Update on the Neurobiology of Alcohol Withdrawal Seizures


Update on the Neurobiology of Alcohol Withdrawal Seizures

Michael A Rogawski, MD, PhD

Epilepsy Research Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Abrupt cessation of alcohol intake after prolonged heavy drinking may trigger alcohol withdrawal seizures. Generalized tonic–clonic seizures are the most characteristic and severe type of seizure that occur in this setting. Generalized seizures also occur in rodent models of alcohol withdrawal. In these models, the withdrawal seizures are triggered by neuronal networks in the brainstem, including the inferior colliculus; similar brainstem mechanisms may contribute to alcohol withdrawal seizures in humans. Alcohol causes intoxication through effects on diverse ion channels and neurotransmitter receptors, including GABAA receptors—particularly those containing δ subunits that are localized extrasynaptically and mediate tonic inhibition—and N-methyl-D-aspartate (NMDA) receptors. Alcohol dependence results from compensatory changes during prolonged alcohol exposure, including internalization of GABAA receptors, which allows adaptation to these effects. Withdrawal seizures are believed to reflect unmasking of these changes and may also involve specific withdrawal-induced cellular events, such as rapid increases in α4 subunit–containing GABAA receptors that confer reduced inhibitory function. Optimizing approaches to the prevention of alcohol withdrawal seizures requires an understanding of the distinct neurobiologic mechanisms that underlie these seizures.

Source: Epilepsy Curr., vol 5(6) pp 225–230,  November 2005.



It is estimated that 2 million Americans experience the symptoms of alcohol withdrawal each year (1). Generalized tonic–clonic seizures (rum fits) are the most dramatic and dangerous component of the alcohol withdrawal syndrome. The brain substrates that trigger these seizures are largely in the brainstem and, therefore, are distinct from those believed to be responsible for other clinically important seizure types. Moreover, because alcohol withdrawal seizures are pharmacologically induced, the pathophysiologic mechanisms almost certainly are different from those of the seizures that occur in genetic and acquired epilepsies. This review provides an overview of the current understanding of the cellular and molecular events that lead to alcohol withdrawal seizures.

Ethanol is a central nervous system depressant that produces euphoria and behavioral excitation at low blood concentrations and acute intoxication (drowsiness, ataxia, slurred speech, stupor, and coma) at higher concentrations. The short-term effects of alcohol result from its actions on ligand-gated and voltage-gated ion channels (24). Prolonged alcohol consumption leads to the development of tolerance and physical dependence, which may result from compensatory functional changes in the same ion channels. Abrupt cessation of prolonged alcohol consumption unmasks these changes, leading to the alcohol withdrawal syndrome, which includes blackouts, tremors, muscular rigidity, delirium tremens, and seizures (56). Alcohol withdrawal seizures typically occur 6 to 48 hours after discontinuation of alcohol consumption and are usually generalized tonic–clonic seizures, although partial seizures also occur (78).

Rodent models that mimic human alcohol withdrawal–related tonic–clonic seizures have been useful in defining the physiologic mechanisms underlying ethanol withdrawal seizures (9). In these models, animals are exposed to alcohol by intragastric intubation, inhalation, or feeding in a nutritionally complete liquid diet for periods of 2 to 21 days. The animals exhibit sound-evoked audiogenic seizures or handling-induced convulsions during the 1- to 3-day period after cessation of alcohol intake and may also experience spontaneous generalized seizures.

