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Kindling in Withdrawal

Howard C. Becker, Ph.D.

In many alcoholics, the severity of withdrawal symptoms increases after repeated withdrawal episodes. This exacerbation may be attributable to a kindling process. Kindling is a phenomenon in which a weak electrical or chemical stimulus, which initially causes no overt behavioral responses, results in the appearance of behavioral effects, such as seizures, when it is administered repeatedly. Both clinical and experimental evidence support the existence of a kindling mechanism during alcohol withdrawal. Withdrawal symptoms, such as seizures, result from neurochemical imbalances in the brain of alcoholics who suddenly reduce or cease alcohol consumption. These imbalances may be exacerbated after repeated withdrawal experiences. The existence of kindling during withdrawal suggests that even patients experiencing mild withdrawal should be treated aggressively to prevent the increase in severity of subsequent withdrawal episodes. Kindling also may contribute to a patient’s relapse risk and to alcohol-related and cognitive impairment. KEY WORDS: AOD withdrawal syndrome; AODR (alcohol and other related) seizure; symptom; disease severity; neurotransmission; neurotransmitter receptors; cell electrophysiology; sensory stimuli; biochemical mechanism; AOD abstinence; AODD (alcohol and other drug dependence) relapse; brain damage; cognitive process; detoxification; treatment; animal model; clinical study; literature review

lcohol dependence and alcohol activation of the CNS remains in effect drawal reaction. In addition, a history frequently involve drink- for several more days, resulting in of withdrawal episodes appears to be a A ing patterns in which bouts of excessive excitability of the CNS (i.e., critical factor in the intensity of with- heavy drinking (i.e., binge drinking) hyperexcitability). This hyperexcitabil- drawal symptoms. Accordingly, some are interspersed with periods of absti- ity manifests itself as alcohol with- researchers have suggested that repeated nence. During the binge-drinking drawal (AW), with symptoms ranging episode, the body, particularly the from tremors and agitation to seizures brain, adapts to the presence of alco- and . As a result of the HOWARD C. BECKER, PH.D., is an hol by compensating for alcohol’s bingeing-abstaining consumption pat- associate professor in the departments effect on the central nervous system tern, many alcoholics experience numer- of and behavioral sciences (CNS). Alcohol has an overall sup- ous withdrawal episodes during the and physiology, Medical University pressing effect on CNS activity. course of their illness (Hillbom 1990). of South Carolina, and an associate Accordingly, the adaptation process The severity of AW symptoms can research career scientist at the Veterans involves several mechanisms to increase differ widely among alcoholics and Affairs Medical Center, Charleston, the excitability of nerve cells (i.e., even among different withdrawal South Carolina. ) in the brain—that is, their episodes in the same person. Both the ability to become activated in response amount of alcohol consumed and the Support for this work was provided by to signals from other neurons. When duration of intoxication just before the National Institute on the alcohol is eliminated from the body cessation of drinking are important and and the Department of during abstinence, this compensatory determinants of the severity of a with- Veterans Affairs Medical Research.

