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Dopaminergic Regulation of Serotonergic Dorsal Raphe Neurons: Role in the Control of Wakefulness and REM Sleep

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Abstract

The neural systems involved in the generation and maintenance of wakefulness (W) and REM sleep (REMS) include dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as serotonergic (5HT) neurons in the dorsal raphe nucleus (DRN). There is also a small group of DAergic neurons in the ventral periaqueductal gray or rostral DRN (also called A10dc region). Retrograde tracer techniques have established that the DRN receives DAergic inputs from the VTA and SNc. Furthermore, autoradiographic and in situ hybridization techniques have shown that dopamine D1 and D2 receptor subtypes are distributed within the DRN. Microinjection of D1 or D2 receptor subtype agonists in the DRN increases the excitability of 5-HT neurons, and intra-DRN administration of D1 and D2 selective receptor agonists SKF38393, bromocriptine and quinpirole to rats, induced a significant reduction of REMS and the number of REM periods. In addition, bromocriptine and quinpirole increased W. Furthermore, microinjection into the DRN of the D1 and D2 receptor antagonists SCH23390 and sulpiride significantly augmented REMS and the number of REM periods. Pretreatment with the above-mentioned antagonists prevented the effects of SKF38393 and bromocriptine on sleep variables. Thus, DAergic signal in the DRN contributes to the regulation of W and REMS.

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References

  1. Abrams JK, Johnson PL, Hollis JH, Lowry CA. Anatomic and functional topography of the dorsal raphe nucleus. Ann NY Acad Sci. 2004;1018:46–57.

    Article  PubMed  Google Scholar 

  2. Aman TK, Shen RY, Haj-Dahmane S. D2-like dopamine receptors depolarize dorsal raphe serotonin neurons through the activation of nonselective cationic conductance. J Pharmacol Exp Ther. 2007;320:376–85.

    Article  CAS  PubMed  Google Scholar 

  3. Azmitia EC. Bilateral serotonergic projections to the dorsal hippocampus of the rat: simultaneous localization of 3H–5HT and HRP after retrograde transport. J Comp Neurol. 1981;203:737–43.

    Article  CAS  PubMed  Google Scholar 

  4. Beckstead RM, Domesick VB, Nauta WJ. Efferent connections of the substantia nigra and ventral tegmental area in the rat. Brain Res. 1979;175:191–217.

    Article  CAS  PubMed  Google Scholar 

  5. Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci. 2002;16:1959–73.

    Article  PubMed  Google Scholar 

  6. Carskadon MA, Dement W. Normal human sleep: an overview. In: Kryger MH, Roth T, Dement W, editors. Principles and practice of sleep medicine. Philadelphia: Elsevier-Saunders; 2011. p. 16–26.

    Chapter  Google Scholar 

  7. Cho JR, Treweek JB, Robinson JE, Xiao C, Bremner LR, Greenbaum A, Gradinaru V. Dorsal raphe dopamine neurons modulate arousal and promote wakefulness by salient stimuli. Neuron. 2017;94:1205–19.

    Article  CAS  PubMed  Google Scholar 

  8. Dahan L, Astier B, Vautrelle N, Urbain N, Kocsis B, Chouvet G. Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep. Neuropsychopharmacology. 2007;32:1232–41.

    Article  CAS  PubMed  Google Scholar 

  9. Dawson TM, Gehlert DR, McCabe RT, Barnett A, Wamsley JK. D-1 dopamine receptors in the rat brain: a quantitative autoradiographic analysis. J Neurosci. 1986;6:2352–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dawson TM, Barone P, Sidhu A, Wamsley JK, Chase TN. The D1 dopamine receptor in the rat brain: quantitative autoradiographic localization using an iodinated ligand. Neuroscience. 1988;26:83–100.

    Article  CAS  PubMed  Google Scholar 

  11. Ferré S, Cortes R, Artigas F. Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats. J Neurosci. 1994;14:4839–46.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Guzmán-Marin R, Alam MN, Szymusiak R, Drucker-Colín R, Gong H, McGinty D. Discharge modulation of rat dorsal raphe neurons during sleep and waking: effects of preoptic/basal forebrain warming. Brain Res. 2000;875:23–34.

    Article  PubMed  Google Scholar 

  13. Haj-Dahmane S. D2-like dopamine receptor activation excites rat dorsal raphe 5-HT neurons in vitro. Eur J Neurosci. 2001;14:125–34.

    Article  CAS  PubMed  Google Scholar 

  14. Hasue RH, Shammah-Lagnado SJ. Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat. J Comp Neurol. 2002;454:15–33.

    Article  CAS  PubMed  Google Scholar 

  15. Hokfelt T, Martensson R, Bjorklund A, Kleinau S, Goldstein M. Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In: Bjorklund HT, editor. Handbook of chemical neuroanatomy, vol. 2. Elsevier; 1984. p. 277–87.

    Google Scholar 

  16. Holstege G, Meiners L, Tan K. Projections of the bed nucleus of the stria terminalis to the mesencephalon, pons, and medulla oblongata in the cat. Exp Brain Res. 1985;58:379–91.

    Article  CAS  PubMed  Google Scholar 

  17. Homann CN, Forstner M, Ivanic G, Ott E. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology. 2002;58:1863–4 (author reply).

    Article  CAS  PubMed  Google Scholar 

  18. Huang KW, Ochandarena NE, Philson AC, Hyun M, Birnbaum JE, Cicconet M, Sabatini BL. Molecular and anatomical organization of the dorsal raphe nucleus. Elife. 2019;8:e46464.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev. 1992;72:165–229.

    Article  CAS  PubMed  Google Scholar 

  20. Jones BE. Arousal and sleep circuits. Neuropsychopharmacology. 2020;45:6–20.

    Article  CAS  PubMed  Google Scholar 

  21. Kalen P, Skagerberg G, Lindvall O. Projections from the ventral tegmental area and mesencephalic raphe to the dorsal raphe nucleus in the rat. Evidence for a minor dopaminergic component. Exp Brain Res. 1988;73:69–77.

    Article  CAS  PubMed  Google Scholar 

  22. Kitahama K, Nagatsu I, Geffard M, Maeda T. Distribution of dopamine-immunoreactive fibers in the rat brainstem. J Chem Neuroanat. 2000;18:1–9.

    Article  CAS  PubMed  Google Scholar 

  23. Lee EH, Geyer MA. Selective effects of apomorphine on dorsal raphe neurons: a cytofluorimetric study. Brain Res Bull. 1982;9:719–25.

    Article  CAS  PubMed  Google Scholar 

  24. Lee HS, Kim MA, Valentino RJ, Waterhouse BD. Glutamatergic afferent projections to the dorsal raphe nucleus of the rat. Brain Res. 2003;963:57–71.

    Article  CAS  PubMed  Google Scholar 

  25. Li YQ, Li H, Kaneko T, Mizuno N. Morphological features and electrophysiological properties of serotonergic and non-serotonergic projection neurons in the dorsal raphe nucleus. An intracellular recording and labeling study in rat brain slices. Brain Res. 2001;900:110–8.

    Article  CAS  PubMed  Google Scholar 

  26. Lowry CA, Evans AK, Gasser PJ, Hale WH, Staub DR, Shekhar A. Topographic organization and chemoarchitecture of the dorsal raphe nucleus and the median raphe nucleus. In: Monti JM, Pandi-Perumal SR, Jacobs BL, Nutt DJ, editors. Serotonin and sleep: molecular, functional and clinical aspects. Basel: Birkhauser; 2008. p. 25–67.

    Chapter  Google Scholar 

  27. Lu J, Jhou TC, Saper CB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci. 2006;26:193–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Luppi PH, Clement O, Sapin E, Peyron C, Gervasoni D, Leger L, Fort P. Brainstem mechanisms of paradoxical (REM) sleep generation. Pflugers Arch. 2012;463:43–52.

    Article  CAS  PubMed  Google Scholar 

  29. Lydic R, McCarley RW, Hobson JA. Serotonergic neurons and sleep. I. Long term recordings of dorsal raphe discharge frequency and PGO waves. Arch Ital Biol. 1987;125:317–43.

    CAS  PubMed  Google Scholar 

  30. Mansour A, Meador-Woodruff JH, Bunzow JR, Civelli O, Akil H, Watson SJ. Localization of dopamine D2 receptor mRNA and D1 and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. J Neurosci. 1990;10:2587–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mansour A, Watson SJ. Dopamine receptor expression in the central nervous system. In: Bloom FE, Kupfer DJ, editors. Neuropsychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p. 207–19.

