Year: 2022
Type: article
Abstract: Neurosteroids that positively modulate GABAA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABAA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain.
Source: Neuropsychopharmacology
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Awards: G1238510323, G1936985973, G2754895010, GABAA RECEPTOR POPULATIONS IN HIPPOCAMPUS AND THALAMUS, G3364830020, Neuroactive steroids as novel psychiatric treatments: mechanistic studies, G3598610624, G3619201366, G377636107, Washington University Intellectual and Developmental Disabilities Research Center, Hippocampal circuit mechanisms of neurosteroids, G6354708928, G67156701, G7012827404, G7423586970, G768774032
OpenAlex ID: W4297338201