Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response.
Substance P (neurokinin-1 [NK1]) receptor antagonists appear to be effective antidepressant and anxiolytic agents, as indicated in 3 double-blind clinical trials. In laboratory animals, they promptly attenuate the responsiveness of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) neurons to agonists of their cell-body autoreceptors, as is the case for some antidepressant drugs that are currently in clinical use. Long-term, but not subacute, antagonism of NK1 receptors in rats increases 5-HT transmission in the hippocampus, a property common to all antidepressant treatments tested thus far. This enhancement seems to be mediated by a time-dependent increase in the firing rate of 5-HT neurons. Mice with the NK1 receptor deleted from their genetic code also have an increased firing rate of 5-HT neurons. Taken together, these observations strongly suggest that NK1 antagonists could become a new class of antidepressant and anxiolytic agents.
Blier
Pierre
P
University of Ottawa Institute of Mental Health Research, Ottawa, ON. pblier@rohcg.on.ca
Gobbi
Gabriella
G
Haddjeri
Nasser
N
Santarelli
Luca
L
Mathew
Gina
G
Hen
René
R
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy*; D000077608:Aprepitant; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004594:Electrophysiology / Q000295:instrumentation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009025:Morpholines / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D010784:Photomicrography; D011903:Raphe Nuclei / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors*
D000316:Adrenergic alpha-Agonists; D000932:Antiemetics; D017660:Autoreceptors; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D010656:Phenylephrine; D012701:Serotonin; D013373:Substance P; D009638:Norepinephrine