Alcohol Withdrawal Kindling: Mechanisms and Implications for Treatment

Abstract

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Larry P. Gonzalez. The presentations were (1) EEG indices of sensitization in a murine model of repeated ethanol withdrawals, by Lynn M. Veatch; (2) Long-term changes in central nervous system function after repeated alcohol withdrawals: Recommendations for the treatment of acute withdrawal, by Larry P. Gonzalez; (3) Differential regulation of GABA A and NMDA receptors by repeated ethanol treatment in cultured mammalian neurons, by Maharaj K. Ticku; and (4) Involvement of GABA A and NMDA receptors in alcohol withdrawal kindling: Implications for treatment, by Howard C. Becker.

Disruption of blood–brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge‐like drinking model

“…It has been shown that during withdrawal, following continuous and intermittent ethanol exposure, ERK phosphorylation was increased in several brain areas (Sanna et al, ). An intermittent model of exposure resulted in significantly higher levels of ERK activation during withdrawal in the amygdala when compared to animals treated continuously which is consistent with the notion that repeated withdrawal produces a sensitizing effect (Gonzalez et al, ; Sanna et al, ). Obviously, we cannot speculate on the number of withdrawal episodes suffered by alcoholics but our results suggest that the dysregulation of the ERK pathway could contribute to the molecular adaptations which are thought to be involved in the development of addiction.…”

Alcohol withdrawal syndromes in the intensive care unit

“…In 1978, Ballenger and Post (24) proposed that the increase in central nervous system hyperexcitability that occurs with each successive withdrawal episode was the result of "kindling." This particularly seems to play a role in alcohol withdrawal seizures, and this may explain the clinical observation of increasing severity of alcohol withdrawal among individual subjects, and the development of benzodiazepine-resistant alcohol withdrawal (25)(26)(27). However, although well described in laboratory studies where repeated episodes of alcohol withdrawal lead to persistent and progressive electroencephalographic abnormalities, with further episodes of withdrawal becoming increasingly resistant to benzodiazepines, it is unclear of the clinical relevance in humans (27).…”

The Interplay between the Hippocampus and Amygdala in Regulating Aberrant Hippocampal Neurogenesis during Protracted Abstinence from Alcohol Dependence

“…For example, N -methyl- d -aspartate (NMDA) receptor activation reduces the proliferation of neural precursors in a normal state, and blockade of NMDA receptors increases the birth and survival of neural precursors in the DG, suggesting that neuronal inputs into the hippocampus regulate DG neurogenesis (Figure 2). Furthermore, recent evidence demonstrates compromised HPA axis activity (Richardson et al, 2008), altered glucocorticoid signaling (Vendruscolo et al, 2012), increased sensitivity to NMDA-mediated function (Becker et al, 1998; Gonzalez et al, 2001), and significant reductions in the rate of DG neurogenesis (Nixon and Crews, 2002; Richardson et al, 2009; Hansson et al, 2010) in a preclinical models of alcohol addiction and dependence. These data suggest that the normalization of alcohol-impaired DG neurogenesis during withdrawal may help reverse altered hippocampal neuroplasticity during protracted abstinence and thus may help reduce the vulnerability to relapse and aid recovery.…”