title: Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression.
abstract: Chronic corticosterone and isolation rearing paradigms may provide reliable mouse models of depression. Using these models, the present study examined if the specific glucocorticoid receptor antagonist, RU-43044, has an antidepressant-like effect, and studied the possible role of prefrontal neurotransmission on the behavioral effects. Chronic administration of corticosterone and isolation rearing increased the immobility time in the forced swim and tail suspension tests. Subchronic treatment with RU-43044 decreased the immobility time in the forced swim test in chronic corticosterone-treated and isolation-reared mice, but not the control mice. Chronic corticosterone decreased the levels of cortical glucocorticoid receptors and stress-induced increases in plasma corticosterone levels, and blocked the response of plasma corticosterone to dexamethasone, while isolation rearing did not cause any changes in the glucocorticoid receptor system. Both chronic corticosterone and isolation rearing markedly increased high K+ -induced dopamine release, but not serotonin release, in the prefrontal cortex. Subchronic RU-43044 reversed the enhanced release of dopamine in the prefrontal cortex of chronic corticosterone-treated and isolation-reared mice. These results suggest that chronic corticosterone and isolation rearing increase the depressive-like behavior in glucocorticoid receptor-dependent and independent manners, respectively, and that RU-43044 shows an antidepressant-like effect, probably via an inhibition of enhanced prefrontal dopaminergic neurotransmission in these mouse models.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Arikawa
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yata
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Michikazu
authors.initials: M
authors.lastname: Abe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005938:Glucocorticoids / Q000097:blood; D019417:Hindlimb Suspension / Q000379:methods; D006889:Hydroxycorticosteroids / Q000627:therapeutic use*; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D045442:Rotarod Performance Test; D013550:Swimming; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D005938:Glucocorticoids; D006889:Hydroxycorticosteroids; D011965:Receptors, Glucocorticoid; C085917:RU 43044; D003907:Dexamethasone; D004298:Dopamine