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

AIMS: We recently demonstrated that T-type calcium channels are affected by alcohol abuse and withdrawal. Treatment with ethosuximide, an antiepileptic drug that blocks T-type calcium channels, reduces seizure activity induced by intermittent ethanol exposures and withdrawals. Here, we expand on these findings to test whether ethosuximide can reduce the sensitivity to pentylenetetrazole-induced seizures during ethanol withdrawal. METHODS: We used an intermittent ethanol exposure model to produce withdrawal-induced hyperexcitability in DBA/2J mice. RESULTS: Ethosuximide (250 mg/kg) reduced seizure severity in mice undergoing ethanol withdrawal with concurrent PTZ treatment (20 mg/kg). Importantly, ethosuximide did not produce rebound excitability and protected against ethanol withdrawal-induced mortality produced by concurrent PTZ treatment (40 mg/kg). CONCLUSION: These results, in addition to previous preclinical findings, suggest that ethosuximide should be further evaluated as a safe, effective alternative to benzodiazepines for the treatment of alcohol withdrawal.

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

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 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.

Activation of group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus.

Novel treatments for epilepsy are necessary because many epilepsy patients are resistant to medication. Metabotropic glutamate receptors (mGluRs), specifically mGluR 2 and 3, may serve as antiepileptic drug targets because of their role in controlling synaptic release. In this study, we administered a Group 2 mGluR agonist, LY379268, one of two mGluR2-specific positive allosteric modulators, BINA or CBiPES, or a cocktail of both BINA and LY379268 in a series of experiments using the pilocarpine model of SE. In one study, groups received treatments 15 min prior to pilocarpine, while in a second study groups received treatments after SE had been initiated to determine whether the drugs could reduce development and progression of SE. We measured bouts of stage 5 seizures, latency to the first seizure, and the maximum Racine score to characterize the seizure severity. We analyzed mouse EEG with implanted electrodes using a power analysis. We found that pretreatment and posttreatment with LY379268 was effective at reducing both behavioral correlates and power in EEG bandwidths associated with seizure, while CBiPES was less effective and BINA was ineffective. These data generally support continued development of mGluR2 pharmacology for novel antiepileptic drugs, though further study with additional drugs and concentrations will be necessary.