Vol. 299, Issue 2, 449-458, November 2001

Selective Blockade of Neurokinin-2 Receptors Produces Antidepressant-Like Effects Associated with Reduced Corticotropin-Releasing Factor Function

Régis Steinberg, Richard Alonso, Guy Griebel, Lionel Bert, Mireille Jung, Florence Oury-Donat, Martine Poncelet, Christiane Gueudet, Christophe Desvignes, Gérard Le Fur and Philippe Soubrié

Central Nervous System Research Department, Sanofi-Synthélabo Recherche, Montpellier, France

The present study investigated the effects of the selective neurokinin-2 (NK₂) receptor antagonist SR48968 in behavioral, electrophysiological, and biochemical tests sensitive to the action of prototypical antidepressants (fluoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor antagonists, which have been proposed recently as potential antidepressants. Results showed that SR48968 (0.3-10 mg/kg i.p.) produced antidepressant-like activity because it reduced immobility in the forced swimming test in both mice and rats, and decreased the amount of maternal separation-induced vocalizations in guinea pig pups. This latter effect appears to involve a reduction of stress-induced substance P release because SR48968 reduced the separation-induced increase in the number of neurons displaying neurokinin-1 receptor internalization in the amygdala. Furthermore, SR48968 increased the expression of the cAMP response-element binding protein mRNA in the rat hippocampus after repeated (1 mg/kg i.p., 21 days), but not acute administration. Finally, neuronal firing of the locus coeruleus (LC) and noradrenergic (NE) release in the prefrontal cortex both elicited by an uncontrollable stressor or an intraventricular administration of CRF were reduced by SR48968 (0.3-1 mg/kg i.p.). The finding that SR48968 (1 mg/kg i.p.) blocked the cortical release of NE induced by an intra-LC infusion of the preferential 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 blockade may constitute a novel mechanism in the treatment of depression and CRF-related disorders.