Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons.

Substance P antagonists have been proposed to be a new class of antidepressants. The present study aimed to determine the effect of the selective non-peptide rat neurokinin-1 (NK1) receptor antagonists WIN 51,708 and CP-96,345 on the firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. While WIN51,708 (2mg/kg, i.v.) and CP-96,345 (0.15 mg/kg, i.v.) did not modify the firing activity of 5-HT and NA neurons, both antagonists attenuated the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of both types of neurons. In contrast, the responsiveness of 5-HT neurons to the i.v. administration of the 5-HT autoreceptor agonist LSD and the 5-HT1A receptor agonist 8-OH-DPAT remained unchanged. These findings suggest that NK1 receptor antagonists affect markedly the NA system via an attenuation of the function of alpha2-adrenoceptors on the cell body of NA neurons and, consequently, may also modulate 5-HT neurotransmission.