The selective neurokinin 1 receptor antagonist R116301 modulates photic responses of the hamster circadian system

The recent development of selective NK(1) receptor antagonists that are active in vivo provides an important research tool to examine the role of substance P in the regulation of circadian rhythmicity. First, we tested whether R116301 [(2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S) hydroxybutanedioate], a new selective NK(1) antagonist, alters the phase-shifting effects of light. Hamsters housed in constant darkness were injected with different doses of R116301, just before being exposed to a light pulse during the subjective night. The results were compared with those obtained with the NK(1) antagonist L-760,735 [2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-trioazol-4-yl)methyl-3-(5)-phenyl)morpholine]. Second, the effects of the NK(1) antagonists R116301 or L-760,735 injected immediately after exposure to a light pulse were similarly determined. Third, we investigated whether R116301 or L-760,735 injected during the mid-subjective day or the late subjective night can phase-shift the circadian rhythm of locomotor activity in hamsters housed in constant light. Both compounds reduced, by more than 30%, the phase-advancing effects of a light pulse in hamsters otherwise maintained in constant darkness, only when the drugs were administered before the light pulse. Under constant light conditions, both NK(1) receptor antagonists induced significant phase-advances when injected during the subjective day, but not during the subjective night. The present results indicate that tachykinergic neurotransmission modulates the photic responses of the circadian system upstream of phase resetting mechanisms and suggest that an inhibition of the NK(1) receptor signals "darkness" to the circadian clock.