Substance P injection into the dorsal raphe increases blood pressure and serotonin release in hippocampus of conscious rats

Gradin, K.; Qadri, Fatimunnisa; Nomikos, George G.; Hillegaart, Viveka; Svensson, Torgny H.

doi:10.1016/0014-2999(92)90194-9

Cited by 27 publications

(14 citation statements)

References 12 publications

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“…However, initial in vitro electrophysiological recordings suggested that SP excites DRN 5-HT neurons via glutamatergic afferents (Liu et al, 2002). These findings were consistent with intracerebral in vivo microdialysis experiments indicating that SP injection into the DRN in conscious rats produces a small, transient increase in hippocampal 5-HT release (by Ͼ30% for 20 min compared with vehicle control) (Gradin et al, 1992). The latter findings have been challenged recently by in vivo electrophysiological data, suggesting that the effects of SP depended on the location of the recording within the DRN, with excitation predominating in the dorsal part of the DRN and inhibition more ventrally .…”

supporting

confidence: 78%

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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supporting

confidence: 78%

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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“…While the injection of SP directly into the raphe nuclei leads to an increase 5-HT release and 5-HT-mediated behaviors, intracisternal administration of SP fails to elicit 5-HT-mediated behaviors (Gradin et al 1992;Stoessl et al 1987). In another in vivo study, it was found that the systemic administration of a SP (NK 1 ) antagonist produced an increase rather than a decrease in 5-HT cell firing (Santarelli et al 2001), again indicating that SP does not have a global activating effect on the 5-HT system.…”

Section: Differences Between the Local And Global Effects Of Activatimentioning

confidence: 98%

“…It has been proposed that neurokinins may increase 5-HT release by activating 5-HT cell firing in the raphe nuclei. This proposal is based on the fact that local injections of SP into the MRN (Forchetti et al 1982) or DRN (Gradin et al 1992) increase 5-HT turnover or 5-HT release in terminal regions of the hippocampus. However, the mechanism by which neurokinins might alter the activity of 5-HT neurons in the DRN (or other raphe nuclei) was not delineated by those studies.…”

Section: Neurokinins Excite 5-ht Neurons In the Drn Indirectly By Actmentioning

confidence: 99%

“…For example, injection of SP into the MRN induces an increase in 5-HT turnover in the hippocampus (Forchetti et al 1982). Similarly, local injection of SP into the DRN increases extracellular levels of 5-HT in the ventral hippocampus of rats (Gradin et al 1992). On a behavioral level, infusion of the selective NK 3 agonist senktide or a SP analog into the MRN induces a 5-HT-dependent increase in locomotor activity (Paris and Lorens 1987;Paris et al 1989).…”

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confidence: 99%

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Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus

Liu

Ding

Aghajanian

2002

Neuropsychopharmacology

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“…BRS-3 is present in brain regions that regulate blood pressure and heart rate (2,11,16), including the medial preoptic, posterior hypothalamic, dorsomedial hypothalamus, periaqueductal gray, dorsal raphe, parabrachial nucleus, and nucleus of the solitary tract (14,31,54). Modulation of other central antiobesity mechanisms (leptin, melanocortin, and ghrelin) can also increase blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism

Lateef

Xiao

Brychta

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Lateef DM, Xiao C, Brychta RJ, Diedrich A, Schnermann J, Reitman ML. Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310: H891-H898, 2016. First published January 22, 2016; doi:10.1152/ajpheart.00963.2015.-Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting ␣ 2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.bombesin-like receptor 3; blood pressure; heart rate; sympathetic nervous system; energy metabolism NEW & NOTEWORTHY MK-5046, a bombesin-like receptor 3 (BRS-3) agonist, increases heart rate and blood pressure via increased central sympathetic tone. Brs3 null mice have a reduced resting heart rate that increases disproportionately with physical activity. BRS-3 contributes to the central regulation of heart rate and blood pressure.OBESITY is strongly associated with cardiovascular risk factors, including hypertension (6). However, the mechanisms linking obesity and hypertension are not fully understood (7,44). A number of neuroendocrine systems controlling energy homeostasis also regulate blood pressure and heart rate, including leptin, the melanocortin system, and ghrelin (12, 36, 45, 48 -50). The genetic and pharmacological manipulations of these systems that reduce adiposity generally also increase blood pressure, which is undesirable in a treatment for obesity.Bombesin-like receptor 3 (BRS-3) is a G protein-coupled receptor for which the endogenous ligand is unidentified (4,21,29,33). Despite the name, BRS-3 has a low affinity for bombesin and the related molecules, neuromedin B and gastrin-releasing ...

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Substance P injection into the dorsal raphe increases blood pressure and serotonin release in hippocampus of conscious rats

Cited by 27 publications

References 12 publications

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

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

Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus

Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism

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