Norepinephrine and REM sleep
Pierre-Hervé Luppi , Christelle Peyron, Claire Rampon, Damien Gervasoni, Bruno Barbagli, Romuald Boissard and Patrice Fort
Rapid Eye Movement Sleep pp. 107-122B.N. Mallick, S. Inoue (Editors) Narosa Publishing House 1999
TABLE OF CONTENTS

Table of contents

1. Introduction

2. Effect of the application of gaba and glycine antagonists on the activity of the rat locus coeruleus neurons during sleep

3. Glycinergic and gaba-ergic afferent projections to the locus coeruleus

4. Physiological role of the glycinergic inputs to the LC

5. Physiological role of the gaba-ergic inputs to the LC

6. Conclusions and new hypothesis

4. Physiological role of the glycinergic inputs to the LC

The effect of strychnine indicates the existence of a tonic glycinergic input on LC cells during W, SWS and PS. Further, we found that when the same neuron was recorded during short successive periods of SWS and W during the strychnine effect, its increases in discharge rate was strongly superior during W than SWS. These results indicate that when the tonic inhibition of LC cells by GLY is completely removed by strychnine, the LC cells are still under a specific inhibition by another neurotransmitter during SWS. Further, our results with bicuculline indicate that GABA appears to be this neurotransmitter (see next chapter). Unfortunately, due to the smaller number of LC cells successively recorded during SWS and PS, we were not able to make the same comparison between these two sleep states. However, with the microdialysis technique, Nitz and Siegel (1997) recently found no detectable change in the GLY concentration in the cat LC during SWS and PS as compared to waking values. The glycinergic tonic inhibition might therefore be kept constant across the sleep-waking cycle and control the general excitability of LC neurons. This control could either arise from the major glycinergic input to the LC from the ventrolateral and lateral parts of the periaqueductal gray (CG) and the adjacent mesencephalic reticular formation or the smaller inputs from the lateral paragigantocellular, raphe magnus, dorsal paragigantocellular and gigantocellular alpha nuclei.

Of interest regarding the periaqueductal gray input, Sastre et al. (1996) in cats recently showed that the inactivation of the ventrolateral periaqueductal gray by muscimol (a GABAa agonist) induced a dramatic increase of PS. This result might be explained by the fact that the glycinergic neurons constitute only a minor proportion of the neurons from the ventrolateral periaqueductal gray. The effect seen by Sastre et al. (1996) could therefore be due to the inhibition of other types of neurons (in particular glutamatergic or GABAergic)(Beitz, 1995)

Besides, we observed a small number of glycinergic neurons in the nucleus gigantocellular alpha and the adjacent raphe magnus projecting to the LC. Based on a number of studies in cats, we made the hypothesis that during PS, the monoaminergic neurons and the cranial and spinal somatic motoneurons might be inhibited by a single population of glycinergic neurons located in the magnocellular reticular nucleus (cat's equivalent of gigantocellular alpha and ventral nuclei, Gia and GiV). However, the present results and those we recently obtained on the glycinergic afferents to the motor trigeminal nucleus (Mo5)(Rampon et al, 1996) indicate at least in rats that the GiV provide only a limited glycinergic input to the LC and Mo5 and are therefore unlikely to contain a single population of neurons responsible for the inhibition of monoaminergic and all somatic motoneurons during PS. In fact, in rats, the only motoneurons receiving a strong glycinergic projection from the Gia and GiV are those of the spinal cord as demonstrated by Holstege and Bongers (1991). In view of these results in rats, the cranial motoneurons might be rather inhibited during PS by neurons from the parvocellular and parvocellular alpha reticular nuclei and glycine might not be specifically involved in the inhibition of monoaminergic neurons during sleep. Additional experiments are nevertheless necessary to confirm such conclusion in particular in cats in which it has been shown that the magnocellular but not the parvocellular reticular nuclei contains C-Fos positive cells following long periods of PS induced by carbachol injections in the pons (Yamuy et al., 1993)

