The antiseizure activity of midazolam is thought to result from its allosteric potentiation of synaptic GABAA receptors in the brain. However, there are indications that benzodiazepines promote neurosteroid synthesis via the cholesterol transporter protein (TSPO). The present study investigated the role of neurosteroids and their extrasynaptic GABAA receptor targets in the antiseizure activity of midazolam using δ-subunit knockout (DKO) mice bearing a targeted deletion of the extrasynaptic receptors. In mice seizure models, midazolam was protective, and the antiseizure potency was undiminished in DKO mice. Pretreatment with a TSPO blocker or a 5α-reductase neurosteroid inhibitor did not affect the antiseizure activity of midazolam. The antiseizure activity of midazolam was significantly reversed by pretreatment with a benzodiazepine antagonist. These studies, therefore, provide strong evidence that neurosteroids and extrasynaptic GABAA receptors are not involved in the antiseizure activity of midazolam, which mainly occurs through synaptic GABAA receptors via direct binding to benzodiazepine sites.
See article at J Pharmacol Exp Ther 2015, 353:517–528.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics