Convergent Excitation of Dorsal Raphe Serotonin Neurons by Multiple Arousal Systems (Orexin/Hypocretin, Histamine and Noradrenaline)

Abstract

Dorsal raphe serotonin neurons fire tonically at a low rate during waking. In vitro, however, they are not spontaneously active, indicating that afferent inputs are necessary for tonic firing. Agonists of three arousal-related systems impinging on the dorsal raphe (orexin/hypocretin, histamine and the noradrenaline systems) caused an inward current and increase in current noise in whole-cell patch-clamp recordings from these neurons in brain slices. The inward current induced by all three agonists was significantly reduced in extracellular solution containing reduced sodium (25.6 mm). In extracellular recordings, all three agonists increased the firing rate of serotonin neurons; the excitatory effects of histamine and orexin A were occluded by previous application of phenylephrine, suggesting that all three systems act via common effector mechanisms. The dose-response curve for orexin B suggested an effect mediated by type II (OX2) receptors. Single-cell PCR demonstrated the presence of both OX1 and OX2 receptors in tryptophan hydroxylase-positive neurons. The effects of histamine and the adrenoceptor agonist, phenylephrine, were blocked by antagonists of histamine H1 and alpha1 receptors, respectively. The inward current induced by orexin A and phenylephrine was not blocked by protein kinase inhibitors or by thapsigargin. Three types of current-voltage responses were induced by all three agonists but in no case did the current reverse at the potassium equilibrium potential. Instead, in many cases the orexin A-induced current reversed in calcium-free medium at a value (-23 mV) consistent with the activation of a mixed cation channel (with relative permeabilities for sodium and potassium of 0.43 and 1, respectively).

Expression of 5-HT7 receptor mRNA in the hamster brain: Effect of aging and association with calbindin-D28K expression

“…Furthermore, the relatively low levels of expression of 5-HT 7 receptor mRNA observed in the DRN (and MRN) suggest that some of the 5-HT 7 receptor protein identified in these regions by binding studies or functional studies may be located on afferent terminals of nerve fibers originating in other brain regions. Some of the brain regions that have been demonstrated to be afferent to the DRN in the rat, such as the bed nucleus of the stria terminalis, the medial preoptic nucleus, the anterior hypothalamic area, the ventral pontine periaqueductal gray, the cingulate cortex, and the paraventricular thalamic nucleus (Peyron et al, 1998;Gervasoni et al, 2000;Brown et al, 2002;Lee et al, 2005), exhibited 5-HT 7 receptor mRNA expression in the hamster brain, although other afferent regions, such as the lateral preoptic area, lateral hypothalamic area, lateral habenula, perifornical nucleus, posterior hypothalamic area, and medial tuberal nucleus, did not show 5-HT 7 receptor mRNA signal in this study. Of the DRN-afferent regions that expressed 5-HT 7 receptor mRNA, only two, the cingulate cortex and the paraventricular thalamic nucleus, exhibited age-related decreases in expression of this mRNA.…”

Serotonin controlling feeding and satiety

“…Orexin neurons are located specifically in the LHA and the LHA projects to almost all parts of the brain [186,187], in particular to serotonergic raphe neurons [187][188][189]. In the LHA, 5-HT1A…”

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

“…Hcrt-induced excitatory responses in CNS neurons are mediated primarily via Na ϩ -dependent mechanisms that include activation of the Na ϩ -Ca ϩ exchanger (Eriksson et al, 2001;Wu et al, 2002;Korotkova et al, 2003) or the nonselective cationic current (Brown et al, 2002;Liu et al, 2002;Yang and Ferguson, 2002;van den Top et al, 2003). Hcrt has also been reported to close K ϩ channels (Ivanov and AstonJones, 2000;Hoang et al, 2003;van den Top et al, 2003).…”

“…2a4 ), suggesting possible involvement of K ϩ channels. Because in a vast majority of septohippocampal cholinergic neurons the Hcrt-induced current was inward between Ϫ65 and Ϫ125 mV, we first tested the effect of replacing 80% of the external Na ϩ with Tris, an approach that is used by most studies investigating ionic mechanisms (Brown et al, 2002;Liu et al, 2002) because 100% Na ϩ replacement can alter neurotransmitter uptake and release (Parsons et al, 1992;Shen and North, 1992). Replacement of external Na ϩ with Tris significantly reduced but did not block the Hcrt-induced inward current (at Ϫ65 mV, control: Ϫ76.7 Ϯ 10.8 pA; low Na ϩ : Ϫ20.5 Ϯ 4.3 pA; p ϭ 0.0005; n ϭ 9) and also produced I-V curves that tended to converge close to E K or even cross at E K , possibly because of involvement of a K ϩ conductance (Fig.…”