PT  - JOURNAL ARTICLE
AU  - Nicolas Froger
AU  - Alain M. Gardier
AU  - Rosario Moratalla
AU  - Israel Alberti
AU  - Isabelle Lena
AU  - Claudette Boni
AU  - Carmen De Felipe
AU  - Nadia M. J. Rupniak
AU  - Stephen P. Hunt
AU  - Christian Jacquot
AU  - Michel Hamon
AU  - Laurence Lanfumey
TI  - 5-Hydroxytryptamine (5-HT)<sub>1A</sub> Autoreceptor Adaptive Changes in Substance P (Neurokinin 1)  Receptor Knock-Out Mice Mimic Antidepressant-Induced Desensitization
AID  - 10.1523/JNEUROSCI.21-20-08188.2001
DP  - 2001 Oct 15
TA  - The Journal of Neuroscience
PG  - 8188--8197
VI  - 21
IP  - 20
4099  - http://www.jneurosci.org/content/21/20/8188.short
4100  - http://www.jneurosci.org/content/21/20/8188.full
SO  - J. Neurosci.2001 Oct 15; 21
AB  - 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-HT1Areceptors 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.