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- Title
Neurokinin<sub>1</sub> Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization.
- Authors
Gobert, Alain; Brocco, Mauricette; Dekeyne, Anne; Di Cara, Benjamin; Bouchez, Gaëlle; Lejeune, Françoise; Gannon, Robert L.; Millan, Mark J.
- Abstract
Though neurokinin1 (NK1) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK1 receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK1 antagonist, GR205171, dose-dependently enhanced citalopram-induced elevations of extracellular levels of 5-HT in frontal cortex, an action expressed stereospecifically vs its less active distomer, GR226206. Further, increases in 5-HT levels in dorsal hippocampus, basolateral amygdala, nucleus accumbens, and striatum were likewise potentiated, and GR205171 similarly facilitated the influence of fluoxetine upon levels of 5-HT, as well as dopamine and noradrenaline. In parallel electrophysiological studies, the inhibitory influence of citalopram and fluoxetine upon raphe-localized serotonergic neurones was stereospecifically blunted by GR205171. Antidepressant actions of citalopram in a forced-swim test in mice were stereospecifically potentiated by GR205171, and it also enhanced attenuation by citalopram of stress-related ultrasonic vocalizations in rats. Further, GR205171 and citalopram additively abrogated the advance in circadian rhythms provoked by exposure to light in hamsters. By contrast, GR205171 stereospecifically blocked anxiogenic actions of citalopram in social interaction procedures in rats and gerbils, and stereospecifically abolished facilitation of fear-induced foot tapping by fluoxetine in gerbils. By analogy to GR205171, a further NK1 antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK1receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK1 receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.Neuropsychopharmacology (2009) 34, 1039–1056; doi:10.1038/npp.2008.176; published online 1 October 2008
- Publication
Neuropsychopharmacology, 2009, Vol 34, Issue 4, p1039
- ISSN
0893-133X
- Publication type
Academic Journal
- DOI
10.1038/npp.2008.176