Vol. 22, No. 1, 1998 25 AW may sensitize a person to subsequent using electrodes implanted into the repeated episodes of this pattern of withdrawal episodes. This hypothesis brain. The researchers found that the followed by absti- implies that the severity of withdrawal- electrical stimuli initially produced no nence and withdrawal may lead to a related symptoms may increase in a overt behavioral effects, such as worsening of future withdrawal-related cumulative fashion, with more severe seizures (i.e., the stimuli were subcon- symptoms. Thus, a kindling process symptoms becoming evident after vulsive). After repeated periodic may underlie the commonly observed years of alcohol abuse and numerous application, however, the same subcon- progression of withdrawal symptoms periods of abstinence. vulsive stimuli induced the develop- from relatively mild responses (e.g., The mechanisms underlying the ment of full motor seizures, suggesting irritability and tremors) characteristic exacerbation of withdrawal symptoms that the brain had become sensitized of initial withdrawal episodes to more following repeated withdrawal episodes to the stimulation. Additional studies severe symptoms (e.g., seizures and delir- are currently unknown. One hypothesis found that sensitization could occur ium tremens) associated with subsequent proposes that the phenomenon may regardless of whether the stimulus was withdrawal episodes (Ballenger and result from a “priming” effect, in which electrical or chemical in nature (e.g., a Post 1978). each consecutive episode of alcohol convulsant drug administered directly exposure evokes stronger compen- into the brain or into other parts of satory (i.e., withdrawal) responses. In the body) (Gilbert 1992; Post et al. Kindling in Alcohol contrast, Ballenger and Post (1978) 1988). For kindling to occur, however, Withdrawal have hypothesized that the progressive it is critical that the subconvulsive exacerbation of AW is the manifesta- stimulus be administered in a repeated, tion of a “kindling” mechanism, intermittent fashion. This requirement Clinical Evidence which has been observed in other is a unique characteristic of kindling. neurological conditions. According to The kindling process is associated A growing body of clinical evidence this model, it is the repeated experi- with increased neuronal excitability, supports the kindling hypothesis for ence of AW, rather than repeated AW. Several clinical studies that retro- alcohol exposure, that underlies the spectively reviewed patient records progressive intensification of symp- revealed that hospitalized alcoholics toms. Although more evidence Some withdrawal who suffered a seizure during detox- supports such a kindling mechanism, symptoms may ification were more likely to have a a priming effect cannot be ruled out. history of numerous withdrawal In fact, the two mechanisms are not be particularly episodes than were hospitalized alco- mutually exclusive, and both may oper- holics who did not suffer seizures. ate in the final expression of the phe- suceptible For example, Brown and colleagues nomenon (Becker and Littleton 1996). to kindling. (1988) found that 48 percent of Over the past two decades, numer- inpatient alcoholics who had seizures ous studies have investigated the during detoxification had experienced phenomenon of withdrawal sensitiza- five or more previous withdrawal epi- tion (Becker and Littleton 1996). whose time course corresponds to that sodes, whereas only 12 percent of a This article provides an overview of of the progressive intensification of control group of hospitalized alco- clinical and experimental research behavioral and convulsive responses. holics who experienced no seizures findings supporting the kindling Furthermore, once the enhanced brain had such a history. More recent stud- hypothesis of AW. The article also excitability and susceptibility to con- ies have corroborated these findings, explores the mechanisms underlying vulsions has been established, it can demonstrating a positive correlation kindling and addresses implications last for several months. This durability between the occurrence of seizures of kindling related to AW treatment of the kindling phenomenon most likely during withdrawal and a history of strategies and to long-term conse- reflects long-term changes in neuronal previous detoxifications (e.g., Lech- quences of alcoholism. circuitry and function (McNamara tenberg and Worner 1991; Moak and and Wada 1997). Anton 1996). When applying the kindling hypoth- An increased risk of seizures in Kindling as a Mechanism esis to AW, researchers have postulated alcoholics with a history of multiple of Neural Sensitization that each withdrawal-induced episode withdrawal episodes is clinically sig- of CNS hyperexcitability may serve nificant, because patients experi- The term “kindling” was first intro- as a stimulus that supports a kindling encing AW-related seizures have a duced by Goddard and colleagues process (Ballenger and Post 1978). poorer prognosis and a higher mortal- (1969) to describe a phenomenon Accordingly, although binge drinking ity rate compared with people with observed after repeated weak electrical may not initially result in serious, or seizures from unknown causes (Pienin- stimulation of discrete brain regions even noticeable, withdrawal symptoms, keroinen et al. 1992). Booth and

