Regulation of serotonin release by inhibitory and excitatory amino acids

  • Sidney B. Auerbach


Serotonergic neurons are spontaneously active with slow regular discharge during alert behavior and decreased activity during sleep. Sleep-related inhibition of serotonergic neurons is mediated by GABAergic inputs that originate in hypothalamic and brainstem sleep centers. During alert behavior, tonic release of GABA contributes to feedback and feedforward inhibitory circuits that, together with serotonin autoreceptors, prevent excess stimulation of serotonergic neurons. Glutamatergic inputs to the raphe originate in the brainstem, several hypothalamic nuclei and cerebral cortex. Although glutamate receptor agonists strongly stimulate serotonergic neuronal discharge, the physiological significance of glutamatergic inputs is not well established. In the dorsal raphe nucleus (DRN), more glutamatergic fibers terminate on GABAergic than serotonergic neurons. Moreover, GABA normally restrains the excitatory influence of glutamatergic inputs to serotonergic neurons in the DRN. Peptidergic neurons modulate the activity of GABAergic and glutamatergic interneurons that synapse with serotonergic neurons in the DRN. These neuropeptides, for example CRF, endogenous opioids and Substance P, are implicated in responses to environmental challenges. Thus, stress can indirectly influence the activity of serotonergic neurons. In the raphe, GABAergic and glutamatergic interneurons may serve as a final common pathway for integrating information about environmental challenges and inputs from hypothalamic and brainstem centers that control the usual sleep-related inhibition of serotonergic neurons. Neuropeptides might thereby promote alert behavior to appropriately cope with stress. However, persistent peptidergic-induced changes in the strength of GABAergic and glutamatergic inputs to serotonergic neurons could contribute to insomnia, anxiety and major psychiatric disorders such as depression and schizophrenia.


