Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic and clinical studies suggest that neurokinin 1 (NK1) receptor antagonists have efficacy in the treatment of affective disorders through effects on the dorsal raphe nucleus (DR), a source of forebrain-projecting serotonin (5-HT) neurons that has also been implicated in affective disorders. To investigate the regulation of the DR-5-HT system by NK1 receptors, the effects of substance P (an NK1 agonist) on rat DR neuronal activity were characterized. Most of the DR neurons (83%; n = 47 total) were inhibited by substance P microinfusion into the DR, and in some cases (17%) this was preceded by a brief activation. Pure excitation was observed in a small population of neurons (17%) that were localized in the dorsal DR, where NK1 receptors are most dense. Sendide, a selective NK1 antagonist, attenuated the effects of substance P, indicating that they were mediated by NK1 receptor activation. The selective 5-HT1A antagonist, WAY 100635, administered systemically or into the DR, prevented the inhibitory effects of substance P, implicating DR 5-HT1A receptors in this response. Finally, microinfusion of the excitatory amino acid antagonist, kynurenic acid, into the DR prevented both excitatory and inhibitory effects. The results suggest that NK1 receptor activation in the DR excites a population of 5-HT neurons via glutamatergic transmission. This results in 5-HT release throughout the DR, activation of 5-HT1A receptors, and subsequent inhibition. Interactions between NK1 and 5-HT1A receptors within DR neural networks may contribute to the mechanism of action of novel antidepressants acting at NK1 receptors.
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PMID:Substance P Acts through local circuits within the rat dorsal raphe nucleus to alter serotonergic neuronal activity. 1290 75

The dorsal raphe nucleus (DR) contains serotonin (5-HT) neurons that innervate the cortex and limbic system and through these projections is thought to regulate cognition and behavior. Clinical and pharmacological findings implicate dysfunctions in the DR-5-HT system in affective disorders, including anxiety, depression and suicide. Although the DR is often considered in light of its 5-HT neurons, recent studies underscore the complexity of this nucleus and its heterogeneous nature. Of particular interest, are peptides that are either present within neurons in the DR, innervate DR-5-HT neurons or act upon local circuitry within the DR to indirectly impact on this 5-HT system. These peptides are positioned to fine-tune the activity of selective groups of serotonergic neurons within the DR and thereby 5-HT release in different terminal fields. This review will focus on substance P and corticotropin-releasing factor as two peptides that act independently and interdependently to influence DR-5-HT function. The role of non-serotonergic components of the DR in translating the effect of each of these peptides is discussed. This synthesis refines our views on the regulation of the DR-5-HT system and importantly, gives insight into mechanisms of endogenous control of DR function, the dysregulation of which may contribute to pathophysiology.
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PMID:Peptides that fine-tune the serotonin system. 1562 94