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Microdialysis Approach to Study Serotonin Outflow in Mice Following Selective Serotonin Reuptake Inhibitors and Substance P (Neurokinin 1) Receptor Antagonist Administration: A Review

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Classical antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs) display several disadvantages, e.g., the onset of action (2 to 3 weeks) to start clinical benefits is too long, and a significant proportion of patients do not respond to this monotherapy. Several strategies have been proposed to overcome these problems, notably the use of potentiating agents, which combined with SSRIs, augment or accelerate their established antidepressant activity. Recent clinical trials proposed that compounds with dual action on both central serotonin (5-HT) and noradrenaline (NA) systems would have a faster action than SSRIs alone. Preclinical electrophysiological and neurochemical studies demonstrated that the putative new class of antidepressants, substance P (neurokinin 1) NK1 receptor antagonists, enhance brain monoaminergic neurotransmissions by reducing the sensitivity of 5-HT1A autoreceptors in the Dorsal Raphe Nucleus, and possibly α2 autoreceptors in the Locus Coeruleus. However, in several clinical studies, a similar delay of therapeutic effects has been reported with NK1 receptor antagonists and SSRIs. Recently intracerebral in vivo microdialysis studies were performed to examine the effects of genetic or pharmacological blockade of Substance P (SP)/ NK1 neurotransmission on SSRIs-induced increases in extracellular 5-HT levels in awake, freely moving mice. New evidences suggest that the combination of a NK1 receptor antagonist with a SSRI should benefit to depressed patients. This review describes our current knowledge of the role of SP and its preferred NK1 receptors mainly in the modulation of brain serotonergic activity.

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Keywords: Microdialysis; NK1 receptors; Selective Serotonin Reuptake Inhibitors; Substance P

Document Type: Research Article

Affiliations: Laboratoire de Neuropharmacologie, EA 3544 MJENR, Faculte de Pharmacie, 5, rue J.B Clement, 92296 Chatenay-Malabry Cedex, France.

Publication date: 2006-02-01

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  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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