Neurokinin1 antagonists potentiate antidepressant properties of serotonin reuptake inhibitors, yet blunt their anxiogenic actions: a neurochemical, electrophysiological, and behavioral characterization.
Though neurokinin(1) (NK(1)) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK(1) receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK(1) 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 NK(1) antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK(1)receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK(1) receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.
Gobert
Alain
A
Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France.
Brocco
Mauricette
M
Dekeyne
Anne
A
Di Cara
Benjamin
B
Bouchez
Gaëlle
G
Lejeune
Françoise
F
Gannon
Robert L
RL
Millan
Mark J
MJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology; D005849:Gerbillinae; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D015283:Citalopram; D004298:Dopamine; D005473:Fluoxetine; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine; D010880:Piperidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013777:Tetrazoles; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C103207:vofopitant