26 Alcohol Health & Research World Kindling in Alcohol Withdrawal

Blow (1993) conducted a retrospec- directly into the stomach, feeding of Researchers have used animal tive analysis of admission records an alcohol-containing liquid diet, and models to investigate various additional for 6,818 male alcoholics treated at exposure to alcohol vapors (for a issues related to kindling in AW with 172 U.S. Veterans Affairs Hospitals. review, see Anton and Becker 1995). the following results: Their study found that a history of These studies found that withdrawal detoxification was associated with a symptoms were more severe in animals • The exacerbated behavioral symp- significantly increased likelihood of with previous withdrawal experience toms (e.g., convulsions) observed in hospital readmission for alcoholism than in animals that experienced first- animals with a history of repeated and alcohol-related problems. Moreover, time withdrawal. Moreover, the results withdrawal episodes were accompa- previous withdrawal episodes were suggested that some withdrawal symp- nied by progressively greater changes associated with more severe and toms (e.g., seizures) may be particularly in brain activity, as determined by medically complicated withdrawal, susceptible to kindling. (EEG) although the mortality from AW- Accordingly, many studies have (Poldrugo and Snead 1984; Veatch induced seizures was not significantly focused on kindling of withdrawal and Gonzalez 1996; Walker and influenced by the patient’s withdrawal seizures. For example, alcohol intoxi- Zornetzer 1974). These changes history (Booth and Blow 1993; Pienin- cation achieved by exposing mice to appear as abnormal patterns of brain keroinen et al. 1992). Collectively, alcohol vapors for 16 hours in inhalation waves (i.e., spikes and sharp waves) these results support the notion that chambers resulted in a mild with- in specific brain regions. More detailed after multiple withdrawal episodes, drawal response when the animals expe- analyses found that the EEG pat- patients become sensitized (possibly rienced a first withdrawal episode. After terns in some brain regions may be through a kindling mechanism) and repeated intoxication-withdrawal particularly sensitive to the individual’s subsequently experience more severe experiences, however, the same alco- history of withdrawal episodes, whereas withdrawal symptoms. hol exposure induced progressively the EEG activity of other brain sites more severe withdrawal-related con- may be more responsive to total Experimental Evidence vulsions (Becker 1994). Other studies amount of alcohol exposure before also found that both the intensity and withdrawal (Veatch and Gonzalez The use of animal models has further the duration of exacerbated withdrawal 1996). (For more information, see validated the kindling concept of AW seizures increased with the number of sidebar by Gonzalez, pp. 34–37.) and substantiated many of the obser- previous withdrawal experiences. vations noted in clinical settings. For The significance of repeated with- • Repeated AW influences the devel- example, several animal studies have drawal also has been demonstrated in opment of subsequent kindling not demonstrated increased neural hyper- experiments that compared withdrawal only in response to alcohol but also excitability and exacerbation of with- responses in two groups of mice in response to electrical stimuli. drawal symptoms following repeated exposed to the same amount of alcohol Whether the susceptibility to electrical withdrawal experiences (Becker and but according to different exposure kindling increases or decreases after Littleton 1996). This experimental schedules (e.g., Becker and Hale 1993; repeated withdrawal episodes depends support is particularly relevant, because Becker et al. 1997). In these experi- on the specific brain regions being numerous concurrent and intervening ments, one group of animals was studied (McCown and Breese 1990; variables associated with alcoholism continuously exposed to alcohol vapors Veatch and Gonzalez 1997). that may affect kindling (e.g., malnu- for 48 hours, whereas the second group trition and variable periods of alcohol was exposed to alcohol for a total of • Repeated withdrawal experiences exposure and abstinence) cannot be 48 hours divided into three cycles of result in changes in local metabolic adequately controlled in studies in 16 hours of intoxication separated by activity (e.g., how the brain metabo- humans and may confound interpre- 8 hours of abstinence. The analyses lizes the sugar glucose) in numerous tation of results. Animal models, in found that mice subjected to interrupted brain regions (Clemmesen et al. contrast, frequently allow analysis of alcohol exposure exhibited more severe 1988). These metabolic changes may the kindling effect under conditions withdrawal seizures compared with reflect alterations in the electrical in which variables such as intensity the animals subjected to uninterrupted activity (i.e., EEG patterns) of those (i.e., blood alcohol levels) and duration alcohol exposure. Moreover, the dif- brain regions. of alcohol exposure, duration of absti- ferences in withdrawal responses did nence, general health, and nutritional not appear to be related to alterations • Studies with mice, rats, and primates status can be rigorously controlled. in the rate of alcohol elimination have shown that a history of with- Animal models to investigate kin- from circulation following withdrawal. drawal decreases the duration and dling of withdrawal symptoms have These results suggest that repeated extent of intoxication necessary to used several different methods of AW, rather than the amount of alcohol provoke a subsequent withdrawal chronic alcohol exposure, including exposure per se, may be critical for response upon cessation of alcohol alcohol administration through a tube the kindling of AW symptoms. exposure (Anton and Becker 1995).