Brain Substrates for Alcohol Withdrawal Seizures

Audiogenic seizures are the best-studied type of alcohol withdrawal seizures. These seizures are mediated largely in the brainstem, although the hippocampus may be invaded after seizure initiation (10). In rodents, the cortical EEG shows no sign of paroxysmal activity (1011). Similarly, in humans, epileptiform activity is rarely observed in the EEG between episodes of alcohol withdrawal–related tonic–clonic seizures (1213). Thus, alcohol withdrawal seizures are unlikely to be triggered in the neocortex. Indeed, electrophysiological studies have demonstrated a critical role for the inferior colliculus (IC) in the initiation of audiogenic seizures in rodents. Acute alcohol intoxication suppresses spontaneously and acoustically evoked neuronal firing in the IC central nucleus (14), whereas at the transition to seizure, sustained increases in firing persist during wild running, the initial phase of the seizure (15). The IC external cortex is believed to amplify and propagate neuronal activity originating in the IC central nucleus. Neurons within the deep layers of the superior colliculus (16) and the periaqueductal gray (17) also may play a role in the initiation of audiogenic seizures. It is hypothesized that seizure activity propagates from the IC to deep layers of the superior colliculus (a major output of the IC) to trigger the wild running phase of the audiogenic seizure. The deep layers of the superior colliculus send projections directly to the spinal cord via the pontine reticular formation and the periaqueductal gray. The periaqueductal gray is thought to trigger clonic seizures, whereas the pontine reticular formation is implicated in the generation of the tonic phase of audiogenic seizures (18). Some evidence suggests that the IC plays a role in alcohol withdrawal seizures in humans, as it does in rodents. Thus, humans with alcohol withdrawal seizures exhibit abnormalities in auditory-evoked potentials that are not observed in other settings, including increased latency to wave V (1920), whose major source is the IC (21).

Cellular Mechanisms of Alcohol Dependence

Until the 1980s, it was generally believed that the actions of ethanol on biologic systems largely result from alterations in the fluidity of cell membranes, perhaps, with secondary effects on integral membrane proteins. This idea arose from the recognition that ethanol is a member of a group of anesthetic substances whose potency is related to their lipid solubility in accordance with the Meyer–Overton rule (22). More recently, it has been appreciated that some anesthetic actions are stereospecific and that direct protein interactions are likely (23). Indeed, ethanol modifies the functional activity of many receptors and ion channels, including NMDA (2425), kainate (26), serotonin 5-HT3 (27), GABAA (28), and glycine (29) receptors as well as G protein–coupled inwardly rectifying potassium channels (30) and calcium channels (31). In most cases, alcohol affects these targets only at high, suprapharmacologic concentrations. However, certain GABAA-receptor isoforms are exquisitely sensitive to alcohol so that functionally relevant effects can occur at concentrations within the intoxicating range (3233).

Since 1980, it has been known that alcohol can positively modulate the activity of some GABAA receptors (3435), but the importance of this finding was questioned because of inconsistency in the results from different laboratories and variability among brain regions. In addition, in experiments with recombinant GABAA receptors, low concentrations of GABA were not found to affect the most abundant GABAA-receptor isoforms, which contain the γ2 subunit. Recently, however, it has been discovered that GABAA receptors containing the δ subunit, in particular α4β2δ (36) and α6β2δ (37) receptors, are exceptionally sensitive to ethanol. Because δ subunit–containing GABAA receptors have a highly specific regional distribution, the lack of uniformity in the experimental results is now understandable. Indeed, brain regions that express δ subunits, including the cerebellum, cortical areas, thalamic relay nuclei, and brainstem (38), are among those that are recognized to mediate the intoxicating effects of alcohol. Mody (39) has proposed that such δ subunit–containing GABAA receptors are located largely perisynaptically or extrasynaptically, where they mediate tonic inhibition of neurons by ambient GABA. The functional role of tonic GABA current is still obscure (40), but the current could act to reduce network oscillations (41). It is interesting to speculate that extrasynaptic GABAA receptors may be activated by spillover of GABA when GABAergic interneurons are intensely activated, such as during a seizure discharge, thus producing negative feedback. Potentiation of extrasynaptic GABA receptors likely contributes to the anticonvulsant activity of ethanol, including its protective activity against alcohol withdrawal seizures.

Alcohol dependence—the existence of spontaneous behavioral disturbances that are produced by alcohol removal and suppressed by alcohol replacement—underlies the alcohol withdrawal syndrome. The mechanisms of alcohol dependence are less well understood than are those responsible for acute intoxication. However, it now appears that compensatory adaptation of GABAA receptors to prolonged ethanol exposure plays a critical role in alcohol dependence (4244). Among the possible adaptive mechanisms, downregulation of GABAA receptors, as a result of decreases in the surface expression of α1 (45,46) or γ2 (47) subunits, is emerging as an important candidate. Indeed, prolonged ethanol exposure has been shown to increase the endocytic internalization of α1 subunit–containing receptors in clathrin-coated vesicles (48). The number of GABAA receptors in the postsynaptic density correlates directly with inhibitory synaptic strength. Thus, when alcohol is withdrawn and its potentiating effects are no longer present, the reduction in synaptic GABAA receptors is associated with impaired inhibitory tone, predisposing to withdrawal seizures. The mechanisms responsible for altered GABAA-receptor trafficking in response to prolonged alcohol exposure are not known. However, it has been proposed that enhancement of tonic GABA current could play a role (40).

In addition to decreases in α1- or γ2-subunit expression that occur with prolonged ethanol exposure, abrupt discontinuation of alcohol leads to a rapid increase in the abundance of α4 subunits (4749). Inhibitory synaptic currents mediated by GABAA receptors containing the α4 subunit exhibit markedly faster decay, leading to reduced charge transfer and decreased inhibitory function. Enhanced seizure susceptibility is observed in animals with increased α4-subunit expression (50,515051). Thus, alcohol withdrawal is associated with reduced density of synaptic GABAA receptors as well as alterations in GABAA-receptor subunit composition that lead to reduced inhibitory efficacy; both effects would be expected to predispose to seizures. Indeed, susceptibility to alcohol withdrawal seizures has been associated with a loss of GABA-mediated inhibition (5253).

Compensatory upregulation of NMDA and kainate receptors (54) as well as calcium channels (5556) also have been implicated in alcohol dependence and withdrawal seizures. For example, the inhibitory effects of ethanol on NMDA receptors (2425) leads to upregulation in the number of NMDA receptors in many brain regions, which may be an additional factor in the susceptibility to alcohol withdrawal seizures (5758). The relevance of this mechanism is highlighted by the fact that NMDA-receptor antagonists are highly effective anticonvulsants in animal models of alcohol withdrawal seizures (59).

Anticonvulsant Drug Pharmacology of Alcohol Withdrawal Seizures

Up to one third of patients with significant alcohol withdrawal may experience alcohol withdrawal seizures. Although seizures in this setting are usually self-limited, they can be associated with status epilepticus and, therefore, are potentially serious (60). In the United States, benzodiazepines are considered the drugs of choice to treat alcohol withdrawal and to prevent the occurrence of seizures (6162). In Europe, carbamazepine, chlormethiazole, and valproate are often used (6364). Although benzodiazepines are protective in some animal models of alcohol withdrawal seizures (6566), they do not exhibit high potency (Table 1). The relatively modest activity of benzodiazepines is not surprising because alcohol withdrawal is associated with increases in α4 subunit–containing GABAA receptors, which are benzodiazepine insensitive (6768). Nevertheless, clinical experience demonstrates that benzodiazepines do reduce the risk of recurrent seizures in patients with an alcohol withdrawal seizure (62), so that in practice, no complete benzodiazepine resistance occurs. However, GABAA-receptor modulators, other than benzodiazepines, might be superior therapeutic agents. Chlormethiazole is a positive modulator of GABAA receptors, which has high efficacy in enhancing GABAA receptors containing α4 subunits (69) and has been shown to protect transiently against alcohol withdrawal seizures in mice withdrawn from exposure to inhaled ethanol (70). Although chlormethiazole may be a preferred agent from a theoretical point of view, it is not currently registered for sale in the United States.

