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5-Hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization

AuthorsFroger, N.; Gardier, A. M.; Moratalla, Rosario ; Alberti Villanueva, Israel ; Lena, I.; Boni, C.; Felipe, Carmen de; Rupniak, Nadia M. J.; Hunt, S. P.; Jacquot, C.; Hamon, M.; Lanfumey, L.
Issue Date2001
PublisherSociety for Neuroscience
CitationJournal of Neuroscience 21: 8188- 8197 (2001)
AbstractAntagonists 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-HT1A 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-HT1A receptor labeling by the selective antagonist radioligand [3H]N-[2-[4-(2-methoxyphenyl)1-piperazinyl]-ethyl]-N- (2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT1A-dependent [35S] GTP-γ-S binding at the level of the dorsal raphe nucleus (DRN) in brain sections, as well as the concentration of 5-HT1A 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-HT1A 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-HT1A autoreceptors resembling that induced by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT1A autoreceptors in NK1 -/- mutants does not reflect the existence of direct NK1-5-HT1A receptor interactions in normal mice.
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