Midazolam Inhibits Hippocampal Long-Term Potentiation and Learning through Dual Central and Peripheral Benzodiazepine Receptor Activation and Neurosteroidogenesis

The study investigated the effects of midazolam, an anesthetic benzodiazepine (BDZ), on hippocampal function compared to clonazepam, an anticonvulsant/anxiolytic BDZ. Midazolam increased neurosteroid levels in CA1 pyramidal neurons and inhibited long-term potentiation, effects not observed with clonazepam. These effects were blocked by finasteride, an inhibitor of neurosteroid synthesis, and 17PA, a neurosteroid effect blocker. The synaptic effects of midazolam were replicated by combining clonazepam with a TSPO agonist or exogenous allopregnanolone. In vivo, finasteride also abolished midazolam's impact on contextual fear learning. The study concluded that midazolam's unique effects were due to dual activation of central BDZ receptors and TSPO, highlighting the role of neurosteroids in regulating neuron function and synaptic plasticity.