    Google Scholar 

  32. Matthews GA, Nieh EH, Vander Weele CM, Halbert SA, Pradhan RV, Yosafat AS, Glober GF, Izadmehr EM, Thomas RE, Lacy GD, Wildes CP, Ungless MA, Tye KM. Dorsal raphe dopamine neurons represent the experience of social isolation. Cell. 2016;164:617–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McGinty DJ, Harper RM. Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res. 1976;101:569–75.

    Article  CAS  PubMed  Google Scholar 

  34. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189–225.

    Article  CAS  PubMed  Google Scholar 

  35. Monti JM, Monti D. The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev. 2007;11:113–33.

    Article  PubMed  Google Scholar 

  36. Monti JM. The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med Rev. 2010;14:307–17.

    Article  PubMed  Google Scholar 

  37. Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15:269–81.

    Article  PubMed  Google Scholar 

  38. Monti JM, Jantos H. The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat. Behav Brain Res. 2018;339:11–8.

    Article  CAS  PubMed  Google Scholar 

  39. Monti JM, Torterolo P. Basic pharmacologic mechanisms of sleep. In: Reference module in neuroscience and biobehavioral psychology. Elsevier; 2021. p. 1–8.

    Google Scholar 

  40. Moore RY, Bloom FE. Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu Rev Neurosci. 1978;1:129–69.

    Article  CAS  PubMed  Google Scholar 

  41. Munsch T, Yanagawa Y, Obata K, Pape HC. Dopaminergic control of local interneuron activity in the thalamus. Eur J Neurosci. 2005;21:290–4.

    Article  PubMed  Google Scholar 

  42. Nair-Roberts RG, Chatelain-Badie SD, Benson E, White-Cooper H, Bolam JP, Ungless MA. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience. 2008;152:1024–31.

    Article  CAS  PubMed  Google Scholar 

  43. Oertel WH, Mugnaini E. Immunocytochemical studies of GABAergic neurons in rat basal ganglia and their relations to other neuronal systems. Neurosci Lett. 1984;47:233–8.

    Article  CAS  PubMed  Google Scholar 

  44. Ogawa S, Cohen JY, Hwang D, Uchida N, Watabe-Uchida M. Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems. Cell Rep. 2014;2014(8):1105–18.

    Article  CAS  Google Scholar 

  45. Pasquier DA, Kemper TL, Forbes WB, Morgane PJ. Dorsal raphe, substantia nigra and locus coeruleus: interconnections with each other and the neostriatum. Brain Res Bull. 1977;2:323–39.

    Article  CAS  PubMed  Google Scholar 

  46. Peyron C, Luppi PH, Kitahama K, Fort P, Hermann DM, Jouvet M. Origin of the dopaminergic innervation of the rat dorsal raphe nucleus. NeuroReport. 1995;6:2527–31.

    Article  CAS  PubMed  Google Scholar 

  47. Peyron C, Petit JM, Rampon C, Jouvet M, Luppi PH. Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience. 1998;82:443–68.

    Article  CAS  PubMed  Google Scholar 

  48. Portas CM, Thakkar M, Rainnie D, McCarley RW. Microdialysis perfusion of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal raphe nucleus decreases serotonin release and increases rapid eye movement sleep in the freely moving cat. J Neurosci. 1996;16:2820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramm P, Beninger RJ, Frost BJ. Functional activity in the lateral habenular and dorsal raphe nuclei following administration of several dopamine receptor antagonists. Can J Physiol Pharmacol. 1984;62:1530–3.

    Article  CAS  PubMed  Google Scholar 

  50. Sakai K, Salvert D, Touret M, Jouvet M. Afferent connections of the nucleus raphe dorsalis in the cat as visualized by the horseradish peroxidase technique. Brain Res. 1977;137:11–35.

    Article  CAS  PubMed  Google Scholar 

  51. Sakai K, Crochet S. Role of dorsal raphe neurons in paradoxical sleep generation in the cat. No evidence for a serotonergic mechanism. Eur J Neurosci. 2001;13:103–12.

    CAS  PubMed  Google Scholar 

  52. Sakai K. Sleep-waking discharge profiles of dorsal raphe nucleus neurons in mice. Neuroscience. 2011;197:200–24.

    Article  CAS  PubMed  Google Scholar 

  53. Saper CB, Swanson LW, Cowan WM. An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat. J Comp Neurol. 1979;183:689–706.

