Neurokinin-1 receptor antagonists modulate brain noradrenaline and serotonin interactions

Substance P (neurokinin-1; NK1) receptor antagonists represent a putative new class of antidepressant/anxiolytic drugs. Using in vivo electrophysiological paradigms in rats, this study examined the effects of acute, sub-acute and long-term administration of these drugs on the firing of rat noradrenaline and serotonin (5-HT) neurons. In the locus coeruleus, neither a 2-day treatment with the tachykinin NK1 receptor antagonists [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345, 10 mg/kg/day, i.p.), CP-99,994 (10 mg/kg/day, i.p.), nor a 14-day of treatment with (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 10 mg/kg/day, s.c.) significantly modified the firing rate of noradrenaline neurons. However, all these treatments attenuated the inhibitory action of the α₂-adrenoceptor agonist clonidine on noradrenaline neuronal firing. While acute administration of the tachykinin NK1 receptor antagonist CP-96,345 (10 mg/kg, i.p.) attenuated the responsiveness of dorsal raphe 5-HT_1A autoreceptors, lesioning noradrenaline neurons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) prevented the enhancing action of a 2-day treatment with CP-96,345 on 5-HT neuronal firing, suggesting that tachykinin NK1 receptor antagonists influence 5-HT system via noradrenaline neurons independently of their firing rate.