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The Journal of Neuroscience, October 15, 2001, 21(20):8188-8197

5-Hydroxytryptamine (5-HT)_1A Autoreceptor Adaptive Changes in Substance P (Neurokinin 1) Receptor Knock-Out Mice Mimic Antidepressant-Induced Desensitization

Nicolas Froger¹, Alain M. Gardier², Rosario Moratalla³, Israel Alberti³, Isabelle Lena², Claudette Boni¹, Carmen De Felipe⁴, Nadia M. J. Rupniak⁵, Stephen P. Hunt⁶, Christian Jacquot², Michel Hamon¹, and Laurence Lanfumey¹

¹ Institut National de la Santé et de la Recherche Médicale U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 75013 Paris, France, ² Laboratory of Neuropharmacology, Faculté de Pharmacie-Université Paris-Sud, 92296 Chatenay-Malabry, France, ³ Instituto Cajal, Madrid, Spain, ⁴ Instituto de Neurociencias, University Miguel Hernandez, San Juan, E-03550 Alicante, Spain, ⁵ Merck Sharp and Dohme Neuroscience Research Center, Harlow, Essex CM20 2QR, United Kingdom, and ⁶ Department of Anatomy and Developmental Biology, University College, London, United Kingdom

Antagonists at substance P receptors of the neurokinin 1 (NK1) type have been shown to represent a novel class of antidepressant drugs, with comparable clinical efficacy to the selective serotonin (5-HT) reuptake inhibitors (SSRIs). Because 5-HT_1A receptors may be critically involved in the mechanisms of action of SSRIs, we examined whether these receptors could also be affected in a model of whole-life blockade of NK1 receptors, i.e. knock-out mice lacking the latter receptors (NK1/). 5-HT_1A receptor labeling by the selective antagonist radioligand [³H]N-[2-[4-(2-methoxyphenyl)1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT_1A-dependent [³⁵S]GTP--S binding at the level of the dorsal raphe nucleus (DRN) in brain sections, as well as the concentration of 5-HT_1A mRNA in the anterior raphe area were significantly reduced (19 to 46%) in NK1/ compared with NK1+/+ mice. Furthermore, a ~10-fold decrease in the potency of the 5-HT_1A receptor agonist ipsapirone to inhibit the discharge of serotoninergic neurons in the dorsal raphe nucleus within brainstem slices, and reduced hypothermic response to 8-OH-DPAT, were noted in NK1/ versus NK1+/+ mice. On the other hand, cortical 5-HT overflow caused by systemic injection of the SSRI paroxetine was four- to sixfold higher in freely moving NK1/ mutants than in wild-type NK1+/+ mice. Accordingly, the constitutive lack of NK1 receptors appears to be associated with a downregulation/functional desensitization of 5-HT_1A autoreceptors resembling that induced by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT_1A autoreceptors in NK1/ mutants does not reflect the existence of direct NK1-5-HT_1A receptor interactions in normal mice.

Key words: 5-HT_1A receptors; desensitization; dorsal raphe; NK1 receptors; electrophysiology; in vivo microdialysis

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21208188-10$05.00/0

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