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The Journal of Neuroscience, September 1, 2002, 22(17):7730-7736
Substance P (Neurokinin 1) Receptor Antagonists Enhance Dorsal Raphe Neuronal Activity
Rachel K. Conley, Michael J. Cumberbatch, Glenn S. Mason, David J. Williamson, Timothy Harrison, Karen Locker, Christopher Swain, Karen Maubach, Ruth O'Donnell, Michael Rigby, Louise Hewson, David Smith, and Nadia M. J. Rupniak Departments of Pharmacology and Medicinal Chemistry, Merck Sharp and Dohme Neuroscience Research Centre, Harlow, Essex CM20 2QR, United Kingdom
Substance P receptor [neurokinin 1 (NK1)] antagonists (SPAs) represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK1 receptor antagonist 1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-phenyl)morpholin-4-yl]methyl}-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine (L-760735) caused an increase in DRN neuronal firing rate. However, unlike chronic treatment with fluoxetine, there was no detectable 5-HT1A autoreceptor desensitization. In vitro electrophysiological investigation showed that these effects were not mediated by a direct action in the DRN, an observation supported by immunocytochemical analysis that identified the lateral habenula (LHb) as a more likely site of action. Subsequently, we found that local application of L-760735 into the LHb increased firing in the DRN, which, together with our data showing that L-760735 increased metabolic activity in the cingulate cortex, amygdala, LHb, and DRN, indicates that the effects of L-760735 may be mediated by disinhibition of forebrain structures acting via a habenulo raphe projection. These findings support other evidence for an antidepressant profile of SPAs and suggest that regulation of DRN neuronal activity may contribute to their antidepressant mechanism of action but in a manner that is distinct from monoamine reuptake inhibitors.
Key words: dorsal raphe; NK1 receptors; lateral habenula; depression; guinea pig; electrophysiology
Copyright © 2002 Society for Neuroscience 0270-6474/02/22177730-07$05.00/0
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