Vol. 22, No. 1, 1998 27 When analyzed together, both the presence of alcohol. When the Interference with the actions of GABA animal and clinical studies have pro- individual stops drinking, however, and the GABAA receptor—for example, vided corroborating evidence for the these adaptive changes result in an treatment with agents that block the kindling hypothesis of AW. These imbalance in inhibitory and excitatory GABAA receptor (i.e., receptor antag- findings indicate that in addition to neurotransmission, resulting in CNS onists)—can cause convulsions, which the alcohol dose and the duration of hyperexcitability that manifests itself are indicators of CNS hyperexcitability. alcohol exposure, a history of with- as withdrawal symptoms. With a Alcohol exposure results in activation drawal episodes represents another drinking pattern of repeated bingeing of the GABAA receptor, which in turn critical factor determining the severity and abstaining, the imbalance occurring leads to reduced CNS excitability and of a given withdrawal episode. during withdrawal may accrue and may thus contribute to alcohol’s seda- intensify with each successive episode tive effects (for a review, see Mihic and and may culminate in a state of per- Harris 1997). In response to chronic Brain Mechanisms sistent CNS hyperexcitability seen as alcohol exposure, the CNS adapts to the Underlying AW Kindling a kindled (i.e., augmented) withdrawal alcohol-induced GABAA activation response (see figure 1). The following by reducing GABA-mediated neuro- Chronic alcohol exposure and subse- sections review changes in inhibitory transmission. quent withdrawal affect many neuro- and excitatory neurotransmitter systems Several studies performed in intact chemical signaling systems in the CNS. that play a role in mediating CNS animals, isolated brain tissue slices, Signal transmission among neurons activity and function during AW. and cultured neurons have indicated occurs primarily through chemicals that the effects of chronic alcohol called neurotransmitters. These Changes in Inhibitory exposure on GABAA receptors may molecules are secreted by the signal- Neurotransmission contribute to exacerbated withdrawal emitting cell and bind to docking responses following multiple withdrawal molecules (i.e., receptors) on the signal- The primary inhibitory neurotrans- episodes, as follows: receiving cell. The interaction between mitter in the mammalian brain is a neurotransmitter and its receptor gamma-aminobutyric acid (GABA), • Various studies using animals exposed initiates a cascade of biochemical events which exerts its effects primarily to alcohol have demonstrated that in the signal-receiving cell. As a result, through the GABAA receptor (for more animals with a history of multiple the signal-receiving cell may become information on the mechanism of action withdrawal episodes exhibited easier or more difficult to excite, of the GABAA receptor, see figure 2). enhanced sensitivity to the convul- depending on the neurotransmitter involved. Neurotransmitters that increase the excitability of the signal- receiving cell are called excitatory neurotransmitters. Conversely, neuro- transmitters that reduce the excitability of the signal-receiving cell are called inhibitory neurotransmitters. Alcohol generally has a suppressive effect on the CNS: It reduces the activity of excitatory neurotransmitters and their receptors and enhances the activity of inhibitory neurotransmitters and their receptors. After long-term alcohol exposure, the body activates a complex set of mechanisms to counteract the effects Severity of Withdrawal Symptoms Withdrawal of Severity of alcohol’s persistent presence in the Alcohol Withdrawal Alcohol Withdrawal Alcohol Withdrawal Alcohol Withdrawal brain. These mechanisms promote Intoxication Intoxication Intoxication Intoxication the activity of excitatory neurotrans- Repeated Cycles of Alcohol Intoxication and Withdrawal mitter systems and suppress the activity of inhibitory neurotransmitter sys- tems, thereby attempting to return Figure 1 Graphic representation of the kindling concept during alcohol withdrawal. The term “kindling” refers to the phenomenon that people undergoing brain function to a “normal” state in repeated cycles of intoxication followed by abstinence and withdrawal will experience increasingly severe withdrawal symptoms with each 1 The is a brain region involved successive cycle. in memory and learning; its function is affected by alcohol.

28 Alcohol Health & Research World Kindling in Alcohol Withdrawal

sant properties of GABAA receptor of rats exposed to chronic inter- • Rats with a history of multiple with- antagonists (Becker and Littleton mittent alcohol treatment (Kang drawal episodes exhibited reduced 1996; Kokka et al. 1993; McCown et al. 1996). GABA-mediated neural inhibition. and Breese 1993). Moreover, the subunit composition • Treatment of cultured mammalian of the GABAA receptor—each recep- • After activation of GABAA receptors, cortical neurons with repeated cycles tor consists of five protein molecules, chloride ions enter the ; the of alcohol exposure and withdrawal or subunits—was altered in the hip- resulting increase in the chloride enhanced the cells’ sensitivity to pocampus of these animals (Mahmoudi concentration within the cell dampens treatment with GABAA receptor antag- et al. 1997). This change in the neural activity. This flow of chloride onists that prevented the GABA- structure of the GABAA receptor may ions into the cell was decreased in mediated flow of chloride ions into contribute to the reduced inhibitory brain slices from the hippocampus1 the cells (Hu and Ticku 1997). actions of GABA and, consequently,

Altered Brain Function Kindled Withdrawal Symptoms and Consequences Imbalance of inhibitory/excitatory neurotransmission ⇓ ⇑ Seizure susceptibility GABAA receptor function Altered adenosine function ⇑ NMDA receptor function ⇑ Anxiety Repeated Abusive ⇑ Voltage-operated Ca2+ Drinking Bingelike Withdrawal channel function (Relapse) Drinking Experiences

Neuroendocrine ⇑ dysregulation ⇑ HPA axis activation

Other neurochemical Altered subjective perturbations perception of alcohol effects ⇓ Dopamine function

Figure 2 Possible mechanisms contributing to kindling during alcohol withdrawal. Repeated binge drinking followed by abstinence leads to repeated withdrawal episodes, resulting in increasingly severe alterations of brain functions. The alterations include (1) a progressive imbalance between suppressive (i.e., inhibitory) and stimulating (i.e., excitatory) influences (i.e., neurotransmission) on brain function, (2) disturbances in certain hormonal systems (i.e., neuroendocrine dysregulation), and (3) other neurochemical perturbations. The changes result in increasingly severe withdrawal symptoms, including seizures, anxiety, toxic effects on nerve cells (i.e., neurotoxicity), and altered perception of alcohol’s effects. Any of those symptoms may increase the patient’s potential for relapse and vulnerability to brain damage.

GABAA receptor: A receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). NMDA receptor: A receptor for the excitatory neurotransmitter glutamate. HPA axis: A system involving produced in the hypothalamus, pituitary gland, and adrenal gland. Voltage-operated Ca2+ channel function: These calcium channels are located on the outer surface of the nerve cell. Electrical activity causes the channels to open, admitting calcium. Calcium entering the cell regulates many important processes related to cellular communication. ⇑ indicates an increase and ⇓ indicates a decrease in the brain function or withdrawal symptom listed.

Vol. 22, No. 1, 1998 29 to increased seizure susceptibility Another type of glutamate receptor Treatment Implications upon cessation of alcohol exposure. is the kainate receptor, which also can of AW Kindling be activated by the chemical kainate, In addition to GABA, changes in but not by NMDA. Kainate receptors Clinicians have used numerous strate- the inhibitory actions of another neuro- generally are located on different transmitter, adenosine, also have been neurons than NMDA receptors. In gies to manage AW. The primary goals implicated in kindling during AW contrast to the effects observed with of treating alcoholics during with- (Jarvis and Becker 1998). NMDA, multiple withdrawal experi- drawal are to prevent the occurrence ences in mice did not increase the of seizures and delirium tremens and animals’ sensitivity to the convulsant to ameliorate discomfort related to Changes in Excitatory autonomic instability (e.g., increased Neurotransmission properties of kainate (Becker et al. in press). This observation suggests that rate or and Along with decreased inhibitory neu- the kindling process does not involve sweating) and psychological instability rotransmission, enhanced excitatory all glutamate receptors but is associ- (e.g., anxiety). Given the high rate of neurotransmission may contribute to ated—at least initially—with selective recidivism among alcoholics, many the exacerbated withdrawal responses neurochemical changes in specific patients presenting for AW treatment resulting from repeated withdrawal brain regions. Recent electrophysio- probably have a history of detoxification. experiences. The primary excitatory Other patients will likely experience neurotransmitter in the brain is gluta- additional withdrawal episodes in the mate, which can interact with several future and are therefore at risk for more receptors. One of these receptors also Treatment of severe withdrawal symptoms during can be activated by the substance N- those future episodes as a result of methyl-D-aspartate (NMDA) and is early withdrawal kindling. Accordingly, the kindling therefore called the NMDA receptor. episodes may phenomenon and the patient’s with- Excessive activation of this receptor drawal history likely have a clinically induces seizures. (For more informa- delay kindled significant effect on treatment strategies. tion on the function of this receptor, Some debate still exists among see figure 2.) The involvement of the withdrawal seizures. clinicians and researchers over whether glutamate-NMDA receptor system in all patients experiencing AW should kindling has been suggested by find- be treated aggressively. On the one ings that animals with a history of mul- logical data have provided additional hand, many clinicians are concerned tiple AW episodes exhibited increased support for this notion (Veatch and about the safety of available pharma- sensitivity to NMDA-induced seizures Gonzalez 1996). cological treatments (e.g., sedatives, compared with animals tested follow- In addition to the NMDA and such as benzodiazepines) because of ing a single withdrawal episode (Becker kainate receptors, other excitatory their abuse and dependence potential. et al. in press). In cortical neurons neurochemical systems are likely This concern is particularly important, grown in culture, repeated alcohol responsive to repeated episodes of because the primary goal of alcoholism exposure and withdrawal increased the alcohol intoxication followed by with- treatment is for the patient to become number of NMDA receptors on the drawal and, therefore, contribute to dependence free. Consequently, some cells. This increase was accompanied the kindling phenomenon. For example, clinicians may fear that they are sub- by a rise in the NMDA-induced flow repeated alcohol exposure and with- stituting one dependence for another of calcium ions through the receptor drawal may result in the perturbation when using benzodiazepines for treating channel into the neurons, resulting in of calcium channels that are activated withdrawal. On the other hand, the enhanced neural excitability (Hu and not by neurotransmitter binding but growing body of evidence for with- Ticku 1997). by changes in the voltage difference drawal sensitization suggests that if Prolonged stimulation of NMDA (i.e., potential) between the inside and left untreated, repeated withdrawal receptors and calcium entry into brain the outside of the neuron. The abnormal episodes (even if they are relatively mild) cells can result in excessive cellular activation of such calcium channels may progress to a more severe, life- activity and, ultimately, neuronal death also may alter calcium levels within threatening syndrome in the future. (i.e., ). In experiments the neurons and subsequently lead to Some experimental evidence has using cultured tissue slices from rat neural damage. Further elucidation of suggested that treatment of early hippocampus, NMDA-induced exci- brain mechanisms underlying kindling withdrawal episodes may delay the totoxicity was enhanced following during AW should yield valuable development of later kindled with- repeated alcohol exposure and with- insight into these processes and provide drawal seizures (Ulrichsen et al. 1992; drawal (Becker and Littleton 1996), critically important guidance for the 1995). Both experimental and clinical suggesting that this mechanism also development and evaluation of new studies have demonstrated, however, may contribute to kindling during AW. pharmacotherapies for managing AW. that repeated administration of sedative

30 Alcohol Health & Research World Kindling in Alcohol Withdrawal

hypnotics for the treatment of multiple consumption. In other experiments, One hormone system that may withdrawal episodes may be associated alcohol consumption in dependent play a role in these processes is called with serious drawbacks (Becker and rats undergoing withdrawal restored the hypothalamic-pituitary-adreno- Littleton 1996; Mayo-Smith and Bernard deficits in the brain levels of the neu- cortical (HPA) axis, because the 1995). In particular, enhanced with- rotransmitter dopamine (Weiss et al. hormones involved in this system are drawal seizures can occur as a result of 1996). Dopamine-mediated neuro- secreted by a brain region called the withdrawal from the sedative hypnotics. transmission in various brain regions hypothalamus, the pituitary gland, Consequently, the development of has been shown to play a key role in and the outer layer (i.e., cortex) of the safer and more effective treatments mediating both alcohol’s rewarding adrenal gland. This hormone system that could be used repeatedly for detox- effects and the dysphoria associated is involved primarily in the body’s ification would be of great benefit. with withdrawal from chronic alcohol response to stress. AW activates the This area of research clearly warrants exposure (e.g., Koob et al. 1998). HPA axis, and the levels of hormones additional investigation. Repeated withdrawal episodes, secreted by the adrenal cortex (i.e., particularly if they occur in similar corticosteroids) increase. Research settings, also may contribute to relapse indicates that this withdrawal-induced Clinical Significance through a mechanism involving a increase in corticosteroid levels is and Implications of AW conditioned withdrawal response. enhanced and more sustained in animals Kindling During a conditioned withdrawal with a history of multiple withdrawal response, environmental stimuli that episodes (Becker and Littleton 1996). are repeatedly associated with with- One group of corticosteroids, the Association of Kindling and Relapse drawal symptoms (e.g., a physician’s , influence neural office or hospital) may themselves excitability by interacting with certain Most animal models and clinical become cues that trigger the neuro- receptors in the brain. Prolonged studies of kindling have focused on chemical changes resulting in the stimulation of these receptors as a withdrawal-related seizures. Kindling physical and psychological withdrawal result of elevated levels during AW may have broader signifi- symptoms. Conditioned withdrawal- in the blood may not only alter seizure cance and clinical implications, how- related responses, which reflect a susceptibility but also may produce ever, if other withdrawal symptoms kindlinglike process, may represent neural damage, particularly in brain also could be exacerbated by repeated the biological basis for cue-induced structures such as the hippocampus. withdrawal experiences. For example, alcohol craving in these circumstances. The progressive magnification of a progressive intensification of psy- Further experimental exploration of neurochemical and neuroendocrine chological symptoms of withdrawal these issues should provide valuable alterations that occurs with successive (e.g., dysphoria2), as well as changes information regarding the possible AW experiences may result in enhanced in the subjective perception of alcohol’s influence of a patient’s withdrawal vulnerability to alcohol-induced neu- intoxicating effects, could substantially history on his or her risk for relapse. rotoxicity. This neuronal damage, increase the patient’s motivation to This knowledge is critical for develop- in turn, may underlie the cognitive resume drinking. ing effective treatment strategies for deficits related to chronic binge-drink- Several studies have suggested that alcoholics who experience recurrent ing patterns (Hunt 1993). In fact, changes in the brain mechanisms in- withdrawal episodes. both clinical and experimental findings volved in mediating alcohol’s rewarding have indicated that repeated AW is effects may become more pronounced associated with increased cognitive following successive intoxication and Role of Kindling in Alcohol-Related dysfunction (Becker and Littleton withdrawal experiences. For example, Brain Damage and Cognitive 1996). This area of research also deserves when alcohol-dependent rats under- Impairment greater experimental attention. going withdrawal were given the oppor- Multiple AW experiences also may tunity to self-administer alcohol, their render a person more vulnerable to alcohol consumption increased and brain damage. One potential mechanism Summary became progressively more stable over contributing to this type of brain successive withdrawal episodes (Roberts damage is the enhanced excitotoxicity Over the past two decades, a large et al. 1996). Treatment with agents associated with progressive increases body of clinical data has suggested that affected the GABA system modi- in excitatory neurotransmission. In that repeated AW may exacerbate the fied this withdrawal-related alcohol addition, withdrawal-induced persis- severity of future withdrawal episodes. tent changes in certain hormonal Researchers have used a variety of 2Dysphoria is a state characterized by , anxiety, and emotional discomfort and involves systems affecting the CNS (i.e., neu- animal models to further extend the the inability to derive pleasure from normally roendocrine changes) may contribute clinical observations and to elucidate rewarding events. to alcohol-related neuropathology. the mechanisms underlying this phe-