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REFERENCES
  1. Aghajanian, G.K. and VanderMaelen, C.P., Intracellular identification of central noradrenergic and serotonergic neurons by a new double labeling procedure, J. Neurosci., 2, 1786, 1982.
  2. Akaoka, H., Charléty, P.J., Saunier, C.F., Buda, M. and Chouvet, G., Combining in vivo volume-controlled pressure microinjection with extracellular unit recording, J. Neurosci. Meth., 42, 119, 1992.
  3. Asala, S.A., Okano, Y., Honda, K., Inoue, S., Effects of medial preoptic area lesions on sleep and wakefulness in unrestrained rats, Neurosci. Lett., 114, 300, 1990.
  4. Aston-Jones, G., Ennis, M., Pieribone, V.A., Nickell, W.T. and Shipley, M.T., The brain nucleus locus coeruleus : restricted afferent control of a broad efferent network, Science, 234, 734, 1986.
  5. Aston-Jones, G. and Bloom, F.E., Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle, J. Neurosci., 1, 876, 1981.
  6. Beitz, A., The Rat Nervous System, Second Edition, G. Paxinos (Ed), San Diego, 173, 1995.
  7. Bird, S.J. and Kuhar, M.J., Iontophoretic applications of opiates to the locus coeruleus, Brain Res., 122, 523, 1977.
  8. Cedarbaum, J.M. and Aghajanian, G.K., Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique, J.Comp.Neurol., 178, 1, 1978.
  9. Chase, M.H., Soja, P.J. and Morales, F.R., Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep, J. Neurosci., 9, 743, 1989.
  10. Cherubini, E., North, R. A. and Williams., J.T., Synaptic potentials in rat locus coeruleus neurons, J. Physiol. (London), 406, 431, 1988.
  11. Chouvet, G., Akaoka, H. and Aston-Jones, G., Serotonin selectively decreases glutamate-induced excitation of locus coeruleus neurons, C.R. Acad. Sci. (Paris), 306, 339, 1988.
  12. Dahlström, A. and Fuxe, K., Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration in the cell bodies of brain stem neurons, Acta Physiol. Scand. (Suppl.), 232, 1, 1964.
  13. Darracq, L., Gervasoni, D., Soulière, F., Lin, J.S., Fort, P., Chouvet, G. and Luppi, P-H., Effect of strychnine on rat locus coeruleus neurons during sleep and wakefulness, NeuroReport , 8, 351, 1996.
  14. Ennis, M. and Aston-Jones, G., GABA-mediated inhibition of locus coeruleus from the dorsomedial rostral medulla, J. Neurosci., 9, 2973, 1989.
  15. Gaillard, J.-M., Principles and Practice of Sleep Medicine, M.H. Kryger, T. Roth and W.C. Dement (Eds), Philadelphia, 349, 1994.
  16. Gallager, D.W. and Aghajanian, G.K., Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin, Eur. J. Pharmacol., 39, 357, 1976.
  17. Gallager, D.W., Benzodiazepines : potentiation of a GABA inhibitory response in the dorsal raphe nucleus, Eur. J. Pharmacol., 49, 133, 1978.
  18. Gervasoni, D., Darracq, L., Fort P., Soulière F., Chouvet, G and Luppi, P.-H., Electrophysiological evidence that noradrenergic neurones of the rat locus coeruleus are tonically inhibited by GABA during sleep. Eur. J. Neurosci., 10, ,1998.
  19. Guyenet, P.G. and Aghajanian, G.K., Ach, Substance P and Met-Enkephalin in the locus coeruleus : pharmacological evidence for independent sites of action, Eur. J. Pharmacol., 53, 319, 1979.
  20. Henley K. and Morrison A.R., A re-evaluation of the effects of lesions of the pontine tegmentum and locus coeruleus on phenomena of paradoxical sleep in the cat. Acta Neurobiol. Exp (Warszawa), 34, 215, 1974.
  21. Hobson, J., McCarley, R. and Wyzinski, P., Sleep cycle oscillation : reciprocal discharge by two brainstem groups, Science, 189, 55, 1975.
  22. Holstege, J.C. and Bongers, C.M.H., A glycinergic projection from the ventromedial lower brainstem to spinal motoneurons. An ultrastructural double labeling study in rat, Brain Res., 566, 308, 1991.
  23. John, J., Kumar, V.M., Gopinath, G., Ramesh, V., Mallick, H., Changes in sleep-wakefulness after kainic acid lesion of the preoptic area in rats, Jpn. J. Physiol., 44, 231, 1994.
  24. Jones, B.E., Harper S.T., and Halaris A.E., Effects of locus coeruleus lesions upon cerebral monoamines content, sleep-wakefulness states and the response to amphetamine in the cat. Brain Res. 124, 473, 1977.
  25. Jones, B.E., Noradrenergic locus coeruleus neurons : their distant connections and their relationship to neighboring, including cholinergic and GABA-ergic neurons of the central gray and reticular formation, Prog. Brain Res., 88, 15, 1991.
