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.

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.

These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels.

The human brain is one of the most complex arrangements of matter of which we know. This reflects the fact that despite current advances in neuroscience we still do not have a comprehensive understanding of the structure or function of the human brain. It is perhaps understandable that there is still much about the evolution of the brain, and how it came to be so complex, that remains a mystery. This complexity did not arise all at once. The lineage of the human brain can be traced back to the origin and subsequent assemblage of the key neural properties necessary for core functions of generating, sharing and propagating electrical signals.