Kindling as a Model for Alcohol Withdrawal Syndromes

Ballenger, James C.; Post, Robert M.

doi:10.1192/bjp.133.1.1

Cited by 415 publications

(194 citation statements)

References 69 publications

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“…Physical withdrawal symptoms represent a gauge of the severity of alcohol dependency. Alcohol withdrawal symptoms range from anxiety, mild tremors and hyperreflexia to severe convulsions and seizures (Victor and Brausch, 1967;Goldstein, 1972;Majchrowicz, 1975;1981;Ballenger and Post, 1978;Crabbe et al, 1991;Babor et al, 1992;Booth and Blow, 1993;Metten and Crabbe, 1996;Becker et al, 1997;Finn and Crabbe, 1997;Metten et al, 1998;Becker, 2000). In general, the physical symptoms associated with alcohol withdrawal reflect hyperexcitation in the central nervous system following chronic consumption of alcohol.…”

Section: Discussionmentioning

confidence: 99%

Severity of alcohol withdrawal symptoms depends on developmental stage of Long–Evans rats

Chung

Wang

Wehman

et al. 2008

Pharmacology Biochemistry and Behavior

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To investigate alcohol dependency and the potential role of age of initial alcohol consumption, Long-Evans (LE) rats were fed an ethanol-containing liquid diet starting at postnatal (P) ages (days): P23-27 (juvenile), P35-45 (adolescent) or P65-97 (young adult). Severity of subsequent withdrawal symptoms was dependent on age when consumption began and on duration of alcohol consumption. Frequency of withdrawal seizures was highest for rats starting consumption as juveniles, intermediate for adolescents and lowest for adults. Normalized to body weight, alcohol consumption was significantly higher for adolescent and juvenile rats than for adults. SpragueDawley rats that began alcohol consumption as adolescents (P35) had a level of alcohol consumption identical to that of the adolescent LE rats but showed much lower frequency of withdrawal seizures when tested after 2, 3 and 5 weeks of alcohol consumption. Based on several indicators, the capacity of the juveniles to metabolize ethanol is equal to or exceeds that of adults. Recoveries from a single dose of ethanol (2.5g ethanol/kg body weight) were faster for juvenile LE rats than adults. The rate of decline in blood ethanol concentration was identical for juvenile and adult rats while the corrected ethanol elimination rate was higher for juveniles. The primary isozyme of alcohol dehydrogenase (ADH) in rat liver, ADH-3, had a similar Km and higher activity in liver preparations from juveniles. In conclusion, LE rats beginning alcohol consumption as juveniles or adolescents develop a severe alcohol withdrawal syndrome that may not be attributed entirely to higher levels of consumption and was not explained by any obvious deficiencies in metabolism.

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Section: Discussionmentioning

confidence: 99%

Severity of alcohol withdrawal symptoms depends on developmental stage of Long–Evans rats

Chung

Wang

Wehman

et al. 2008

Pharmacology Biochemistry and Behavior

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“…Ballenger and Post (1978) indeed implied that symptoms of alcoholics unrelated to seizure sensitivity increased with the duration of chronic excessive drinking. Anxiety, negative affective states and depression are known to be prominent symptoms of acute withdrawal in the alcoholic (Duka et al 2002;Liappas et al 2002).…”

Section: Sensitization Of Multiple Withdrawal-induced Anxiety-like Bementioning

confidence: 98%

“…Pinel et al (1975) introduced the concept that multiple stimulations of brain can sensitize the alcohol withdrawal syndrome. Ballenger and Post (1978) noted that the number of repeated detoxifications increased the susceptibility of alcoholics for withdrawal-induced seizures and proposed a kindling process to account for this correlation. This theory of kindling seizure activity was subsequently supported by several clinical investigations (Booth and Blow 1993;Brown et al 1988;Lechtenberg and Worner 1990, 1991Worner 1996).…”

Section: Concept Of Kindling Seizure Susceptibility With Repeated Witmentioning

confidence: 99%

“…3, phase IIIa; Duka et al 2002;Liappas et al 2002)-the nature of the withdrawal symptoms being dependent on the amount of alcohol previously ingested and the duration of alcohol abuse (Ballenger and Post 1978). When alcohol drinking occurs during an acute withdrawal state, alcoholics indicate they "feel better."…”

Section: Stress During Withdrawal From Multiple Alcohol Exposures Incmentioning

confidence: 99%

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Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

2004

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Rationale-The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.Objective and results-An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence-a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.Conclusions-The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse-and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

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“…After Ballenger and Post (1978) first called attention to the phenomenon, several investigators documented the changes in seizure susceptibility (Becker et al, 1997(Becker et al, , 1998McCown and Breese, 1990;Veatch and Gonzalez, 1996, 1999. There have also been reports that human subjects who have experienced multiple detoxifications may have increased craving for ethanol and a greater risk of relapse (Brown et al, 1988;Malcolm et al, 2000a,b).…”

Section: Introductionmentioning

confidence: 99%

Similar anxiety-like responses in male and female rats exposed to repeated withdrawals from ethanol

Overstreet

Knapp

Breese

2004

Pharmacology Biochemistry and Behavior

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Previous research indicated that male rats exhibited anxiety-like behavior following withdrawal from chronic ethanol exposure. This behavior, as well as other symptoms of withdrawal such as seizure susceptibility, may be sensitized in male rats repeatedly withdrawn from chronic ethanol exposure. Because there are sex differences in some alcohol effects, the present study explored whether male and female rats would respond differently to a course of repeated ethanol withdrawals. Similarly aged male and female rats were exposed to a control liquid diet or a diet containing ethanol (7% w/ v). Ethanol-exposed rats had only one 5-day cycle of exposure or three cycles, with 2 days of control diet (CD) between cycles. At 5 h after the final ethanol was removed, the rats were placed as samesexed pairs in the social interaction test; approximately half of the rats were tested later in the elevated plus maze. Rats withdrawn from ethanol after three cycles exhibited reduced the time spent in social interaction and general activity in the social interaction test and reduced the open and closed arm entries in the elevated plus maze. There were no sex differences in these effects. However, male rats exhibited a small anxiety-like response after one cycle of 5 days' exposure to ethanol and female rats did not. Thus, there are no sex differences in the three-cycle multiple-withdrawal paradigm, but there may be differences after briefer exposures.

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Kindling as a Model for Alcohol Withdrawal Syndromes

Cited by 415 publications

References 69 publications

Severity of alcohol withdrawal symptoms depends on developmental stage of Long–Evans rats

Severity of alcohol withdrawal symptoms depends on developmental stage of Long–Evans rats

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

Similar anxiety-like responses in male and female rats exposed to repeated withdrawals from ethanol

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