    Article  CAS  PubMed  Google Scholar 

  54. Sapin E, Lapray D, Berod A, Goutagny R, Leger L, Ravassard P, Clement O, Hanriot L, Fort P, Luppi PH. Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS ONE. 2009;4:e4272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Schultz W, Apicella P, Ljungberg T. Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J Neurosci. 1993;13:900–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Simon H, Le Moal M, Calas A. Efferents and afferents of the ventral tegmental-A10 region studied after local injection of [3H]leucine and horseradish peroxidase. Brain Res. 1979;178:17–40.

    Article  CAS  PubMed  Google Scholar 

  57. Smialowska M. The effect of apomorphine on serotonin neurons in dorsal raphe nucleus and catecholamine nerve terminals in paraventricular hypothalamic nucleus. Histofluorescence studies. Pol J Pharmacol Pharm. 1975;27:419–28.

    CAS  PubMed  Google Scholar 

  58. Taylor SR, Badurek S, Dileone RJ, Nashmi R, Minichiello L, Picciotto MR. GABAergic and glutamatergic efferents of the mouse ventral tegmental area. J Comp Neurol. 2014;522:3308–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Torterolo P, Monti J, Vanini G. Neurochemistry and pharmacology of sleep. In: Murillo E, editor. The behavioral, molecular, pharmacological, and clinical basis of the sleep-wake cycle. Elsevier Inc; 2019. p. 45–83.

    Chapter  Google Scholar 

  60. Trulson ME, Jacobs BL. Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res. 1979;163:135–50.

    Article  CAS  PubMed  Google Scholar 

  61. Uchimura N, Higashi H, Nishi S. Hyperpolarizing and depolarizing actions of dopamine via D-1 and D-2 receptors on nucleus accumbens neurons. Brain Res. 1986;375:368–72.

    Article  CAS  PubMed  Google Scholar 

  62. Unguez GA, Schneider JS. Dopaminergic dorsal raphe neurons in cats and monkeys are sensitive to the toxic effects of MPTP. Neurosci Lett. 1988;1988(94):218–23.

    Article  Google Scholar 

  63. Urbain N, Creamer K, Debonnel G. Electrophysiological diversity of the dorsal raphe cells across the sleep-wake cycle of the rat. J Physiol. 2006;573:679–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Versteeg DH, Van Der Gugten J, De Jong W, Palkovits M. Regional concentrations of noradrenaline and dopamine in rat brain. Brain Res. 1976;113:563–74.

    Article  CAS  PubMed  Google Scholar 

  65. Vertes RP, Linley SB. Efferent and afferent connections of the dorsal and median raphe nuclei in the rat. In: Monti JM, Pandi-Perumal SR, Jacobs BL, Nutt DJ, editors. Serotonin and sleep: molecular, functional and clinical aspects. Basel: Birkhauser; 2008. p. 69–102.

    Chapter  Google Scholar 

  66. Wang QP, Guan JL, Shioda S. Immunoelectron microscopic study of beta-endorphinergic synaptic innervation of GABAergic neurons in the dorsal raphe nucleus. Synapse. 2001;42:234–41.

    Article  CAS  PubMed  Google Scholar 

  67. Wu MF, John J, Boehmer LN, Yau D, Nguyen GB, Siegel JM. Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs. J Physiol. 2004;554:202–15.

    Article  CAS  PubMed  Google Scholar 

  68. Yang CR, Bourque CW, Renaud LP. Dopamine D2 receptor activation depolarizes rat supraoptic neurones in hypothalamic explants. J Physiol. 1991;443:405–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yetnikoff L, Lavezzi HN, Reichard RA, Zahm DS. An update on the connections of the ventral mesencephalic dopaminergic complex. Neuroscience. 1991;282:23–48.

    Article  CAS  Google Scholar 

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  1. Department of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, University of the Republic, Montevideo, Uruguay

    Jaime M. Monti

  2. Department of Physiology, School of Medicine, University of the Republic, Montevideo, Uruguay

    Pablo Torterolo

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Monti, J.M., Torterolo, P. Dopaminergic Regulation of Serotonergic Dorsal Raphe Neurons: Role in the Control of Wakefulness and REM Sleep. Sleep Vigilance 6, 21–29 (2022). https://doi.org/10.1007/s41782-021-00179-9

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