Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function - PubMed (original) (raw)
. 2001 Nov;299(2):449-58.
Affiliations
- PMID: 11602654
Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function
R Steinberg et al. J Pharmacol Exp Ther. 2001 Nov.
Abstract
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.
Similar articles
- Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models.
Louis C, Stemmelin J, Boulay D, Bergis O, Cohen C, Griebel G. Louis C, et al. Pharmacol Biochem Behav. 2008 Mar;89(1):36-45. doi: 10.1016/j.pbb.2007.10.020. Epub 2007 Nov 5. Pharmacol Biochem Behav. 2008. PMID: 18045668 - SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin 1 receptor: II. Neurochemical and behavioral characterization.
Steinberg R, Alonso R, Rouquier L, Desvignes C, Michaud JC, Cudennec A, Jung M, Simiand J, Griebel G, Emonds-Alt X, Le Fur G, Soubrié P. Steinberg R, et al. J Pharmacol Exp Ther. 2002 Dec;303(3):1180-8. doi: 10.1124/jpet.102.040279. J Pharmacol Exp Ther. 2002. PMID: 12438542 - Effects of SR48968, a selective non-peptide NK2 receptor antagonist on emotional processes in rodents.
Griebel G, Perrault G, Soubrié P. Griebel G, et al. Psychopharmacology (Berl). 2001 Nov;158(3):241-51. doi: 10.1007/s002130100830. Psychopharmacology (Berl). 2001. PMID: 11713613 - Pharmacology of locus coeruleus spontaneous and sensory-evoked activity.
Valentino RJ, Curtis AL. Valentino RJ, et al. Prog Brain Res. 1991;88:249-56. doi: 10.1016/s0079-6123(08)63814-5. Prog Brain Res. 1991. PMID: 1813924 Review. - Recent developments in the medicinal chemistry of NK2 receptor antagonists.
Johansson A. Johansson A. Curr Top Med Chem. 2003;3(12):1436-45. doi: 10.2174/1568026033451835. Curr Top Med Chem. 2003. PMID: 12871174 Review.
Cited by
- PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.
Katrinli S, Zheng Y, Gautam A, Hammamieh R, Yang R, Venkateswaran S, Kilaru V, Lori A, Hinrichs R, Powers A, Gillespie CF, Wingo AP, Michopoulos V, Jovanovic T, Wolf EJ, McGlinchey RE, Milberg WP, Miller MW, Kugathasan S, Jett M, Logue MW, Ressler KJ, Smith AK. Katrinli S, et al. Brain Behav Immun. 2021 Jan;91:429-436. doi: 10.1016/j.bbi.2020.10.023. Epub 2020 Nov 3. Brain Behav Immun. 2021. PMID: 33152445 Free PMC article. - Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression.
Paschos KA, Veletza S, Chatzaki E. Paschos KA, et al. CNS Drugs. 2009 Sep;23(9):755-72. doi: 10.2165/11310830-000000000-00000. CNS Drugs. 2009. PMID: 19689166 Review. - Trends in the development of new antidepressants. Is there a light at the end of the tunnel?
Pacher P, Kecskemeti V. Pacher P, et al. Curr Med Chem. 2004 Apr;11(7):925-43. doi: 10.2174/0929867043455594. Curr Med Chem. 2004. PMID: 15078174 Free PMC article. Review. - Depression and antidepressants: molecular and cellular aspects.
Lanni C, Govoni S, Lucchelli A, Boselli C. Lanni C, et al. Cell Mol Life Sci. 2009 Sep;66(18):2985-3008. doi: 10.1007/s00018-009-0055-x. Epub 2009 Jun 12. Cell Mol Life Sci. 2009. PMID: 19521663 Free PMC article. Review. - Proof of concept trials in bipolar disorder and major depressive disorder: a translational perspective in the search for improved treatments.
Machado-Vieira R, Zarate CA Jr. Machado-Vieira R, et al. Depress Anxiety. 2011 Apr;28(4):267-81. doi: 10.1002/da.20800. Epub 2011 Feb 24. Depress Anxiety. 2011. PMID: 21456037 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical