewis, E. & Hastey, J. (1974) Acute alcohol withdrawal syndrome. In The Biology of Alcoholism: Clinical Pathology, Volume III (eds Kissin, B. and Begleiter, H.). New York: Plenum Press.
Gross, M. M., Kierszenbaum, H. S., Lewis, E. & Lee, Y. (1976) Desire to drink: relationship to age, blood alcohol concentration, and severity of withdrawal syndrome on admission for detoxification. Ann. N.T. Acad. Sci., 273, 360–3.
Gross, M. M., Rosenblatt, S. M., Malinowski, B., Broman, M. & Lewis, E. (1971) A factor analytic study of the clinical phenomena in the acute alcohol withdrawal syndromes. In Selected Papers given at the 16th International Institute on the Prevention and Treatment of Alcoholism, Volume II. Toronto: Press of Addiction Research Foundation.
Gross, M. M., Rosenblatt, S. M., Lewis, E., Chartoff, S. & Malenowski, B. (1972) Acute alcoholic psychoses and related syndromes: psychsocial and clinical characteristics and their implications. Br. J. Addict., 67, 1531.
Guerrero-Figueroa, R., Rye, M. M., Gallant, D. M. & Bishop, M. (1970) Electrographic and behavioral effects of diazepam during alcohol withdrawal stage in cats. Neuropharmacology, 9, 143–50.
Hernandez-Peon, R. (1964) Anticonvulsive action of G32883. In Proceedings of the Third Collegium Internationale Neuropsychopharmacologicum, Munich, 1962. Amsterdam: Elsevier.
Hill, D. (1953) Psychiatric disorders of epilepsy. Med. Res., 20, 473–5.
Himwich, H. E., Diperri, R., Dravid, A. & Schweigerdt, A. (1966) Comparative susceptibility to alcohol of the cortical area and midbrain reticular formation of the cat. Psychosom. Med., 28, 258–62.
Horn, J. & Wanberg, K. (1969) Symptom patterns related to excessive use of alcohol. Q. J. Stud. Alcohol, 30, 3558.
Hunt, W. A. (1973) Changes in the neuro-excitability of alcohol dependent rats undergoing withdrawal as measured by the pentylenetetrazole seizure threshold. Neuropharmacology, 12, 1097–102.
Hunter, B. E., Walker, D. W. & Riley, J. N. (1974) Dissociation between physical dependence and volitional ethanol consumption: role of multiple withdrawal episodes. Pharmacol. Biochem. Beh., 2, 523–9.
Hunter, B. E., Boast, C. A., Walker, D. W. & Zornetzer, S. F. (1973) Alcohol withdrawal syndrome in rats: neural and behavioral correlates. Pharmacol. Biochem. Beh., 1, 719–25.
Isbell, H., Fraser, H. F., Wikler, A., Belleville, R. & Eisenman, A. (1955) An experimental study of the etiology of ‘rum fits’ and delirium tremens. Q. J. Stud. Alcohol, 16, 133.
Jellinek, E. M. (1946) Phases in the drinking histories of alcoholics. Q. J. Stud. Alcohol, 7, 188.
Jellinek, E. M. (1952) Phases of alcohol addiction. Q. J. Stud. Alcohol, 13, 673–84.
Johnson, R. M. (1961) The alcohol withdrawal syndrome. Q. J. Stud. Alcohol (suppl. 1), 6676.
Kaim, S. C. (1971) Drug treatment of the alcohol withdrawal syndrome. In Recent Advances in Studies of Alcoholism: An Interdisciplinary Symposium, Washington, D.C., 25–27 June 1970 (eds Mello, N. K. and Mendelson, J.). Washington, D.C.: U.S. Government Printing Office, NIH Publ. No. (HSM) 71–9045.
Kalant, H. (1961) The pharmacology of alcohol intoxication. Q. J. Stud. Alcohol (suppl. 1), 123.
Kalant, H. Leblang, A. & Gibbins, R. (1971) Tolerance to, and dependence on, ethanol. In Biological Basis of Alcoholism (eds Israel, Y. and Mardones, J.). New York: Wiley and Sons.
Kissin, B. & Charnoff, S. M. (1967) Clinical evaluations of tranquillizers and antidepressants in the long term treatment of chronic alcoholism. In Alcoholism: Behavioral Research, Therapeutic Approaches (ed. Fox, R.). New York: Springer Publishing Co.
Kotani, K. (1967) EEG studies on endogenous psychoses and alcohol intoxication. Bull. Osaka Med. Sch. (suppl. 12), 303–14.
Lennox, W. G. (1941) Alcohol and epilepsy. Q. J. Stud. Alcohol, 2, 111.
Lundquist, G. (1961) Delirium tremens: a comparative study of pathogenesis, course, and prognosis with delirium tremens. Acta Psychiatr. Scand., 36, 443–66.
MacIntyre, D. C. (in press) Kindling and memory: the adrenal system and the bisected brain. In Proceedings of the Symposium on the Continuing Evolution of the Limbic System Concept (eds Livingston, K. and Hornykiewicz, O.). New York/London: Plenum Press.
Macdonnell, M. F., Fessock, L. & Brown, S. H. (1971) Ethanol and the neural substrate for affective defense in the cat. Q. J. Stud. Alcohol, 32, 406–19.
Majchrowicz, E. & Hunt, W. A. (1976) Temporal relationship of the induction of tolerance and physical dependence after continuous intoxication with maximum tolerable doses of ethanol in rats. Psychopharmacology, 50, 107–12.
Marinacci, A. A. (1963) A special type of temporal lobe (psychomotor) seizures following ingestion of alcohol. Bull. Los Angeles Neurol. Soc., 28, 241–50.
Mason, C. R. & Cooper, R. M. (1972) A permanent change in convulsion threshold in normal and brain damaged rats with small repeated doses of pentylenetetrazol. Epilepsia, 13, 663–74.
McNamee, H., Mello, N. & Mendelson, J. (1968) Experimental analysis of drinking patterns of alcoholics: concurrent psychiatric observations. Am. J. Psychiatry, 124, 1063–9.
McQuarrie, D. & Fingl, E. (1958) Effect of single doses and chronic administration of ethanol on experimental seizures in mice. J. Pharmacol. Exp. Ther., 124, 264–71.
Mello, N. K. (1972) Behavioral studies on alcoholics. In The Biology of Alcoholism: Physiology and Behavior, Volume II (eds Kissin, B. and Begleiter, H.). New York: Plenum Press.
Mello, N. K. (1973) A review of methods to induce alcohol addiction in animals. Pharmacol. Biochem. Beh., 1, 89101.
Mello, N. K. & Mendelson, J. H. (1976) The development of alcohol dependence: a clinical study. McLean Hosp. J., 1, 6484.
Mendelson, J. H. (ed.) (1964) Experimentally induced chronic intoxication and withdrawal in alcoholics. Q. J. Stud. Alcohol (suppl. 2).
Mendelson, J. H. (x 1972) Biochemical mechanisms of alcohol addiction. In The Biology of Alcoholism: Biochemistry, Volume I (eds Kissin, B. and Begleiter, H.). New York: Plenum Press.
Mendelson, J. H. & La Dou, J. (1964) Experimentally induced chronic intoxication and withdrawal in alcoholics: psychophysiological findings. Q. J. Stud. Alcohol (suppl. 2), 1439.
Mendelson, J. H. Stein, S. & McGuire, M. T. (1966) Comparative psychophysiological studies of alcoholic and nonalcoholic subjects undergoing experimentally induced ethanol intoxication. Psychosom. Med., 28, 112.
Naitoh, P. (1972) The effects of alcohol on the autonomic nervous system of humans: psychophysiological approach. In The Biology of Alcoholism: Physiology and Behavior, Volume II (eds Kissin, B. and Begleiter, H.). New York: Plenum Press.
Nielsen, J. (1965) Delirium tremens in Copenhagen: part of a cross-national investigation of delirium tremens in the Nordic counties sponsored by the Nordic Committee for alcohol research. Acta Psychiatr. Scand., 187, 192.
Park, P. (1973) Developmental ordering of experiences in alcoholism. Q. J. Stud. Alcohol, 34, 473–88.
Pinel, J. P. J. & Van Oot, P. H. (1975) Generality of the kindling phenomenon: some clinical implications. Can. J. Neurol. Sci., 2, 467–75.
Pinel, J. P. J. & Van Oot, P. H. (1975) Intensification of the alcohol withdrawal syndrome by repeated brain stimulation. Nature, 254, 510–11.
Pinel, J. P. J. Treit, D. & Rovner, L. I. (1977) Temporal lobe aggression in rats. Science, 197, 1088–9.
Post, R. M., Kopanda, R. T. & Lee, A. (1975) Progressive behavioral changes during chronic lidocaine administration: relationship to kindling. Life Sci, 17, 943–50.
Post, R. M., Kopanda, R. T. & Black, K. E. (1976) Progressive effects of cocaine on behavior and central amine metabolism in rhesus monkeys: relationship to kindling and psychosis. Biol. Psychiatry, 11, 403–19.
Pritchard, J. W., Gallagher, B. B. & Glaser, G. H. (1969) Experimental seizure threshold testing with flurothyl. J. Pharmacol. Exp. Ther., 166, 170–8.
Racine, R. J. (1972) Modification of seizure activity by electrical stimulation: II. Motor seizures. Electroencephalogr. Clin. Neurophysiol., 32, 281–94.
Racine, R. J. Livingston, K. & Joaquin, A. (1975) Effects of procaine hydrochloride, diazepam, and diphenylhydantoin on seizure development in cortical and subcortical structures in rats. Electroencephalogr. Clin. Neurophysiol., 38, 355–65.
Ratcliff, F. (1972) Ethanol dependence in the rat: its production and characteristics. Arch. Int. Pharmacodyn. Ther., 196, 146–56.
Rawat, A. K. (1974) Brain levels and turnover rates of presumptive neurotransmitters as influenced by administration of ethanol in mice. J. Neurochem., 22, 915–22.
