1. ¹Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France
2. ²Department of Biology, Valdosta State University, Valdosta, GA, USA

Correspondence: Dr MJ Millan, Neuropharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, Croissy-sur-Seine 78290, Paris, France. Tel: +33 1 55 72 24 25; Fax: +33 1 55 72 20 82; E-mail: mark.millan@fr.netgrs.com

Received 9 July 2008; Revised 5 August 2008; Accepted 19 August 2008; Published online 1 October 2008.

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.