Vol. 22, No. 1, 1998 31 nomenon (see figure 2). The results of subsequent withdrawal seizures: An animal model KOKKA, N.; SAPP, D.W.; TAYLOR, A.M.; AND of alcohol withdrawal “kindling.” Alcoholism: OLSEN, R.W. The kindling model of alcohol these investigations have advanced the Clinical and Experimental Research 17:94–98, 1993. dependence: Similar persistent reduction in notion that the progressive intensifi- seizure threshold to pentylenetetrazol in animals cation of withdrawal symptoms may be BECKER, H.C., AND LITTLETON, J.M. The alcohol receiving chronic or chronic pentylenete- the manifestation of a kindling mech- withdrawal “kindling” phenomenon: Clinical and trazol. Alcoholism: Clinical and Experimental experimental findings. Alcoholism: Clinical and Research 17:525–531, 1993. anism. Moreover, the findings indicate Experimental Research 20:121A–124A, 1996. that this sensitization process reflects KOOB, G.F.; ROBERTS, A.J.; SCHULTEIS, G.; PARSONS, BECKER, H.C.; DIAZ-GRANADOS, J.L.; AND a persistent perturbation in excitatory L.H.; HEYSER, C.J.; HYYTIA, P.; MERLO-PICH, E.; WEATHERSBY, R.T. Repeated ethanol withdrawal and inhibitory influences on overall AND WEISS, F. Neurocircuitry targets in ethanol experience increases the severity and duration of reward and dependence. Alcoholism: Clinical and brain function. Kindling also may subsequent withdrawal seizures in mice. Alcohol Experimental Research 22:3–9, 1998. contribute to an exacerbation of the 14:319–326, 1997. psychological components of withdrawal, LECHTENBERG, R., AND WORNER, T.M. Relative BECKER, H.C.; VEATCH, L.M.; AND DIAZ-GRANADOS, kindling effects of detoxification and non-detoxi- which, in turn, may affect relapse risk. J.L. Repeated ethanol withdrawal experience fication admissions in alcoholics. Alcohol and Finally, incremental changes in neuro- selectively alters sensitivity to different chemoconvul- Alcoholism 26:221–225, 1991. chemical and neuroendocrine systems sant in mice. Psychopharmacology, in press. MAHMOUDI, M.; KANG, M.H.; TILLAKARANTE, following repeated withdrawal episodes BOOTH, B.M., AND BLOW, F.C. The kindling N.; TOBIN, A.J.; AND OLSEN, R.W. Chronic may render the brain more vulnerable hypothesis: Further evidence from a U.S. national intermittent ethanol treatment in rats increases study of alcoholic men. Alcohol and Alcoholism to neurological damage and associated GABAA receptor alpha4-subunit expression: cognitive impairments. 28:593–598, 1993. Possible relevance to . Journal of Neurochemistry 68:2485–2492, 1997. The potential consequences of BROWN, M.E.; ANTON, R.F.; MALCOLM, R.; AND BALLENGER, J.C. and with- kindling during AW highlight the clini- MAYO-SMITH, M.F., AND BERNARD, D. 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Now New Public Education Materials Available

A variety of public education materials are now available from NIAAA. All of these materials are free and may be obtained in English and Spanish versions. Quantities also are available for school and other educational programs.

Alcoholism: Getting the Facts. A brief, research-based brochure to educate the general public about alcohol abuse and dependence. Provides answers to commonly asked questions; includes a list of resources for information and assistance.

How to Cut Down on Your Drinking. The companion brochure to NIAAA’s The Physicians’ Guide to Helping Patients With Alcohol Problems. Presents tips for those who are acting on medical advice to

Y reduce their alcohol consumption. Includes a list of resources for treatment and additional information.

Drinking and Your Pregnancy. A short pamphlet to answer common questions about alcohol consumption during pregnancy. Describes the consequences of drinking during pregnancy, focusing on fetal alcohol syndrome. Includes resources for help and additional information.

To order, write to: National Institute on Alcohol Abuse and Alcoholism, Publications Distribution Center, P.O. Box 10686, Rockville, MD 20849Ð0686. Fax: (202) 842Ð0418. Full text is available on the World Wide Web at http://www.niaaa.nih.gov

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