{"doi":"10.1016/j.bja.2022.09.025","title":"Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid","abstract":"BackgroundThe novel synthetic neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABAA) currents like other anaesthetic neurosteroids. As 3β-OH has sex-specific hypnotic effects in adult rats, we studied the mechanism contributing to sex differences in its effects.MethodsWe used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the CaV3.1 T-type calcium channel isoform to study the mechanisms by which 3β-OH and its metabolite produces sex-specific hypnotic effects.ResultsAdult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABAA receptor positive allosteric modulator (3α,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3α-OH) to a greater extent than males. The 3α-OH metabolite has T-channel blocking properties with sex-specific hypnotic and pharmacokinetic effects. Sex-dependent suppression of the cortical electroencephalogram is more pronounced with 3α-OH compared with 3β-OH.ConclusionsThe sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH.","journal":"British Journal of Anaesthesia","year":2022,"id":277261,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9642,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465402,"name":"Omar H. Cabrera","orcid":"0000-0002-9501-6720","position":1,"is_corresponding":false},{"id":365224,"name":"Davis Wilkey","orcid":null,"position":2,"is_corresponding":false},{"id":923348,"name":"Brier Fine-Raquet","orcid":null,"position":3,"is_corresponding":false},{"id":267871,"name":"Jelena Klawitter","orcid":"0000-0003-1893-6141","position":4,"is_corresponding":false},{"id":322135,"name":"Kathiresan Krishnan","orcid":null,"position":5,"is_corresponding":false},{"id":246033,"name":"Douglas F. Covey","orcid":"0000-0002-9316-8683","position":6,"is_corresponding":false},{"id":363447,"name":"Vesna Jevtović‐Todorović","orcid":"0000-0001-8688-9768","position":7,"is_corresponding":false},{"id":363448,"name":"Slobodan M. Todorovic","orcid":"0000-0003-2613-0391","position":8,"is_corresponding":false},{"id":363446,"name":"Francesca M. Manzella","orcid":"0000-0003-1296-2015","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T00:28:34.768552Z","pmid":"36428160","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}