As shown in Table 1, the sodium channel–blocking antiepileptic drugs carbamazepine and phenytoin are weak or ineffective in rodent models of alcohol withdrawal seizures, which corresponds with their lack of effectiveness in many other types of generalized seizures. In line with results from animal studies, there is little evidence that carbamazepine prevents alcohol withdrawal seizures and delirium in humans, although it may be useful to treat alcohol craving (1). Similarly, phenytoin is not effective in protecting against the occurrence of seizures in withdrawing alcoholics (71,72). Valproate is protective against alcohol withdrawal convulsions in mice (73). The intravenous formulation is gaining acceptance in the clinical management of status epilepticus so that it could potentially be used in prophylaxis against alcohol withdrawal seizures. Increasing interest is expressed in the potential of gabapentin as a treatment for alcohol withdrawal (7478) and of topiramate in alcohol dependence (79). Animal studies confirm that both drugs have protective activity against ethanol withdrawal seizures (8081), and evidence from a preliminary clinical trial suggests that topiramate is effective in preventing seizures in human subjects undergoing withdrawal (82).

TABLE 1. Potencies of Anticonvulsant Substances for Protection in Rodent Alcohol Withdrawal Seizure Models
  ED50 (mg/kg)
Substance Audiogenic seizures (rat) Handling-induced convulsions (mouse)
GABAA-receptor Modulators
Diazepam NE* 20
Lorazepam ∼1
Chlormethiazole ∼100§
Sodium-channel Modulators
Phenytoin 50|| NE
Carbamazepine 150** NE††
Antiepileptic Drugs: Other Antiepileptic Drugs
Gabapentin ∼50 (mouse)‡‡
Valproic acid 300§§
NMDA-receptor Antagonist
Dizocilpine (MK-801) 0.33||||


Adapted from N'Gouemo and Rogawski (9), with permission.

ED50, median effective dose; NE, not effective.

*Little et al. (91);
Crabbe (92);
Becker and Veach (66);
§Green et al. (70);
||Chu (93);
Gessner (94);
**Chu (95);
††Grant et al. (59);
‡‡Watson et al. (80);
§§Goldstein (73);
||||Morrissett et al. (96).

Multiple Detoxifications Kindle Susceptibility to Alcohol Withdrawal Seizures

The severity of alcohol withdrawal symptoms progressively increases over years of alcohol abuse, and repeated detoxifications augment the likelihood of alcohol withdrawal seizures (8384). Similarly, studies in rodents have shown that repeated alcohol withdrawal experiences increase the severity and duration of subsequent withdrawal seizures (8586). These observations have led to the view that alcohol withdrawal causes permanent epileptogenic changes in brain systems relevant to ethanol withdrawal seizures—a type of kindling phenomenon. Indeed, in accordance with the central role of the IC in triggering alcohol withdrawal seizures, multiple alcohol withdrawal episodes in rats facilitate the development of IC kindling (8788). There is no recognized treatment to slow or prevent this kindling process. In animals, benzodiazepines have yielded variable effects, in some cases slowing withdrawal-induced kindling, and in other cases, causing paradoxical worsening (656689). Whether other agents used in the treatment of alcohol withdrawal have antiepileptogenic potential remains to be determined.


In the past several years, dramatic advances have been made in understanding the short- and long-term effects of alcohol on the central nervous system. These advances have provided new insight into the pathophysiology of alcohol withdrawal seizures. In contrast to epileptic seizures, alcohol withdrawal seizures originate in brainstem systems and involve unique cellular and molecular mechanisms. Older antiepileptic drugs, such as phenytoin and carbamazepine, are not useful in the prophylaxis of alcohol withdrawal seizures, and even benzodiazepines, the current mainstay of therapy in the United States, may not be optimal. Newer agents, such as chlormethiazole, topiramate, gabapentin, and valproate are promising, but validation in controlled clinical trials is necessary. The emerging understanding of the neurobiology of alcohol withdrawal suggests additional treatment approaches. For example, because NMDA-receptor antagonists are highly effective in animal models of alcohol withdrawal seizures (59) and, in addition, have antiepileptogenic activity in kindling models (90), it will be of interest to determine whether such agents will be clinically useful in prophylaxis against acute withdrawal seizures or in the kindling that occurs with multiple detoxifications.



I thank Prosper N'Gouemo for insights into the physiology of alcohol withdrawal seizures.


