Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex

Abstract

Preclinical studies suggest that substance P (SP) neurokinin 1 (NK1) receptor antagonists are efficient in the treatment of anxiety and depression. This therapeutic activity could be mediated via stimulation of serotonin (5-HT) neurons located in the dorsal raphe nucleus (DRN), which receive important SP-NK1 receptor immunoreactive innervations. The present study examined the effects of intraraphe injection of SP on extracellular 5-HT levels in the frontal cortex, ventral hippocampus, and DRN by using intracerebral microdialysis in conscious mice. Intraraphe SP injection dose dependently decreased cortical 5-HT release, whereas no effects were detected in the ventral hippocampus. Cortical effects were blocked by the selective NK1 receptor antagonist N- [[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine (GR205171) and completely dampened in mice lacking NK1 receptors. Furthermore, genetic (in knockout 5-HT 1A Ϫ/Ϫ mice) or pharmacological inactivation of 5-HT 1A autoreceptors blocked cortical responses to SP. Contrasting with its cortical effects, intraraphe SP injection increased 5-HT outflow in the DRN in wild-type mice; this effect was potentiated by a local perfusion of the selective 5-Finally, SP-induced changes in frontal cortex and DRN dialysate 5-HT levels were blocked by the DRN perfusion of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate ionotropic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These data support the hypothesis that SP-induced overactivation of 5-HT 1A autoreceptors within the DRN limits cortical 5-HT release. A better knowledge of the complex relationship between tachykininergic, serotonergic, and glutamatergic systems within the DRN might help better understand the pathophysiology and subsequent treatment of depression.Substance P (SP), a small peptide that belongs to the tachykinins family with neurokinins A and B, is widely distributed in the brain, specifically in limbic regions and brainstem nuclei such as the dorsal raphe nucleus (DRN) (Froger et al., 2001;Commons et al., 2002;Lacoste et al., 2006). In several species, including rodents and humans, SP distribution overlaps with that of its high-affinity NK1 receptor (Ribeiro-da-Silva and Hokfelt, 2000). Recent clinical and preclinical studies have pointed out the potential therapeutic action of SP (neurokinin 1) receptor antagonists in major depressive disorders (Kramer et al., 1998;Chahl, 2006). Data obtained from NK1 receptor knockout mice have suggested that the antidepressant-like action of NK1 receptor inactivation may result, at least in part, from an increase in central 5-HT neurotransmission through functional desensitization B.P.G. was the recipient of a fellowship from La Fondation pour la Recherche Medicale (FRM) during the performance of this work.Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.107.040113.ABBREVIATIONS: SP, substance P; DRN, dorsal raphe nucleus; NK,...

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…However, they are unlikely to be involved in the activations of GR205171 as the sensitivity of postsynaptic 5-HT 1A receptors is unaffected by NK 1 antagonists (Froger et al, 2001;Haddjeri and Blier, 2001;Santarelli et al, 2001). Further, though microinjection of substance P into the FCX suppressed 5-HT release, this action did not involve frontocortical 5-HT 1A receptors (Guiard et al, 2007).…”

“…That is, in line with the present observations, NK 1 receptors are 'upstream' of 5-HT 1A autoreceptors. Interestingly, by analogy to lateral septum (Ebner et al, 2008), frontocortical perfusion of substance P suppressed local release of 5-HT in mice, an effect blocked by GR205171 and absent in mice lacking NK 1 receptors (Guiard et al, 2007). Thus, NK 1 antagonists conceivably also enhance SSRI-induced increase in 5-HT levels by actions in the FCX and other structures innervated by the DRN.…”

“…Indeed, the inhibitory influence of 5-HT 1A agonists on the DRN is blunted by chronic treatment with NK 1 antagonists (Haddjeri and Blier, 2001;Guiard et al, 2005), and by genetic deletion of NK 1 receptors (Froger et al, 2001;Santarelli et al, 2001). However, acute blockade of NK 1 receptors does not generally desensitize 5-HT 1A autoreceptors (Blier et al, 2004;Guiard et al, 2007;Gobbi et al, 2007), and GR205171 did not modify the influence of 5-HT 1A agonists on DRN firing rate in vitro (Guiard et al, 2005). Correspondingly, the lack of influence of GR205171 upon the inhibition of DRN firing (Figure 4) by two 5-HT 1A agonists, 8-OH-DPAT and buspirone (Lejeune et al, 1997), suggests that it does not markedly affect the sensitivity of 5-HT 1A autoreceptors.…”

“…This would enhance their responsiveness to SSRIs, by analogy to GABA B antagonists (Millan, 2006;Cremers et al, 2007). Glutamatergic terminals targeting serotonergic DRN neurones also bear NK 1 receptors (Liu et al, 2002;Valentino et al, 2003), and their stimulation by intraraphe perfusion of substance P enhances local release of 5-HT via recruitment of AMPA receptors (Guiard et al, 2007). This results in a (delayed) decrease in cortical 5-HT release due to activation of 5-HT 1A autoreceptors.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…This concept is of particular interest because blockade of NK 1 receptors promotes the activity of corticolimbic adrenergic and dopaminergic pathways, complementing the effects of 5-HT reuptake inhibition. [173][174][175][176][177] Blockade of NK 1 receptors also accelerates the long-term facilitatory influence of SSRIs on serotonergic transmission, possibly by accelerating desensitization of inhibitory 5-HT 1A autoreceptors. [175][176][177] These observations suggest that dual agents may be both more effective and rapid-acting than SSRIs and, inasmuch as NK 1 antagonists enhance antidepressant actions of SSRIs yet curtail their anxiogenic effects, 3,177,178 they should be devoid of the symptoms of nervousness that patients may experience at the beginning of SSRI therapy.…”