  26. Jouvet, M., The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep, Ergebn. Physiol., 64, 166, 1972.
  27. Jouvet, M. and Delorme F. Locus coeruleus et sommeil paradoxal. C.R. Soc. Biol. (Paris), 159, 895, 1965.
  28. Kaitin, K.I., Preoptic area unit activity during sleep and wakefulness in the cat, Exp. Neurol., 83, 347, 1984.
  29. Kaur, S., Saxena, R.N. and Mallick, B.N., GABA in locus coeruleus regulates spontaneous rapid eye movement sleep by acting on GABAA receptors in freely moving rats, Neurosci. Lett., 223, 105, 1997.
  30. King C.D. and Jewet R.E., The effects of a-methyl-tyrosine on sleep and brain norepinephrine in cats. J. Pharmacol. Exp. Ther., 177, 188, 1971.
  31. Koyama, Y. and Kayama, Y., Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by iontophoresis of these transmitters in rat brainstem nuclei, Neuroscience, 55, 117, 1993.
  32. Koyama, Y. and Hayaishi, O., Firing of neurons in the preoptic/anterior hypothalamic areas in rat : its possible involvement in slow wave sleep and paradoxical sleep, Neurosci. Res., 19, 31, 1994.
  33. Lidbrink P., The effect of lesions of ascending noradrenaline pathways on sleep and waking in the rat. Brain Res.;74, 19, 1974
  34. Lin, J-S, Hou, Y., Sakai, K. and Jouvet, M., Histaminergic inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat, J. Neurosci., 15, 1523, 1996.
  35. Lin, J.S., Sakai, K., Vanni-Mercier, G. and Jouvet, M., A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjections of muscimol in freely moving cats, Brain Res., 429, 225, 1989.
  36. Lucas, E.A. and Sterman, M.B., Effect of a forebrain lesion on the polycyclic sleep wake patterns in the cat, Exp. Neurol., 46, 368, 1975.
  37. Luppi, P-H, Charléty, P.J., Fort, P., Akaoka, H., Chouvet, G. and Jouvet, M., Anatomical and electrophysiological evidence for a glycinergic inhibitory innervation of the rat locus coeruleus, Neurosci. Lett., 128, 33, 1991.
  38. Luppi, P.H., Aston-Jones, G., Akaoka, H., Chouvet, G. and Jouvet, M. Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin, Neuroscience, 65, 119, 1995.
  39. Luppi, P-H., Fort, P., and Jouvet, M., Iontophoretic application of unconjugated cholera toxin B subunit CTb combined with immunohistochemistry of neurochemical substances : a method for transmitter identification of retrogradely labeled neurons, Brain Res., 534, 209, 1990.
  40. Luque, J.M., Malherbe, P. and Richards, J.G., Localization of GABAA receptor subunit mRNAs in the rat locus coeruleus, Mol. Brain Res., 24, 219, 1994.
  41. Maloney K.J. and Jones B.E., C-Fos expression in cholinergic, GABAergic and monoaminergic cell groups during paradoxical sleep deprivation and recovery, Abstr. Soc. Neurosci., 23, 2131, 1997.
  42. Maloney, K.J., Cape, E.G., Gotman, J. and Jones, B.E., High-frequency g- encephalogram activity in association with sleep-wake states and spontaneous behaviors in the rat, Neuroscience, 76, 541, 1997.
  43. McCarley R. and Hobson J.A., Single neuron activity in cat gigantocellular tegmental field: Selectivity of discharge in desynchronized sleep. Science, 174, 1250, 1971.
  44. McGinty, D.J and Stermann, M.B., Sleep suppression after basal forebrain lesions in the cat, Science, 160, 1253, 1968.
  45. McGinty, D.J. and Harper, R.M., Dorsal raphe neurons : depression of firing during sleep in cats, Brain Res., 101, 569, 1976.
  46. Masuko, S., Nakajima, Y., Nakajima, S. and Yamaguchi, K., Noradrenergic neurons from the locus coeruleus in dissociated cell culture : culture methods, morphology, and electrophysiology, J. Neurosci., 6, 3229, 1986.
  47. Mendelson, W.B., Neuropharmacology of sleep induction by benzodiazepines, Crit. Rev. Neurobiol., 622, 1, 1992
  48. Nitz, D.A. and Siegel, J.M., GABA release in the locus coeruleus as a function of sleep/wake state, Neuroscience, 78, 795, 1997.
  49. Osmanovic, S.S. and Shefner, S.A., g-aminobutyric acid responses in rat locus coeruleus neurons in vitro : a current-clamp and voltage-clamp study, J. Physiol. (London), 421, 151, 1990.
  50. Pan, W.J., Osmanovic, S.S. and Shefner, S.A., Characterization of the adenosine A1 receptor-activated potassium current in rat locus coeruleus neurons, J. Pharmacol. Exp. Ther., 273, 537, 1995.
