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

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 mechan...

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Bibliographic Details
Published in:The Journal of neuroscience 2001-10, Vol.21 (20), p.8188-8197
Main Authors: Froger, Nicolas, Gardier, Alain M, Moratalla, Rosario, Alberti, Israel, Lena, Isabelle, Boni, Claudette, De Felipe, Carmen, Rupniak, Nadia M. J, Hunt, Stephen P, Jacquot, Christian, Hamon, Michel, Lanfumey, Laurence
Format: Article
Language:English
Subjects:
8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology
Animals
Antidepressive Agents - pharmacology
Autoreceptors - metabolism
Drug Resistance - physiology
Electrophysiology
Immunohistochemistry
In Vitro Techniques
Male
Mice
Mice, Knockout
Neurons - drug effects
Neurons - metabolism
Paroxetine - pharmacology
Piperazines - pharmacokinetics
Pyridines - pharmacokinetics
Pyrimidines - pharmacology
Raphe Nuclei - cytology
Raphe Nuclei - drug effects
Raphe Nuclei - metabolism
Receptors, Neurokinin-1 - deficiency
Receptors, Neurokinin-1 - genetics
Receptors, Serotonin - genetics
Receptors, Serotonin - metabolism
Receptors, Serotonin, 5-HT1
RNA, Messenger - metabolism
Serotonin Antagonists - pharmacokinetics
Serotonin Receptor Agonists - pharmacology
Serotonin Uptake Inhibitors - pharmacology
Substance P - metabolism
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Summary: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 [(3)H]N-[2-[4-(2-methoxyphenyl)1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT(1A)-dependent [(35)S]GTP-gamma-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 approximately 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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/jneurosci.21-20-08188.2001