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.