RT Journal Article
SR Electronic
T1 Selective Blockade of Neurokinin-2 Receptors Produces Antidepressant-Like Effects Associated with Reduced Corticotropin-Releasing Factor Function
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 449
OP 458
VO 299
IS 2
A1 Régis Steinberg
A1 Richard Alonso
A1 Guy Griebel
A1 Lionel Bert
A1 Mireille Jung
A1 Florence Oury-Donat
A1 Martine Poncelet
A1 Christiane Gueudet
A1 Christophe Desvignes
A1 Gérard Le Fur
A1 Philippe Soubrié
YR 2001
UL http://jpet.aspetjournals.org/content/299/2/449.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics