title: Drug-induced suppression of ACTH secretion does not promote anti-depressive or anxiolytic effects.
abstract: Mammals respond to a real or perceived stress in an integrated physiological and psychological fashion. Psychiatric disorders like major depression and anxiety have been associated to stressful events. In a previous study we demonstrated that the stress-induced ACTH secretion can be robustly inhibited by the concurrent use of CRF1 (CP154,526 - Pfizer) and V1B (SSR149415 - Sanofi-Aventis) non-peptide antagonists. A proof of mechanism was offered by substituting CP154,526 by SSR125543 and obtaining the same results on three stress models: forced swimming, ether vapor inhalation and restraint. SSR125543 effectively blocked only restraint stress-induced ACTH secretion. We then challenged the hypothesis that the concurrent use of both antagonists would have a potent effect on behavioral models of anxiety and depression. Decreasing doses (30-0.1 mg/kg s.c.) of both drugs were tested in three behavioral models: Porsolt forced swimming test, elevated plus maze and social interaction. Results showed that these drugs had no effect on anxiety models (plus maze and social interaction) but significantly reduced immobility time in the forced swimming test, suggesting anti-depressive action in a dose-range from 1 to 30 mg/kg, not different from the reported in the literature referring to one drug or the other. This negates the proposed hypothesis of summation/potentiation of effects as observed in stress-induced ACTH secretion. These results point toward the involvement of extra-hypothalamic sites for the anti-depressive effects. Recent Phase II clinical research on anti-depressive effects of these drugs has failed rising strong criticisms against the predictive value of behavioral tests currently employed.
authors.affiliation: Department of Psycobiology, Universidade Federal de São Paulo (UNIFESP), R. Botucatú 862, São Paulo, SP, Brazil; Laboratory of Pharmacology, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503900, Brazil.
authors.forename: Adriana de Toledo
authors.initials: Ade T
authors.lastname: Ramos
authors.affiliation: Laboratory of Pharmacology, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503900, Brazil.
authors.forename: Karen Silvia de Carvalho
authors.initials: KS
authors.lastname: Homem
authors.affiliation: Department of Psycobiology, Universidade Federal de São Paulo (UNIFESP), R. Botucatú 862, São Paulo, SP, Brazil.
authors.forename: Deborah
authors.initials: D
authors.lastname: Suchecki
authors.affiliation: Department of Psycobiology, Universidade Federal de São Paulo (UNIFESP), R. Botucatú 862, São Paulo, SP, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Tufik
authors.affiliation: Laboratory of Pharmacology, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503900, Brazil. Electronic address: lanfranco.troncone@butantan.gov.br.
authors.forename: Lanfranco Ranieri Paolo
authors.initials: LR
authors.lastname: Troncone
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000627:therapeutic use; D007398:Interpersonal Relations; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D013550:Swimming / Q000523:psychology
chemical_list: C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D014151:Anti-Anxiety Agents; C101628:CP 154526; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone
keywords: Anxiety; Corticotropin-releasing factor; Depression; SSR125543; SSR149415; Vasopressin