Bayard MJ, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician. 2004;69:1443–1450.
Crews FT, Morrow AL, Criswell H, Breese G. Effects of ethanol on ion channels. Int Rev Neurobiol. 1996;39:283–367.
Deitrich, RA.; Erwin, VG. Pharmacological Effects of Ethanol on the Nervous System. Boca Raton, FL: CRC Press; 1996.
Nevo I, Hamon M. Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism. Neurochem Int. 1995;26:305–336. discussion 337–342.
Hillbom M, Pieninkeroinen I, Leone M. Seizures in alcohol-dependent patients. CNS Drugs. 2003;17:1013–1030.
Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003;348:1786–1795.
Freedland ES, McMicken DB. Alcohol-related seizures, Part I: pathology, differential diagnostic, and evaluation. J Emerg Med. 1993;11:463–473.
Mattson, RH. Seizures associated with alcohol use and alcohol withdrawal. In: Feldman B. , editor. Epilepsy:Diagnosis and Management. Boston: Little Brown; 1983. pp. 325–332.
N'Gouemo, P.; Rogawski, MA. Alcohol withdrawal seizures. In: Pitkänen A, Schwartzkroin PA, Moshé SL. , editors. Models of Seizures and Epilepsy. Amsterdam: Elsevier; 2006.
Hunter BE, Boast CA, Walker DW, Zornetzer SF. Alcohol withdrawal syndrome in rats: Neural and behavioral correlates. Pharmacol Biochem Behav. 1973;1:161–177.
Maxson SC, Sze PY. Electroencephalographic correlates of audiogeneic seizures during ethanol withdrawal in mice. Psychopharmacology. 1976;47:17–20.
Sand T, Brathen G, Michler R, Brodtkorb E, Helde G, Bovim G. Clinical utility of EEG in alcohol-related seizures. Acta Neurol Scand. 2002;105:18–24.
Touchon J, Besset A, Baldy-Moulinier M, Billiard M, Uziel A, Passouant P. Electrophysiological aspect of alcoholic epilepsy. Rev Electroencephalogr Neurophysiol. 1981;14:133–137.
Faingold CL, Riaz A. Ethanol withdrawal induces increased firing in inferior colliculus neurons associated with audiogenic seizure susceptibility. Exp Neurol. 1995;132:91–98.
Chakravarty DN, Faingold CL. Comparison of neuronal response patterns in the external and central nuclei of inferior colliculus during ethanol administration and ethanol withdrawal. Brain Res. 1998;783:102–108.
Yang L, Long C, Faingold CL. Neurons in the deep layers of superior colliculus are a requisite component of the neuronal network for seizures during ethanol withdrawal. Brain Res. 2001;920:134–141.
Yang L, Long C, Faingold CL. Neurons in the periaqueductal gray are critically involved in the neuronal network for audiogenic seizures during ethanol withdrawal. Neuropharmacology. 2003;44:275–281.
Faingold CL. Emergent properties of CNS neuronal networks as targets for pharmacology: application to anticonvulsant drug action. Prog Neurobiol. 2004;72:55–85.
Touchon J, Rondouin G, DeLustrac C, Billiard M, Baldy-Moulinier M, Cadilhac M. Brainstem auditory evoked potential in “alcoholic epilepsy.” Rev Electroencephalogr Neurophysiol. 1984;14:133–137.
Neiman J, Noldy NE, El-Nesr B, McDonough M, Carlen PL. Late auditory evoked potentials in alcoholics: identifying those with a history of epileptic seizures during withdrawal. Ann N Y Acad Sci. 1991;620:73–81.
Hughes JR, Fino JJ. A review of generators of the brainstem auditory evoked potentials: contribution of an experimental study. J Clin Neurophysiol. 1985;2:355–381.
Goldstein DB, Chin JH. Interaction of ethanol with biological membranes. Fed Proc. 1981;34:2073–2076.
Franks NP, Lieb WR. Is membrane expansion relevant to anaesthesia? Nature. 1981;292:248–251.
Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science. 1989;243:1721–1724.
Lovinger DM, White G, Weight FF. NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat. J Neurosci. 1990;10:1372–1379.
