title: Sex and estrous cycle influence diazepam effects on anxiety and memory: Possible role of progesterone.
abstract: Studies with rodents and humans show the relationship between female sex hormones and cognitive/emotional tasks. However, despite the greater incidence of anxiety disorders in women, the data are still inconclusive regarding the mechanisms related to this phenomenon. We evaluated the effects of a classical anxiolytic/amnestic drug (diazepam; DZP) on female (at different estrous cycle phases) and male rats tested in the plus-maze discriminative avoidance task (PMDAT), that allows the concomitant evaluation of memory and anxiety-like behavior. Further, in order to investigate the role of progesterone and its metabolites in the effects of DZP in the PMDAT, female rats were pre-treated with the progesterone receptor antagonist mifepristone or the 5-alpha-reductase inhibitor finasteride. The main findings were: (1) DZP caused memory impairment and anxiolysis in both sexes, but only the highest dose induced the anxiolytic effect in females; (2) females in proestrus did not present the amnestic and anxiolytic effects of DZP (at 2.0 and 4.0mg/kg, respectively) and (3) the co-administration of mifepristone reestablished both amnestic and anxiolytic effects of DZP, while finasteride reinstated the amnestic effect in proestrus female rats. These results suggest that changes in the endogenous levels of progesterone and its metabolites are important in the modulation of emotional/cognitive behavior in female rats. Based on the influence on different aspects of DZP action, the mechanisms related to this modulation are probably linked to GABAergic transmission, but this point remains to be investigated. Further, the variation in therapeutic and adverse effects of DZP depending on sex and hormonal state is of great relevance considering the higher prevalence of anxiety disorders in women.
authors.affiliation: Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
authors.forename: Anatildes Feitosa
authors.initials: AF
authors.lastname: Silva
authors.affiliation: Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
authors.forename: Diego Silveira
authors.initials: DS
authors.lastname: Sousa
authors.affiliation: Laboratory of Behavioral Neuroscience, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: André Macêdo
authors.initials: AM
authors.lastname: Medeiros
authors.affiliation: Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
authors.forename: Priscila Tavares
authors.initials: PT
authors.lastname: Macêdo
authors.affiliation: Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
authors.forename: Anderson Henrique
authors.initials: AH
authors.lastname: Leão
authors.affiliation: Laboratory of Neuroscience and Bioprospecting of Natural Products, Biosciences Department, Universidade Federal de São Paulo, Santos, Brazil.
authors.forename: Alessandra Mussi
authors.initials: AM
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Behavioral Genetics, Cell Biology, Embryology and Genetics Department, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Geison Souza
authors.initials: GS
authors.lastname: Izídio
authors.affiliation: Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do Norte, Natal, Brazil; Laboratory of Behavioral Neuroscience, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address: reginahsilva@gmail.com.
authors.forename: Regina Helena
authors.initials: RH
authors.lastname: Silva
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: D058891:5-alpha Reductase Inhibitors; D006727:Hormone Antagonists; D011619:Psychotropic Drugs; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone; D018120:Finasteride; D003975:Diazepam
keywords: Anxiety-like behavior; Finasteride; Learning/memory; Mifepristone; Sex differences, progesterone