The Kindling Model of Alcohol Dependence: Similar Persistent Reduction in Seizure Threshold to Pentylenetetrazol in Animals Receiving Chronic Ethanol or Chronic Pentylenetetrazol

Kokka, Norio; Sapp, Douglas W.; Taylor, Anna M.; Olsen, Richard W.

doi:10.1111/j.1530-0277.1993.tb00793.x

Cited by 134 publications

(99 citation statements)

References 31 publications

(1 reference statement)

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“…This finding is similar to that reported earlier in male WSP and WSR mice (Finn and Crabbe, 1999) and male rats (Kokka et al, 1993) during ethanol withdrawal. Increased sensitivity to (+)bicuculline also has been reported in male and female rats (e.g., Devaud et al, 1995Devaud et al, , 1996 during ethanol withdrawal.…”

Section: Discussionsupporting

confidence: 93%

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Beckley¹,

Fretwell²,

Tanchuck³

et al. 2008

Neuropharmacology

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SUMMARYThe GABAergic neurosteroid allopregnanolone (ALLO) has been repeatedly shown to have an increased anticonvulsant effect during ethanol withdrawal in rats and in C57BL/6J mice. In contrast, the seizure prone DBA/2J inbred strain and the Withdrawal Seizure-Prone (WSP) selected line exhibited decreased sensitivity to ALLO's anticonvulsant effect during ethanol withdrawal, with no change in sensitivity in the Withdrawal Seizure-Resistant (WSR) line. To date, only male mice have been tested. Thus, the present study examined ALLO sensitivity during ethanol withdrawal in female WSP and WSR mice, since females display less severe physical symptoms of withdrawal and have higher circulating ALLO levels than males. Female WSP and WSR mice were exposed to ethanol vapor or air for 72 hr. During peak ethanol withdrawal, separate groups of mice were injected with vehicle or ALLO (0, 3.2, 10, or 17 mg/kg, ip) prior to the timed tail vein infusion of pentylenetetrazol (PTZ). ALLO injection significantly increased the threshold dose for onset to PTZ-induced convulsions, indicating an anticonvulsant effect, in female WSP and WSR mice. During ethanol withdrawal, sensitivity to ALLO's anticonvulsant effect was slightly increased in female WSR mice but was significantly decreased in female WSP mice. This line difference in sensitivity to ALLO during ethanol withdrawal in female mice was similar to that in the male mice. Notably, all seizure prone genotypes tested to date displayed tolerance to the anticonvulsant effect of ALLO during ethanol withdrawal, suggesting that decreased sensitivity of GABA A receptors to ALLO may contribute to the increased ethanol withdrawal phenotype.

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Section: Discussionsupporting

confidence: 93%

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Beckley¹,

Fretwell²,

Tanchuck³

et al. 2008

Neuropharmacology

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“…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). Work in rats showing that repeated withdrawals from chronic alcohol facilitate inferior collicular kindling afforded critical support for the kindling hypothesis (McCown and Breese 1990), as did other animal studies that demonstrated enhanced seizure susceptibility following repeated withdrawals (Baker and Cannon 1979;Becker and Hale 1993;Becker et al 1997Becker et al , 1998Clemmesen and Hemmingsen 1984;Kokka et al 1993;Maier and Pohorecky 1989;Meert and Huysmans 1994;Ripley et al 2002;Stephens et al 2001;Ulrichsen et al 1995Ulrichsen et al , 1998. This concept of "kindling" of seizure activity following repeated detoxifications has been a major advance, as it provided an appreciation of the necessity of progressive adaptive change preceding withdrawal-induced seizure activity in alcoholics.…”

Section: Concept Of Kindling Seizure Susceptibility With Repeated Witmentioning

confidence: 81%

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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“…The schedule used for chronic alcohol exposure was modified from previous studies. 16,17 These animals are referred to as the chronic alcohol-exposed (CA) rats. The remaining animals (n = 45) received an equal volume of NS and are referred to as the nonalcohol-exposed (NA) animals.…”

Section: Methodsmentioning

confidence: 99%

The Effects of Acute and Chronic Alcohol Ingestion on Outcome following Multiple Episodes of Mild Traumatic Brain Injury in Rats

Biros

Kukielka

Sutton

et al. 1999

Academic Emergency Medicine

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Abstract.Objective: Recent studies suggest that in some circumstances, alcohol intoxication at the time of severe head injury may be neuroprotective. The objective of this study was to determine the effect of acute and chronic alcohol ingestion on outcome in rodents sustaining multiple episodes of mild traumatic brain injury while intoxicated. Methods: For two weeks before experimentation, adult male SpragueDawley rats received intoxicating levels of 95% ethanol (3 g/kg) or normal saline (NS) every other day by orogastric instillation. On the day of experimentation, the animals were randomized to receive alcohol or NS. Two hours later, the animals received either mild (1.2 Ϯ 0.4 ATA) fluid percussion injury (FPI) or no injury. The injured animals received a total of three episodes of FPI (once every four days). Mean reflex recovery time (RRT) was determined (seconds Ϯ SEM) immediately after each episode. Mean latency time (seconds Ϯ SEM) for Morris Water Maze (MWM) performance was assessed at posttrauma days 11-19. Results: The chronic alcoholexposed (CA) and the non-alcohol-exposed (NA) animals intoxicated when injured had prolonged escape, righting, and corneal RRTs after each FPI compared with the nonintoxicated injured animals and the noninjured shams. However, the CA animals had significantly shorter RRTs when compared with the NA rats. All the injured animals had MWM deficits on testing days 1-6 compared with the noninjured controls. On the last two MWM testing days, the injured NA animals had significantly better MWM performance than the injured CA rats. Conclusions: The injured intoxicated CA animals had a more rapid recovery of reflexes compared with the injured intoxicated NA animals. Despite initial MWM deficits, the injured NA rodents eventually began to learn the MWM. The injured CA rats never learned the maze. Under the conditions of this study, acute alcohol intoxication at the time of multiple episodes of minor head trauma did not provide neuroprotection for NA or CA rodents.

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The Kindling Model of Alcohol Dependence: Similar Persistent Reduction in Seizure Threshold to Pentylenetetrazol in Animals Receiving Chronic Ethanol or Chronic Pentylenetetrazol

Cited by 134 publications

References 31 publications

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

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

The Effects of Acute and Chronic Alcohol Ingestion on Outcome following Multiple Episodes of Mild Traumatic Brain Injury in Rats

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