title: Altered serotonergic neurotransmission but normal hypothalamic-pituitary-adrenocortical axis activity in mice chronically treated with the corticotropin-releasing hormone receptor type 1 antagonist NBI 30775.
abstract: Antagonists of the corticotropin-releasing hormone receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
authors.affiliation: Max Planck Institute of Psychiatry, Sections of Neurochemistry and Neuropsychopharmacology, Munich, Germany.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oshima
authors.forename: Cornelia
authors.initials: C
authors.lastname: Flachskamm
authors.forename: Johannes M H M
authors.initials: JM
authors.lastname: Reul
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Astrid C E
authors.initials: AC
authors.lastname: Linthorst
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011863:Radioimmunoassay; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism; D013550:Swimming; D013997:Time Factors
chemical_list: D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D003345:Corticosterone