Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function

The present study investigated the effects of the selective neurokinin-2 (N K2) receptor antagonist SR48968 in behavioral, electrophysiological, and bi ochemical tests sensitive to the action of prototypical antidepressants (fl uoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor a ntagonists, which have been proposed recently as potential antidepressants. Results showed that SR48968 (0.3-10 mg/kg i.p.) produced antidepressant-li ke activity because it reduced immobility in the forced swimming test in bo th mice and rats, and decreased the amount of maternal separation-induced v ocalizations in guinea pig pups. This latter effect appears to involve a re duction of stress-induced substance P release because SR48968 reduced the s eparation-induced increase in the number of neurons displaying neurokinin-1 receptor internalization in the amygdala. Furthermore, SR48968 increased t he expression of the cAMP response-element binding protein mRNA in the rat hippocampus after repeated (11 mg/kg i.p., 21 days), but not acute administ ration. Finally, neuronal firing of the locus coeruleus (LC) and noradrener gic (NE) release in the prefrontal cortex both elicited by an uncontrollabl e stressor or an intraventricular administration of CRF were reduced by SR4 8968 (0.3-1 mg/kg i.p.). The finding that SR48968 (1 mg/kg i.p.) blocked th e cortical release of NE induced by an intra-LC infusion of the preferentia l NK2 receptor agonist neurokinin A suggested the presence of NK2 receptors in this latter region. Importantly, SR48965 (1-10 mg/kg i.p.), the optical antipode of SR48968, which is devoid of affinity for the NK2 receptor, was inactive in all the models used. These data suggest that NK2 receptor bloc kade may constitute a novel mechanism in the treatment of depression and CR F-related disorders.