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

Abstract

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.

Fig. 1

Repeated alcohol sensitization of withdrawal-induced anxiety-like behavior. Male Sprague-Dawley rats (8–10 per group) were exposed to either control diet, one cycle of 5 days of 4.5% alcohol diet (alcohol diet, 1-cycle), three cycles of 5 days of 4.5% alcohol diet with 2 days interruption after withdrawal from the first two cycles of alcohol exposure (alcohol diet, 3-cycles), or 15 consecutive days of 4.5% alcohol diet (alcohol diet, continuous). Social interaction was measured 5–6 h after the final withdrawal from alcohol diet. No change in locomotor activity was observed in these groups. Social interaction was the primary approach used to assess anxiety-like behavior because this test is well validated (File 1980; File and Hyde 1978; File and Seth 2003; Sams-Dodd 1995). Data modified from Overstreet et al. (2002) by permission of publisher. *P<0.01 compared with the other groups

Fig. 2

Stress induces anxiety-like behavior in animals with previous experience of chronic alcohol (ethanol) diet. Rats (8–10 per group) were exposed to restraint stress for 45 min 3 days after receiving control diet (control diet stress) or multiple withdrawals from 4.5% ethanol diet (ethanol diet stress). Included were groups that received control diet without stress (control diet, no stress) or multiple withdrawals with no stress (ethanol diet, no stress). To assess anxiety-like behavior, social interaction was measured 30 min after receiving restraint stress. *P<0.02 when alcohol diet stress is compared with the other groups

Fig. 3

Schematic representation of the “kindling”/stress contribution to the etiology of alcoholism. The initial engagement of “kindling” in alcoholism (phase I) is proposed to follow withdrawals from repeated cycles of alcohol abuse. This “kindling” results in an insidious neural adaptation that persists (i.e., an increasing allostatic load), a change that accounts for the progression of alcohol use from social drinking to alcohol dependence (phase II). The adaptation to repeated alcohol exposures reflects the “kindling” component of the “kindling”/stress hypothesis. The accumulated adaptive change caused by repeated withdrawals facilitates negative affect during acute withdrawal (phase IIIa) and results in craving and an increased probability of relapse (phase IV). Following recovery from acute withdrawal, the persistent adaptation induced by alcohol abuse interacts with stress to promote negative affect during abstinence (phase IIIb), a circumstance that also induces a desire to drink (craving) and an increased probability of relapse (phase IV). This negative affect and craving initiated by stress during abstinence forms the “stress” component of the “kindling”/stress hypothesis. The persistent adaptation related to alcohol abuse presumably contributes to the inability of an alcoholic to control intake upon relapse (phase V). The renewed alcohol abuse with relapse and subsequent repeated withdrawals will continue over years to “kindle” adaptation until an increased sensitivity for withdrawal seizure susceptibility evolves (Ballenger and Post 1978)