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

Department of Pharmacology and Therapeutics, School of Medicine Clinics Hospital, Montevideo, Uruguay.
Sleep Medicine Reviews (Impact Factor: 8.51). 02/2010; 14(5):307-17. DOI: 10.1016/j.smrv.2009.11.004
Source: PubMed


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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    • "There is evidence that MCHergic fibers reach the dorsal raphe nucleus (DRN) in rats (Bittencourt et al., 1992; Lagos et al., 2011a; Yoon and Lee, 2013). The DRN contains the vast majority of the serotonergic neurons of the brain (Azmitia and Segal, 1978; Jacobs and Azmitia, 1992; Monti, 2010; Calizo et al., 2011) and it has been suggested that a dysfunction in the serotonergic neurons of the DRN underlies major depression (Underwood et al., 1999; Arango et al., 2002). "
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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 · 2.15 Impact Factor
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    • "Projections from the thalamus excite cortical neurons. There are numerous projections from higher brain regions to the DRN (Monti, 2010); in particular there are inhibitory projections from medial prefrontal cortex (mPFC) (Celada et al., 2001). In addition, SNc projections excite DRN neurons (DiMatteo et al., 2008) and DRN neurons inhibit SNc neurons (Guiard et al., 2008). "
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    ABSTRACT: It has been well established that serotonin (5-HT) plays an important role in the striatum. For example, during levodopa therapy for Parkinson’s disease (PD), the serotonergic projections from the dorsal raphe nucleus release dopamine as a false transmitter, and there are strong indications that this pulsatile release is connected to dyskinesias that reduce the effectiveness of the therapy. Here we present hypotheses about the functional role of 5-HT in the normal striatum and present computational studies showing the feasibility of these hypotheses. Dopaminergic projections to the striatum inhibit the medium spiny neurons (MSN) in the striatopalladal (indirect) pathway and excite MSNs in the striatonigral (direct) pathway. It has long been hypothesized that effect of dopamine (DA) depletion caused by the loss of SNc cells in PD is to change the “balance” between the pathways to favor the indirect pathway. Originally, “balance” was understood to mean equal firing rates, but now it is understood that the level of DA affects the patterns of firing too. There are dense 5-HT projections to the striatum from the dorsal raphe nucleus and it is known that increased 5-HT in the striatum facilitates DA release from DA terminals. The direct pathway excites various cortical nuclei and some of these nuclei send inhibitory projections to the DRN. Our hypothesis is that this feedback circuit from the striatum to the cortex to the DRN to the striatum stabilizes the balance between the direct and indirect pathways, and this is confirmed by our model calculations. Our calculations also show that this circuit contributes to the stability of the dopamine concentration in the striatum as SNc cells die during Parkinson’s disease progression (until late phase). There may be situations in which there are physiological reasons to “unbalance” the direct and indirect pathways, and we show that projections to the DRN from the cortex or other brain regions could accomplish this task.
    Frontiers in Integrative Neuroscience 05/2013; 7:41. DOI:10.3389/fnint.2013.00041
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    • "While there are anatomical and functional distinctions among the raphe nuclei, it is known that even the DRN can also be parsed into anatomically and functionally distinct subregions. For example, the DRN in rats has been suggested to be divided as six subdivisions of the rostral, ventral, dorsal, caudal, and interfascicular parts, as well as the lateral wings (Monti 2010). Furthermore, the DRN contains serotonin and non-serotonin neurons with the expression of many different neurotransmitters (Jacobs and Azmitia 1992). "
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    ABSTRACT: Chronic stress and dysfunction of the serotonergic system in the brain have been considered as two of the major risks for development of depression. In the present study, adult Fischer 344 rats were subjected to a regimen of chronic social defeat (CSD). To mimic stressful conditions some rats were not exposed to CSD but instead treated with corticosterone (CORT) in oral solution while maintained in their home cage. Protein levels of the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN), hippocampus, frontal cortex and amygdala were examined by western blotting or immunofluorescence staining. The results showed that CSD up-regulated SERT protein levels in the DRN, hippocampus, frontal cortex and amygdala regions. This upregulation was abolished or prevented by adrenalectomy, or treatment with antagonists of corticosteroid receptors mifepristone and spironolactone, alone or in combination. Similarly, up-regulated SERT protein levels in these brain regions were also observed in rats treated with oral CORT ingestion, which was analogously prevented by treatment with mifepristone and spironolactone. Furthermore, both CSD- and CORT-induced upregulation of SERT protein levels in the DRN and three brain regions were attenuated by simultaneous treatment with fluoxetine, an antidepressant that specifically inhibits serotonin reuptake. The results indicate that upregulation in SERT protein levels in the DRN and forebrain limbic structures caused by CSD regimen was mainly motivated by CORT through corticosteroid receptors. The present findings demonstrate that chronic stress is closely correlated with the serotonergic system by acting on the regulation of the SERT expression in the DRN and its projection regions, which may contribute to the development of depression. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12055.
    Journal of Neurochemistry 10/2012; 123(6). DOI:10.1111/jnc.12055 · 4.28 Impact Factor
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