Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response

Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response


J Psychiatry Neurosci 2004;29(3):208-218

Pierre Blier, MD, PhD; Gabriella Gobbi, MD, PhD; Nasser Haddjeri, PhD; Luca Santarelli, MD; Gina Mathew, BSc; René Hen, PhD

Blier — University of Ottawa Institute of Mental Health Research, Ottawa, Ont.; Gobbi — Department of Psychiatry,
McGill University, Montréal, Que.; Haddjeri — Université Claude Bernard, Lyons, France; Santarelli, Hen — Department of Psychiatry and Pharmacology, Columbia University, NY; Mathew — Department of Psychiatry and Neuroscience, University of Florida, Gainesville, Fla.


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.


Les antagonistes des récepteurs de la substance P (neurokinine-1 [NK1]) semblent efficaces comme antidépresseurs et anxiolytiques, ainsi que l’indiquent trois études cliniques à double insu. Chez des animaux de laboratoire, ces agents atténuent rapidement la réponse des neurones à sérotonine (5-hydroxytryptamine [5-HT]) et à norépinéphrine (NE) aux agonistes de leurs autorécepteurs du corps cellulaire, comme dans le cas de certains antidépresseurs actuellement utilisés en clinique. L’antagonisme à long terme mais non subaigu des récepteurs de la NK1 chez le rat accroît la transmission de la 5-HT dans l’hippocampe, caractéristique commune à tous les traitements aux antidépresseurs étudiés à ce jour. Une augmentation de la fréquence de décharge des neurones de la 5-HT liée au temps semble intervenir dans cette élévation. Les souris dont on a éliminé le récepteur de la NK1 du code génétique ont aussi une fréquence de décharge plus élevée des neurones de la 5-HT. Globalement, ces observations indiquent fortement que les antagonistes de la NK1 pourraient devenir une nouvelle catégorie d’antidépresseurs et d’anxiolytiques.

Medical subject headings: antidepressive agents; depression; norepinephrine; receptors, adrenergic; receptors, neurokinin-1; serotonin; substance P.

Submitted July 4, 2003; Revised Oct. 29, 2003; Accepted Nov. 11, 2003

Competing interests: None declared by Drs. Gobbi, Haddjeri, Santarelli and Hen and by Ms. Mathew. Dr. Blier has been a consultant for Pfizer, Merck Frosst and Roche and has received an honorarium from Merck Frosst for research on an unnamed drug and an educational grant from Merck Frosst.

Correspondence to: Dr. Pierre Blier, University of Ottawa Institute of Mental Health Research, 1145 Carling Ave., Lady Grey Bldg., Rm. 2043, Ottawa ON K1Z 7K4; fax 613 792-3935;