It is well known that continued excessive alcohol consumption can lead to the development of physiological dependence. When drinking is abruptly terminated or substantially reduced in the dependent individual, a characteristic withdrawal syndrome ensues. As with other central nervous system (CNS) depressants, withdrawal symptoms associated with cessation of chronic alcohol use are opposite in nature to the effects of intoxication. Thus, clinical features of alcohol withdrawal include signs of heightened autonomic nervous system activation (e.g., tachycardia, elevated blood pressure, diaphoresis, tremor), CNS hyperexcitability that may culminate in motor seizures, and, in its most severe form, hallucinosis and delerium tremens (1-3). In addition to physical signs of withdrawal, a constellation of symptoms contributing to psychological discomfort (e.g., irritability, agitation, anxiety, dysphoria) constitute a significant component of the withdrawal syndrome (4-7). The overall intensity of the withdrawal syndrome is presumed to reflect the degree of physiological dependence developed during the course of chronic alcohol use/abuse.
Although a number of factors have been shown to influence the development and expression of alcohol dependence, the amount, duration, and pattern of alcohol consumption appear to play a critical role in influencing the intensity of withdrawal symptoms (8). Alcoholism and alcohol abuse often are characterized by frequent bouts of heavy drinking interspersed with periods of abstinence. Thus, it is not uncommon for many alcoholics to experience multiple episodes of withdrawal during the course of the disease (9). It has been suggested that repeated experience with alcohol may render individuals more vulnerable and susceptible to more complicated and severe withdrawal episodes in the future. Furthermore, the progressive intensification of withdrawal symptoms that results from repeated withdrawal experience has been postulated to represent the manifestations of a "kindlinglike" phenomenon. This chapter will provide an overview of this "kindling" hypothesis of alcohol withdrawal, as well as review experimental evidence suggestive of an important role for glutamate neurotransmission in mediating this phenomenon and related consequences.
2. THE KINDLING HYPOTHESIS OF ALCOHOL DEPENDENCE AND WITHDRAWAL
The term "kindling" was first introduced by Goddard et al. (10) and refers to the phenomenon wherein subthreshold electrical stimulation of discrete brain regions that initially produces no overt behavioral effects comes to produce, upon repeated periodic application, full motor seizures. It subsequently has been demonstrated that the stimulus may be chemical in nature as well (i.e., repeated systemic or central administration of subthreshold doses of various chemoconvulsants will come to produce full motor seizures). Enhanced brain excitability and susceptibility to behavioral convulsions
From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ
resultant from this kindling process has been shown to be long-lasting and thought to be most likely reflective of long-term changes in neuronal circuitry and function (11).
Extending this kindling phenomenon to alcohol withdrawal, it has been postulated that each episode of CNS hyperexcitability that normally accompanies alcohol withdrawal may serve as a stimulus supportive of a "kindling" process. Thus, although episodes of heavy drinking may not initially result in serious, or even noticeable, withdrawal symptoms, repeated experience with this pattern of excessive alcohol intoxication followed by periods of interrupted drinking (abstinence) may lead to a worsening of future withdrawal-related symptoms. This kindling or sensitization process then may underlie the commonly observed progression of withdrawal symptoms, from relatively mild responses characteristic of initial withdrawal episodes (irritability, tremors) to more severe symptoms associated with subsequent withdrawal syndromes, such as seizures and delirium tremens (12).
A substantial body of clinical and experimental evidence has accumulated in support of the "kindling" hypothesis of alcohol withdrawal (13-15). Clinical studies have revealed that alcoholics with a history of multiple previous detoxifications are more likely to experience a seizure during detoxification than patients without such detoxification histories (16-20). Additionally, a history of previous detoxifications was found to be associated not only with more severe and medically complicated withdrawal syndromes but also with an increased likelihood of hospital readmission for alcohol-related problems (16). More recently, clinical studies have revealed that a history of multiple detoxifications is associated with abnormal regional brain activity (21), as well as greater resistance to treatment and enhanced susceptibility to relapse (22,23).
Animal models have provided critical support for these findings, where multiple detoxifications are studied in models of repeated alcohol "withdrawals." For example, we have established a mouse model of alcohol dependence that is sensitive to the effects of a prior withdrawal experience (24). Mice experiencing repeated cycles of alcohol intoxication and withdrawal exhibit a significantly more severe withdrawal seizure response in comparison to animals tested following a single-withdrawal episode. Both intensity and duration of exacerbated withdrawal seizures were found to be positively correlated with the number of previously experienced withdrawal episodes (25,26). This sensitized withdrawal seizure response was observed even when the total amount of alcohol exposure was equated across groups (24,27). Importantly, the differential withdrawal response among groups with different histories of withdrawal experience does not appear to be related to an alteration in alcohol pharmacokinetics; that is, both peak blood alcohol levels and rate of alcohol elimination did not differ between animals following single or multiple cycles of alcohol intoxication and withdrawal (25).
Other studies employing different experimental procedures have similarly demonstrated an increase in the severity of alcohol-withdrawal symptoms following prior withdrawal experience (28-32). Although this "kindling" or sensitization of alcohol withdrawal has primarily focused on withdrawal-related CNS hyperexcitability (e.g., seizures), there is some evidence that other aspects of the withdrawal syndrome (e.g., anxiety) may be susceptible to this kindling phenomenon as well (33).
Exacerbated behavioral symptoms (i.e., indices of CNS hyperexcitability) observed in animals that experienced repeated episodes of withdrawal have been shown to be accompanied by progressively greater changes in EEG, including bursts of spike activity that reverberate among several brain regions, as well as abnormal patterns of epileptiform activity in specific brain regions (34-37). In fact, electrical activity in some brain regions (as measured by electroencepalography [EEG]) may be particularly sensitive to repeated withdrawal experience, whereas activity of other brain sites may be more responsive to total amount of alcohol exposure prior to withdrawal (35). In addition, multiple-withdrawal experience has been shown to result in more intense changes in brain local metabolic activity (38) and neuroendocrine responses (15), as well as cognitive/memory impairments (39) and susceptibility to neurotoxicity (40). There is also some evidence suggesting cross-sensitization between alcohol withdrawal and other forms of kindling. For example, animal studies have shown that prior electrical or chemical kindling potentiates the symptoms of subsequent alcohol withdrawal (30,41). Conversely, repeated experience with alcohol withdrawal has been reported to subsequently alter the development of electrical kindling in various brain structures (42-45).
Taken together, both preclinical and clinical studies have provided corroborating evidence supportive of the kindling hypothesis of alcohol withdrawal. The significance of this collective body of evidence is that, in addition to the amount (dose) and duration of alcohol consumption prior to withdrawal, a history of previous withdrawal experience appears to represent a critical factor that contributes to the severity of a given withdrawal episode.
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