Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

Abstract

Chronic alcohol abuse depresses the nervous system and, upon cessation, rebound hyperexcitability can result in withdrawal seizure. Withdrawal symptoms, including seizures, may drive individuals to relapse, thus representing a significant barrier to recovery. Our lab previously identified an upregulation of the thalamic T-type calcium (T channel) isoform CaV3.2 as a potential contributor to the generation and propagation of seizures in a model of withdrawal. In the present study, we examined whether ethosuximide (ETX), a T-channel antagonist, could decrease the severity of ethanol withdrawal seizures by evaluating electrographical and behavioral correlates of seizure activity. DBA/2J mice were exposed to an intermittent ethanol exposure paradigm. Mice were treated with saline or ETX in each withdrawal period, and cortical EEG activity was recorded to determine seizure severity. We observed a progression in seizure activity with each successive withdrawal period. Treatment with ETX reduced ethanol withdrawal-induced spike and wave discharges (SWDs), in terms of absolute number, duration of events, and contribution to EEG power reduction in the 6–10 Hz frequency range. We also evaluated the effects of ETX on handling-induced convulsions. Overall, we observed a decrease in handling-induced convulsion severity in mice treated with ETX. Our findings suggest that ETX may be a useful pharmacological agent for studies of alcohol withdrawal and treatment of resulting seizures.

Ethosuximide Reduces Mortality and Seizure Severity in Response to Pentylenetetrazole Treatment During Ethanol Withdrawal

“…In these experiments, we utilized an intermittent exposure paradigm that included four ethanol exposures and four withdrawal periods. This is a well-established model that consistently generates increased excitability during withdrawal (Becker and Hale, 1993;Becker, 1994;Becker et al, 1997a,b;Veatch and Becker, 2002;Riegle et al, 2014). Previous studies using other mouse strains have established that mice undergoing withdrawal have increased sensitivity to chemoconvulsants and a reduction in seizure threshold (Kokka et al, 1993;Becker et al, 1998;Stephens et al, 2001;Cagetti et al, 2004).…”

“…Ethosuximide (ETX), a T channel antagonist, was found to restore certain patterns of sleep activity that had been disrupted in mice undergoing ethanol withdrawal (Wiggins et al, 2013). We also found that ETX reduced the increased spike and wave discharge activity that was observed in mice undergoing ethanol withdrawal, decreased the severity of handling-induced convulsions and the number of tonic-clonic seizures (Riegle et al, 2014). These studies suggest that T channels are a novel target for intervention and that ETX may be a potentially effective treatment for ethanol withdrawal symptoms.…”

“…Experiment 1: Seizure severity Male, 6-8 weeks old DBA/2J mice (Jackson Laboratory, Bar Harbor, ME) underwent an intermittent ethanol exposure paradigm as previously described in Riegle et al (2014). The model was adapted from a previous investigation of ethanol withdrawal seizure progression (Becker and Hale, 1993).…”

“…All mice were injected subcutaneously with pyrazole (100 mg/kg, Sigma Aldrich, St. Louis, MO, USA), an alcohol dehydrogenase inhibitor used to maintain blood ethanol concentration (BEC) levels, prior to each exposure. BEC measurements were made at the beginning of each withdrawal period as previously described in Riegle et al (2014). Briefly, a NAD-ADH enzyme assay (Carolina Liquid Chemistries Corp, Winston-Salem, NC, USA) was utilized to measure the ethanol levels, and no differences in BEC levels were found between the treatment groups.…”

Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity

“…Ca 2+ channels are upregulated during EW (Walter and Messing, 1999; N’Gouemo and Morad, 2003) and Ca 2+ channel inhibitors are cerebroprotective against EW stress. In mice, EW increased expression of T-type Ca 2+ channel genes (Graef et al, 2011), and the T-type Ca 2+ channel blocker ethosuximide reduced seizures provoked by intermittent ethanol exposures and withdrawals (Riegle et al, 2014, 2015) and restored EW-disrupted sleep activity (Wiggins et al, 2013). Similarly, the Ca 2+ channel antagonists nitrendipine and nimodipine attenuated EW-induced seizures and mortality in rats (Little et al, 1986).…”