Carta M, Ariwodola OJ, Weiner JL, Valenzuela CF. Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons. Proc Natl Acad Sci U S A. 2003;100:6813–6818.
Lovinger DM, White G. Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol. 1991;40:263–270.
Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci. 2003;28:263–274.
Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature. 1997;389:385–389.
Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, Kumanishi T. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci. 1999;2:1091–1097.
Walter H, Messing RO. Regulation of neuronal voltage-gated calcium channels by ethanol. Neurochem Int. 1999;35:95–101.
Wei W, Faria LC, Mody I. Low ethanol concentrations selectively augment the tonic inhibition mediated by δ subunit-containing GABAA receptors in hippocampal neurons. J Neurosci. 2004;24:8379–8382.
Hanchar HJ, Wallner M, Olsen RW. Alcohol effects on γ-aminobutyric acid type A receptors: are extrasynaptic receptors the answer? Life Sci. 2004;76:1–8.
Nestoros JN. Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex, Science. 1980;209:708–710.
Suzdak PD, Schwartz RD, Skolnick P, Paul SM. Ethanol stimulates γ-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes. Proc Natl Acad Sci U S A. 1986;83:4071–4075.
Sundstrom-Poromaa I, Smith DH, Gong QH, Sabado TN, Li X, Light A, Wiedmann M, Williams K, Smith SS. Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat Neurosci. 2002;5:721–722.
Wallner M, Hanchar HJ, Olsen RW. Ethanol enhances α4β3δ and α6β3δγ-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci U S A. 2003;100:15218–15223.
Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience. 2000;101:815–850.
Mody I. Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem Res. 2001;26:907–913.
Kullmann DM, Ruiz A, Rusakov DM, Scott R, Semyanov A, Walker MC. Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why? Prog Biophys Mol Biol. 2005;87:33–46.
Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci. 2005;6:215–229.
Morrow AL, Montpied P, Lingford-Hughes A, Paul SM. Chronic ethanol and pentobarbital administration in the rat: effects on GABAA receptor function and expression in brain. Alcohol. 1990;7:237–244.
Mhatre MC, Pena G, Sieghart W, Ticku MK. Antibodies specific for GABAA receptor α subunits reveal that chronic alcohol treatment downregulates α-subunit expression in rat brain regions. J Neurochem. 1993;61:1620–1625.
Kang M, Spigelman I, Sapp DW, Olsen RW. Persistent reduction of GABAA receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment. Brain Res. 1996;709:221–228.
Montpied P, Morrow AL, Karanian JW, Ginns EI, Martin BM, Paul SM. Prolonged ethanol inhalation decreases γ-aminobutyric acidA receptor a subunit mRNAs in the rat cerebral cortex. Mol Pharmacol. 1991;39:157–163.
Charlton ME, Sweetnam PM, Fitzgerald LW, Terwilliger RZ, Nestler EJ, Duman RS. Chronic ethanol administration regulates the expression of GABAA receptor α1 and α5 subunits in the ventral tegmental area and hippocampus. J Neurochem. 1997;68:121–127.
Follesa P, Mancuso L, Biggio F, Mostallino MC, Manca A, Mascia MP, Busonero F, Talani G, Sanna E, Biggio G. γ-Hydroxybutyric acid and diazepam antagonize a rapid increase in GABAA receptors α4 subunit mRNA abundance induced by ethanol withdrawal in cerebellar granule cells. Mol Pharmacol. 2003;63:896–907.
Kumar S, Kralic JE, O'Buckley TK, Grobin AC, Morrow AL. Chronic ethanol consumption enhances internalization of α1 subunit-containing GABAA receptors in cerebral cortex. J Neurochem. 2003;86:700–708.
