Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission.
BACKGROUND
Antagonists of neurokinin-1 (NK(1)) 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 NK(1) antagonist CP-96,345 on the firing activity of rat dorsal raphe 5-HT neurons, the responsiveness of pre- and postsynaptic 5-HT(1A) 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-HT(1A) autoreceptor responsiveness. In contrast, the inactive enantiomer of CP-96,345 at NK(1) receptors, CP-96,344, did not alter these parameters after short-term administration. Because 5-HT(1A) receptor activation inhibits the firing activity of dorsal hippocampus CA(3) pyramidal neurons, the degree of disinhibition produced by the selective 5-HT(1A) receptor antagonist WAY 100635 was determined to assess the net change in 5-HT neurotransmission. Intravenous injection of WAY 100635 did not disinhibit CA(3) 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-HT(1A) 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.
Haddjeri
N
N
Department of Psychiatry, McKnight, Brain Institute, University of Florida, Gainesville, Florida 32610-0256, USA.
Blier
P
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D012701:Serotonin; D013373:Substance P; C066892:CP 96345