Rosenblatt, S. M., Gross, M. M., Malenowski, B., Broman, M. & Lewis, E. (1972) Factor analysis of the daily clinical course rating scale of the acute alcoholic psychoses. Q. J. Stud. Alcohol, 33, 1060–4.
Rothstein, E. (1973) Prevention of alcohol withdrawal seizures: the roles of diphenylhydantoin and chlordiazepoxide. Am. J. Psychiatry, 130, 1381–2.
Segal, B. M., Kushnarev, V. M., Urakov, I. G. & Misionzhnik, E. U. (1970) Alcoholism and disruptions of activity of deep cerebral structures. Q. J. Stud. Alcoholism, 31, 587601.
Serafetinides, E. A. (1965) Aggressiveness in temporal lobe epileptics and its relation to cerebral dysfunction and environmental factors. Epilepsia, 6, 3342.
Singer, K. & Wong, M. (1973) Alcoholic psychoses and alcoholism in the Chinese. Q. J. Stud. Alcohol, 34, 878–86.
Slater, E. & Moran, P. A. P. (1969) The schizophreniclike psychoses of epilepsy: relationship between ages of onset. Br. J. Psychiatry, 11, 599600.
Spitzer, R., Endicott, J. & Robins, E. (1975) Research Diagnostic Criteria. New York: New York State Department of Mental Hygiene, New York State Psychiatric Institute, Biometrics Research.
Stevens, J. R. (1975) Interictal clinical manifestations of complex partial seizures. In Advances in Neurology: Complex Partial Seizures and Their Treatment, Volume II (eds Penry, J. K. and Daly, D. D.). New York: Raven Press.
Tamerin, J. S. & Mendelson, J. H. (1969) The psycho-dynamics of chronic inebriation: observations of alcoholics during the process of drinking in an experimental group setting. Am. J. Psychiatry, 125, 886–99.
Thomas, D. W. & Freedman, D. X. (1964) Treatment of the alcohol withdrawal syndrome: comparison of promazine and paraldehyde. JAMA, 188, 316–18.
Thompson, W. L., Johnson, A. D. & Maddrey, W. L. (1975) Diazepam and paraldehyde for treatment of severe delirium tremens: a controlled trial. Arm. Intern. Med., 82, 175–80.
Trice, H. & Wahl, R. (1958) A rank order analysis of symptoms of alcoholism. Q. J. Stud. Alcohol, 19, 636–48.
Victor, M. (1970) The alcohol withdrawal syndrome. Postgrad. Med., 47, 6872.
Victor, M. (1973) Withdrawal, neurological syndromes, and EEG. Ann. N.Y. Acad. Sci., 215, 210–13.
Victor, M. & Adams, R. D. (1953) The effect of alcohol on the nervous system. Proc. A. Res. Nero. Ment. Dis., 32, 526–73.
Victor, M. & Brausch, J. (1967) The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia, 8, 120.
Vosu, H. & Wise, R. A. (1975) Cholinergic seizure kindling in the rat: comparison of caudate, amygdala, and hippocampus. Behav. Biol., 13, 491–5.
Wada, J. & Sato, M. (1974) Generalized convulsive seizures induced by daily electrical stimulation of the amygdala in cats: correlative electrographic and behavioral features. Neurology, 24, 565–74.
Wada, J. & Osawa, T. (1976) Spontaneous recurrent seizure state induced by daily electric amygdaloid stimulation in Senegalese baboons (Papio papio). Neurology, 26, 273–86.
Wada, J. Sato, M., Wake, A., Green, J. & Troupin, S. (1976) Prophylactic effects of phenytoin, phenobarbital, and carbamazepine examined in kindling cat preparations. Arch. Neurol., 33, 426–34.
Walker, D. W. & Zornetzer, S. F. (1974) Alcohol withdrawal in mice: electroencephalographic and behavioral correlates. Electroencephalogr. Clin. Neurophysiol., 36, 233–43.
Whitwell, F. D. (1975) A study into the etiology of delirium tremens. Br. J. Addict., 70, 156–61.
Wikler, A., Pescor, F. T., Fraser, H. F. & Isbell, H. (1956) Electroencephalographic changes associated with chronic alcoholic intoxication and the alcohol abstinence syndrome. Am. J. Psychiatry, 113, 106–14.
Wise, R. & Chinbrman, J. (1974) Effects of diazepam and phenobarbital on electrically induced amygdaloid seizures and seizure development. Exp. Neurol., 45, 355–63.
Wolfe, S. M. & Victor, M. (1971) The alcohol withdrawal syndrome. In Recent Advances in Studies of Alcoholism: An Interdisciplinary Symposium, Washington, D.C., 25–27 June 1970 (eds Mello, N. K. and Mendelson, J.). Washington, D.C.: U.S. Government Printing Office, NIH Publ. No. (HSM) 71–9045.
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Kindling as a Model for Alcohol Withdrawal Syndromes

  • James C. Ballenger (a1) and Robert M. Post (a1)
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