Mahmoudi M, Kang MH, Taillakaratne N, Tobin AJ, Olsen RW. Chronic intermittent ethanol treatment in rats increases GABAA receptor α4-subunit expression: possible relevance to alcohol dependence. J Neurochem. 1997;68:2485–2492.
Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JM, Li X. GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature. 1998;392:926–930.
Hsu FC, Smith SS. Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABAA receptor α4 subunit upregulation. J Neurophysiol. 2003;89:186–198.
N'Gouemo P, Caspary DM, Faingold CL. Decreased GABA effectiveness in the inferior colliculus neurons during ethanol withdrawal in rats' susceptibility to audiogenic seizures. Brain Res. 1996;724:200–204.
Faingold CL, Li Y, Evans MS. Decreased GABA and increased glutamate receptor-mediated activity on inferior colliculus neurons in vitro are associated with susceptibility to ethanol withdrawal seizures. Brain Res. 2000;868:287–295.
Whittington MA, Lambert JD, Little HJ. Increased NMDA receptor and calcium channel activity underlying ethanol withdrawal hyperexcitability. Alcohol Alcohol. 1995;30:105–114.
Perez-Velazquez JL, Valiante TA, Carlen PL. Changes in calcium currents during ethanol withdrawal in a genetic mouse model. Brain Res. 1994;649:305–309.
N'Gouemo P, Morad M. Ethanol withdrawal seizure susceptibility is associated with upregulation of L-and P-type Ca2+ channel currents in inferior colliculus neurons. Neuropharmacology. 2003;45:429–437.
Grant KA, Valverius P, Hudspith M, Tabakoff B. Ethanol withdrawal seizures and the NMDA receptor complex. Eur J Pharmacol. 1990;176:289–296.
Kalluri HS, Mehta AK, Ticku MK. Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment. Brain Res Mol Brain Res. 1998;58:221–224.
Grant KA, Snell LD, Rogawski MA, Thurkauf A, Tabakoff B. Comparison of the effects of the uncompetitive N-methyl-d-aspartate antagonist (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (ADCI) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures. J Pharmacol Exp Ther. 1992;260:1017–1022.
Alldredge BK, Lowenstein DH. Status epilepticus related to alcohol abuse. Epilepsia. 1993;34:1033–1037.
Mayo-Smith MF. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA. 1977;278:144–151.
D'Onofrio G, Rathlev NK, Ulrich AS, Fish SS, Freedland ES. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med. 1999;340:915–919.
Majumdar SK. Chlormethiazole: current status in the treatment of the acute ethanol withdrawal syndrome. Drug Alcohol Depend. 1990;27:201–207.
Morgan MY. The management of alcohol withdrawal using chlormethiazole. Alcohol Alcohol. 1995;30:771–774.
Mhatre MC, McKenzie SE, Gonzalez LP. Diazepam during prior ethanol withdrawals does not alter seizure susceptibility during a subsequent withdrawal. Pharmacol Biochem Behav. 2001;68:339–346.
Becker HC, Veatch LM. Effects of lorazepam treatment for multiple ethanol withdrawals in mice. Alcohol Clin Exp Res. 2002;26:371–380.
Devaud LL, Fritschy JM, Sieghart W, Morrow AL. Bidirectional alterations of GABAA receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal. J Neurochem. 1997;69:126–130.
Cagetti E, Liang J, Spigelman I, Olsen RW. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol. 2003;63:53–64.
Usala M, Thompson SA, Whiting PJ, Wafford KA. Activity of chlormethiazole at human recombinant GABAA and NMDA receptors. Br J Pharmacol. 2003;140:1045–1050.
Green, AR.; Davies, EM.; Little, HJ.; Whittington, MA.; Cross, AJ. Psychopharmacology. Berl: 1990. Action of chlormethiazole in a model of ethanol withdrawal. pp. 239–242.
Alldredge BK, Lowenstein DH, Simon RP. Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures. Am J Med. 1989;87:645–648.
Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med. 1991;20:520–522.
Goldstein DB. Sodium bromide and sodium valproate: effective suppressants of ethanol withdrawal reactions in mice. J Pharmacol Exp Ther. 1979;208:223–227.
Myrick H, Malcolm R, Brady KT. Gabapentin treatment of alcohol withdrawal. Am J Psychiatry. 1998;155:1632.
Bonnet U, Banger M, Leweke FM, Maschke M, Kowalski T, Gastpar M. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry. 1999;32:107–109.
Bozikas V, Petrikis P, Gamvrula K, Savvidou I, Karavatos A. Treatment of alcohol withdrawal with gabapentin. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:197–199.
Voris J, Smith NL, Rao SM, Thorne DL, Flowers QJ. Gabapentin for the treatment of ethanol withdrawal. Subst Abuse. 2003;24:129–132.
Rustembegovic A, Sofic E, Tahirovic I, Kundurovic Z. A study of gabapentin in the treatment of tonic-clonic seizures of alcohol withdrawal syndrome. Med Arh. 2004;58:5–6.
Johnson BA. An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence. Expert Opin Pharmacother. 2004;5:1943–1955.
Watson WP, Robinson E, Little HJ. The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome. Neuropharmacology. 1997;36:1369–1375.
Cagetti E, Baicy KJ, Olsen RW. Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats. Neuroreport. 2004;15:207–210.
Rustembegovic A, Sofic E, Kroyer G. A pilot study of topiramate (Topamax) in the treatment of tonic-clonic seizures of alcohol withdrawal syndromes. Med Arh. 2002;56:211–112.
Ballenger JC, Post RM. Kindling as a model for alcohol withdrawal syndromes. Br J Psychiatry. 1978;133:1–14.
Duka T, Gentry J, Malcolm R, Ripley TL, Borlikova G, Stephens DN, Veatch LM, Becker HC, Crews FT. Consequences of multiple withdrawals from alcohol. Alcohol Clin Exp Res. 2004;28:233–246.
Becker HC, Hale RL. Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal kindling. Alcohol Clin Exp Res. 1993;17:94–98.
Becker, HC.; Veatch, LM.; Diaz-Granados, JL. Psychopharmacology. Berl: 1998. Repeated ethanol withdrawal experience selectively alters sensitivity to different chemoconvulsant drugs in mice. pp. 145–153.
McCown TJ, Breese GR. Multiple withdrawals from chronic ethanol “kindles” inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism. Alcohol Clin Exp Res. 1990;14:394–399.
Gonzalez LP, Veatch LM, Ticku MK, Becker HC. Alcohol withdrawal kindling: mechanisms and implications for treatment. Alcohol Clin Exp Res. 2001;25(5 suppl ISBRA):197S–201S.
Ulrichsen, J.; Bech, B.; Allerup, P.; Hemmingsen, R. Psychopharmacology. Vol. 121. Berl: 1995. Diazepam prevents progression of kindled alcohol withdrawal behaviour. pp. 451–460.
Löscher, W.; Rogawski, MA. Epilepsy. In: Lodge D, Danysz W, Parsons CG. , editors. Ionotropic Glutamate Receptors as Therapeutic Targets. Johnson City, TN: FP Graham Publishing; 2002. pp. 91–132.
Little HJ, Dolin SJ, Halsey MJ. Calcium channel antagonists decrease the ethanol withdrawal syndrome. Life Sci. 1986;39:2059–2065.
Crabbe JC. Antagonism of ethanol withdrawal convulsions in withdrawal seizure prone mice by diazepam and abecarnil. Eur J Pharmacol. 1992;221:85–90.
Chu NS. Prevention of alcohol withdrawal seizures with phenytoin in rats. Epilepsia. 1981;22:179–184.
Gessner PK. Failure of diphenylhydantoin to prevent alcohol withdrawal convulsions in mice. Eur J Pharmacol. 1974;27:120–129.
Chu NS. Carbamazepine: prevention of alcohol withdrawal seizures. Neurology. 1979;29:1397–1401.
Morrisett RA, Rezvani AH, Overstreet D, Janowsky DS, Wilson WA, Swartzwelder HS. MK-801 potently inhibits alcohol withdrawal seizures in rats. Eur J Pharmacol. 1990;176:103–105.