Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission

Background: Antagonists of neurokinin-1 (NK1) receptors, through which substance P acts, have been proposed to belong to a new class of antidepressants with a unique mode of action. It was postulated that they exert this putative therapeutic effect independently of the serotonin (5-HT) neurons. Methods: The aim of the present study was to assess, using in vivo electrophysiological paradigms, the effects of sustained administration of the nonpeptidic NK1 antagonist CP-96,345 on the firing activity of rat dorsal raphe 5-HT neurons, the responsiveness of pre- and postsynaptic 5-HT1A receptors, and overall 5-HT neurotransmission in the hippocampus. Results: Both short- and long-term treatments with CP-96,345 significantly increased the spontaneous firing activity of dorsal raphe 5-HT neurons, and this increase was associated with an attenuation of somatodendritic 5-HT1A autoreceptor responsiveness. In contrast, the inactive enantiomer of CP-96,345 at NK1 receptors, CP-96,344, did not alter these parameters after short-term administration. Because 5-HT1A receptor activation inhibits the firing activity of dorsal hippocampus CA3 pyramidal neurons, the degree of disinhibition produced by the selective 5-HT1A receptor antagonist WAY 100635 was determined to assess the net change in 5-HT neurotransmission. Intravenous injection of WAY 100635 did not disinhibit CA3 pyramidal neuron firing in rats given saline, CP-96,345 for 2 days, or CP-96,344 for 14 days, but produced a significant enhancement of firing in rats treated with CP-96,345 for 2 weeks. Therefore, only long-term treatment with CP-96,345 enhanced the tonic activation of postsynaptic 5-HT1A receptors. Conclusions: Similar to all other major types of antidepressant treatments, these data indicate that substance P antagonists might alleviate anxiety and major depression, at least in part, by enhancing the degree of activation of some 5-HT receptors in the forebrain.