The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness.

Department of Pharmacology and Therapeutics, School of Medicine Clinics Hospital, Montevideo, Uruguay.
Sleep Medicine Reviews (Impact Factor: 9.14). 02/2010; 14(5):307-17. DOI: 10.1016/j.smrv.2009.11.004
Source: PubMed

ABSTRACT Serotonergic (5-HT) cells in the rat dorsal raphe nucleus (DRN) appear in topographically organized groups. Based on cellular morphology, expression of other neurotransmitters, afferent and efferent connections and functional properties, 5-HT neurons of the DRN have been grouped into six cell clusters. The subdivisions comprise the rostral, ventral, dorsal, lateral, caudal and interfascicular parts of the DRN. In addition to 5-HT cells, neurons containing γ-aminobutyric acid (GABA), glutamate, dopamine, nitric oxide and the neuropeptides corticotropin-releasing factor, substance P, galanin, cholecystokinin, neurotensin, somatostatin, vasoactive intestinal peptide, neuropeptide Y, thyrotropin-releasing hormone, growth hormone, leu-enkephalin, met-enkephalin and gastrin have been characterized in the DRN. Moreover, numerous brain areas have neurons that project to the DRN and express monoamines (norepinephrine, histamine), amino acids (GABA, glutamate), acetylcholine or neuropeptides (orexin, melanin-concentrating hormone, corticotropin-releasing factor and substance P) that directly or indirectly, through local circuits, regulate the activity of 5-HT cells. The 5-HT cells predominate along the midline of the rostral, dorsal and ventral subdivisions of the DRN and outnumber the non-5-HT cells occurring in the raphe nucleus. The GABAergic and glutamatergic neurons are clustered mainly in the lateral and dorsal subdivisions of the DRN, respectively. The 5-HT(1A) receptor is located on the soma and the dendrites of 5-HT neurons and at postsynaptic sites (outside the DRN). It is expressed, in addition, by non-5-HT cells of the DRN. The 5-HT(1B) receptor is located at presynaptic and postsynaptic sites (outside the boundaries of the DRN). It has been described also in the ventromedial DRN where it is expressed by non-5-HT cells. The 5-HT(2A) and 5-HT(2C) receptors are located within postsynaptic structures. At the level of the DRN the 5-HT(2A) and 5-HT(2C) receptor-containing cells are predominantly GABAergic interneurons and projection neurons. Within the boundaries of the DRN the 5-HT(3) receptor is expressed by, among others, glutamatergic interneurons. 5-HT(7) receptors in the DRN are not localized to serotonergic neurons but, at least in part, to GABAergic cells and terminals. The complex structure of the DRN may have important implications for neural mechanisms underlying 5-HT modulation of wakefulness and REM sleep.

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    ABSTRACT: Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25-100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant.
    Behavioural Pharmacology 08/2014; 25(4):316-324. DOI:10.1097/FBP.0000000000000056 · 2.19 Impact Factor
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    ABSTRACT: The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability. Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics. We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions. This model may prove useful to predict the effects of orexin receptor antagonists in sleep disorders and other conditions.
    Frontiers in Pharmacology 02/2014; 5:16. DOI:10.3389/fphar.2014.00016
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    ABSTRACT: Purpose To measure the activity of individual raphe nuclei with fluorine 18 fluorodeoxyglucose (FDG) and carbon 11 ((11)C) 3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile (DASB) imaging using a brain positron emission tomography(PET)/magnetic resonance (MR) imaging fusion system. Materials and Methods The study was approved by the Institutional Review Board of Gil Medical Center, and all volunteers provided written informed consent. FDG PET, (11)C-DASB PET, and T2*-weighted MR images from seven healthy volunteers were acquired by using a PET/MR imaging fusion system. The standard uptake value ratio (SUVR) of FDG (FDG-SUVR) and nondisplaceable binding potential (BPnd) of (11)C-DASB (DASB-BPnd) were determined for each raphe nucleus. A Pearson correlation analysis was performed to show the correlation between FDG-SUVR and DASB-BPnd for the raphe nuclei. Results Each raphe nucleus could be distinguished in both FDG (identifiability ratio, 0.86; κ = 0.77) and (11)C-DASB (identifiability ratio, 0.89; κ = 0.72) images. The mean values of DASB-BPnd for each raphe nucleus from dorsal to caudal direction were 6.08 (raphe nucleus 1), 5.93 (raphe nucleus 2), 3.86 (raphe nucleus 3), 3.18 (raphe nucleus 4), and 2.74 (raphe nucleus 5); the mean FDG-SUVR values were 1.00 (raphe nucleus 1), 1.00 (raphe nucleus 2), 0.87 (raphe nucleus 3), 0.94 (raphe nucleus 4), and 0.90 (raphe nucleus 5). FDG-SUVR and DASB-BPnd for the raphe nuclei were significantly correlated (r = 0.506, P = .002). Conclusion Serotonergic activity, both glucose metabolism and transporter binding potential of raphe nuclei, were measured with a brain-dedicated PET/MR imaging system and showed a significant correlation. © RSNA, 2014 Online supplemental material is available for this article.
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