Substance P Acts through Local Circuits within the Rat Dorsal Raphe Nucleus to Alter Serotonergic Neuronal Activity

Valentino, Rita J.; Bey, Vincent; Pernar, Luise I.M.; Commons, Kathryn G.

doi:10.1523/jneurosci.23-18-07155.2003

Cited by 60 publications

(50 citation statements)

References 20 publications

(43 reference statements)

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“…VGLUT3-positive terminals within the raphe arise either from 5HT neurons or from local VGLUT3-only glutamatergic neurons. Glutamatergic raphe neurons were recently shown to send projections (1) to the hippocampus and the septum (Jackson et al, 2009) and (2) locally to the dorsolateral subdivision of the DRN (Commons and Valentino, 2002;Valentino et al, 2003). In Vglut3 Ϫ/Ϫ mice, the lack of VGLUT3 in these glutamatergic fibers somehow triggers the desensitization of 5-HT 1A receptors.…”

Section: -Vglut3 Modulates 5-ht Transmission In the Raphementioning

confidence: 99%

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

Amilhon¹,

Lepicard²,

Renoir³

et al. 2010

J. Neurosci.

161

192

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Three different subtypes of Hϩ -dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT 1A -mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3-and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.

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Section: -Vglut3 Modulates 5-ht Transmission In the Raphementioning

confidence: 99%

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

Amilhon¹,

Lepicard²,

Renoir³

et al. 2010

J. Neurosci.

161

192

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“…We next investigated the possibility that this inhibition was mediated via the release of other neurotransmitters, as has been described for substance P actions in the nucleus accumbens and dorsal raphe nucleus (Liu et al, 2002;Kombian et al, 2003;Valentino et al, 2003). To test this, we examined the effects of substance P on evoked IPSCs after blockade of a number of G-proteincoupled receptors that are known to presynaptically suppress GABA A receptormediated synaptic transmission in the PAG (Vaughan and Christie, 1997;Bagley et al, 1999;Kishimoto et al, 2001;Yang et al, 2003).…”

Section: Substance P Suppresses Evoked Ipscs Through Activation Of Mgmentioning

confidence: 99%

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Drew¹,

Lau²,

Vaughan³

2009

J. Neurosci.

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Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA B , ,␦-opioid, adenosine A 1 , and 5HT 1A receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.

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“…Thus, whether 5-HT neurotransmission were increased or decreased in projection brain regions of the DRN would depend on the specific DRN subregion that projects to the serotonergic nerve terminal area studied. Based on their findings, Valentino et al, (2003) have drawn an in vivo model of SP regulation of 5-HT neuronal activity. They propose that excitation of DRN 5-HT neurons synaptically linked with glutamate neurons expressing NK1 receptors allows 5-HT release and subsequent activation of somatodendritic 5-HT 1A autoreceptors.…”

mentioning

confidence: 99%

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

Guiard

Guilloux²,

Repérant³

et al. 2007

Mol Pharmacol

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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,...

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Substance P Acts through Local Circuits within the Rat Dorsal Raphe Nucleus to Alter Serotonergic Neuronal Activity

Cited by 60 publications

References 20 publications

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

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

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