  51. Pan, Z.Z. and Williams, J.T., GABA- and glutamate-mediated synaptic potentials in rat dorsal raphe neurons in vitro, J. Neurophysiol., 61, 719, 1989.
  52. Peyron, C., Luppi, P.-H., Fort, P., Rampon, C. and Jouvet, M., Lower brainstem catecholamine afferents to the rat dorsal raphe nucleus, J. Comp. Neurol., 364, 402, 1996.
  53. Peyron, C., Luppi, P-H., Rampon, C. and Jouvet, M., Location of the GABA-ergic neurons projecting to the dorsal raphe nucleus and the locus coeruleus of the rat, Soc. Neurosci. Abstr., 21, 373, 1995.
  54. Porkka-Heiskanen, T., Strecker, R.E., Thakkar, M., Bjorkum, A.A., Greene, R.W. and McCarley, R.W., Adenosine : a mediator of the sleep-inducing effects of prolonged wakefulness, Science, 276, 1265, 1997.
  55. Rampon, C., Peyron, C., Petit, J.M., Fort, P., Gervasoni, D.and Luppi, P.H., Origin of the glycinergic innervation of the rat trigeminal motor nucleus, NeuroReport, 7, 3081, 1996.
  56. Rampon, C., Peyron, C., Gervasoni, D., Cespuglio, R., Fort, P. and Luppi, P-H., Localization of the glycinergic neurons projecting to the rat locus coeruleus, dorsal raphe and trigeminal motor nuclei, Soc. Neurosci. Abstr., 22, 1838,1996.
  57. Sakai, K., Sleep : Neurotransmitters and Neuromodulators, A. Wauquier, J.M. Monti, J.M. Gaillard and M. Radulovacki (eds), New York, 29, 1985.
  58. Sastre, J.P., Buda, C., Kitahama, K. and Jouvet, M., Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjection in the cat, Neuroscience, 74, 415, 1996.
  59. Sallanon, M., Denoyer, M., Kitahama, K., Aubert, C., Gay, N. and Jouvet, M., Long lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat, Neuroscience, 32, 669, 1989.
  60. Shefner, S.A. and Chiu, T.H., Adenosine inhibits locus coeruleus neurons : an intracellular study in a rat brain slice preparation, Brain Res., 366, 364, 1986.
  61. Sherin, J.E., Shiromani, P.J., McCarley, R.W., Saper, C.B., Activation of ventrolateral preoptic neurons during sleep, Science, 271, 216, 1996.
  62. Shimizu N., Morikawa N. and Hokada M. Histochemical studies of monoamine oxidase of the brain of rodents. Zeitschrift für Zellforschung, 49, 389, 1959.
  63. Sterman, M.B. and Clemente, C.D., Forebrain inhibitory mechanisms, sleep pattern induced by basal forebrain stimulation in behaving cat, Exp. Neurol., 6, 103, 1962.
  64. Szymusiak, R. and McGinty, D.J., Sleep-related discharge in the basal forebrain of cats, Brain Res., 370, 82, 1986.
  65. Tononi G., Pompeiano M. and Pompeiano O., Modulation of desynchronized sleep through microinjection of beta-adrenergic agonists and antagonists in the dorsal pontine tegmentum of the cat. Pflugers Arch, 415, 142, 1989.
  66. Vanni-Mercier, G., Sakai, K., Salvert, D. and Jouvet, M., Waking-state specific neurons in the caudal hypothalamus of the cat, C.R. Acad. Sci. (Paris), 298, 195, 1984.
  67. Von Economo, C., Handbuch des Normalen und Patholigischen Physiologie, A. Von Bethe G.V., Bergman G., Embden and U.A. Ellinger (Eds), Berlin, 291, 1926.
  68. Wang, Q.P., Ochiai, H. and Nakai, Y., GABA-ergic innervation of serotonergic neurons in the dorsal raphe nucleus of the rat studied by electron microscopy double immunostaining, Brain Res. Bull., 6, 943, 1992.
  69. Williams, J.T., Bobker, D.H. and Harris, G.C., Synaptic potentials in locus coeruleus neurons in brain slices, Prog. Brain Res., 88, 167, 1991.
  70. Williams, J.T., North, R.A., Shefner, A., Nishi, S. and Egan, T.M., Membrane properties of rat locus coeruleus neurons, Neuroscience, 13, 137, 1984.
  71. Woch, G., Davies, R.O., Pack, A.I. and Kubin, L., Behavior of raphe cells projecting to the dorsomedial medulla during carbachol-induced atonia in the cat, J. Physiol. (London), 490, 745, 1996.
  72. Yamuy, J. Mancillas, J.R., Morales, F.R. and Chase, M.H., C-Fos expression in the pons and medulla of the cat during carbachol-induced active sleep, J. Neurosci., 13, 2703, 1993.
  73. Yamuy, J., Sampagna, S., Lopez-Rodriguez, F., Luppi, P-H., Morales, F.R. and Chase, M.H., Fos and serotonin immunoreactivity in the raphe nuclei of the cat during carbachol-induced active sleep : a double-labeling study, Neuroscience, 67, 211, 1995.