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 be en shown to represent a novel class of antidepressant drugs, with comparabl e clinical efficacy to the selective serotonin (5-HT) reuptake inhibitors ( SSRIs). Because 5-HT1A receptors may be critically involved in the mechanis ms of action of SSRIs, we examined whether these receptors could also be af fected in a model of whole-life blockade of NK1 receptors, i.e. knock-out m ice lacking the latter receptors (NK1-/-). 5-HT1A receptor labeling by the selective antagonist radioligand [H-3]N-[2-[4-(2-methoxyphenyl)1-piperaziny l]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT1A-de pendent [S-35]GTP-gamma -S binding at the level of the dorsal raphe nucleus (DRN) in brain sections, as well as the concentration of 5-HT1A mRNA in th e anterior raphe area were significantly reduced (-19 to -46%) in NK1-/- co mpared with NK1+/+ mice. Furthermore, a similar to 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 slic es, and reduced hypothermic response to 8-OH-DPAT, were noted in NK1-/- ver sus NK1+/+ mice. On the other hand, cortical 5-HT overflow caused by system ic injection of the SSRI paroxetine was four- to sixfold higher in freely m oving NK1-/- mutants than in wild- type NK1+/+ mice. Accordingly, the const itutive lack of NK1 receptors appears to be associated with a downregulatio n/functional desensitization of 5-HT1A autoreceptors resembling that induce d by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT1A autore ceptors in NK1+/+ mutants does not reflect the existence of direct NK1-5-HT 1A receptor interactions in normal mice.