Excitatory Amino Acid Raphe Nucleus GABAergic Neuron Dorsal Raphe Nucleus Serotonergic Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gallager DW, Aghajanian GK (1976) Effect of antipsychotic drugs on the firing of dorsal raphe cells. 2. Reversal by picrotoxin. Eur J Pharmacol 39: 357–364PubMedGoogle Scholar
  2. 2.
    Hery F, Simonnet G, Bourgoin S, Soubrie P, Artaud F, Hamon M, Glowinski J (1979) Effect of nerve activity on the in vivo release of [3H]serotonin continuously formed from L-[3H]tryptophan in the caudate nucleus of the cat. Brain Res 169: 317–334PubMedGoogle Scholar
  3. 3.
    Tao R, Auerbach S B (1996) Differential effect of NMDA on extracellular serotonin in rat midbrain raphe and forebrain sites. J Neurochem 66: 1067–1075PubMedGoogle Scholar
  4. 4.
    Tao R, Ma Z, Auerbach S B (1996) Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br J Pharmacol 119: 1375–1384PubMedGoogle Scholar
  5. 5.
    Tao R, Ma Z, Auerbach SB (1997) Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain. Br J Pharmacol 121: 1707–1715PubMedGoogle Scholar
  6. 6.
    Tao R, Auerbach SB (2000) Regulation of serotonin release by GABA and excitatory amino acids. J Psychopharmacol 14: 100–113PubMedGoogle Scholar
  7. 7.
    Tao R, Auerbach SB (2003) Influence of inhibitory and excitatory inputs on serotonin efflux differs in the dorsal and median raphe nuclei. Brain Res 961: 109–120PubMedGoogle Scholar
  8. 8.
    Levine ES, Jacobs BL (1992) Neurochemical afferents controlling the activity of serotonergic neurons in the dorsal raphe nucleus: microiontophoretic studies in the awake cat. J Neuroscience 12: 4037–4044Google Scholar
  9. 9.
    Gervasoni D, Peyron C, Rampon C, Barbagli B, Chouvet G, Urbain N, Fort P, Luppi PH (2000) Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J Neurosci 20: 4217–4225PubMedGoogle Scholar
  10. 10.
    VanderMaelen CP, Matheson G, Wilderman RC, Patterson LA (1986) Inhibition of dorsal raphe neurons by systemic and iontophoretic administration of buspirone, a non-benzodiazepine anxiolytic drug. Eur J Pharmacol 129: 123–130PubMedGoogle Scholar
  11. 11.
    Jacobs B, Fornal CA (1991) Activity of brain serotonergic neurons in the behaving animal. Pharmacol Rev 43: 563–578PubMedGoogle Scholar
  12. 12.
    Lucas G, Compan V, Charnay Y, Neve R, Nestler EJ, Bockaert J, Barrot M, Debonnel G (2005) Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists. Biol Psychiatry 57: 918–925PubMedGoogle Scholar
  13. 13.
    Jankowski MP, Sesack SR (2004) Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features and associations with serotonin and gamma-aminobutyric acid neurons. J Comp Neurol 468: 518–529PubMedGoogle Scholar
  14. 14.
    Jolas T, Aghajanian GK (1997) Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currents in the dorsal raphe nucleus of the rat in vitro. Brain Res 755: 229–245PubMedGoogle Scholar
  15. 15.
    Pan ZZ, Williams JT (1989) GABA-and glutamate-mediated synaptic potentials in rat dorsal raphe neurons in vitro. J Neurophysiol 61: 719–726PubMedGoogle Scholar
  16. 16.
    Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 31: 302–312PubMedGoogle Scholar
  17. 17.
    Zarate CA Jr, Du J, Quiroz J, Gray NA, Denicoff KD, Singh J, Charney DS, Manji HK (2003) Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci 1003: 273–291PubMedGoogle Scholar
  18. 18.
    Sanacora G, Rothman DL, Mason G, Krystal JH (2003) Clinical studies implementing glutamate neurotransmission in mood disorders. Ann NY Acad Sci 1003: 292–308PubMedGoogle Scholar
  19. 19.
    Tamminga CA, Lahti, AC, Medoff DR, Gao XM, Holcomb HH (2003) Evaluating glutamatergic transmission in schizophrenia. Ann N Y Acad Sci 1003: 113–118PubMedGoogle Scholar
  20. 20.
    Zarate CA, Jr, Singh, JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63: 856–864PubMedGoogle Scholar
  21. 21.
    Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17: 2921–2927PubMedGoogle Scholar
  22. 22.
    Tao R, Auerbach SB (1994) Anesthetics block morphine-induced increases in serotonin release in rat CNS. Synapse 18: 307–314PubMedGoogle Scholar
  23. 23.
    Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72: 165–229PubMedGoogle Scholar
  24. 24.
    Kalén P, Strecker RE, Rosengren E, Bjorklund A (1989) Regulation of striatal serotonin release by the lateral habenula-dorsal raphe pathway in the rat as demonstrated by in vivo microdialysis: role of excitatory amino acids and GABA. Brain Res 492: 187–202PubMedGoogle Scholar
  25. 25.
    Charara A, Parent A (1998) Chemoarchitecture of the primate dorsal raphe nucleus. J Chem Neuroanat 15: 111–127PubMedGoogle Scholar
  26. 26.
    Jacobs BL, Martin-Cora FJ, Fornal CA (2002) Activity of medullary serotonergic neurons in freely moving animals. Brain Res Brain Res Rev 40: 45–52PubMedGoogle Scholar
  27. 27.
    Richerson GB (2004) Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5: 449–461PubMedGoogle Scholar
  28. 28.
    Lee HS, Kim MA, Valentino RJ, Waterhouse BD (2003) Glutamatergic afferent projections to the dorsal raphe nucleus of the rat. Brain Res 963: 57–71PubMedGoogle Scholar
  29. 29.
    Waselus M, Valentino RJ, Van Bockstaele EJ (2005) Ultrastructural evidence for a role of gamma-aminobutyric acid in mediating the effects of corticotropin-releasing factor on the rat dorsal raphe serotonin system. J Comp Neurol 482: 155–165PubMedGoogle Scholar
  30. 30.
    Valentino RJ, Liouterman L, Van Bockstaele EJ (2001) Evidence for regional heterogeneity in corticotropin-releasing factor interactions in the dorsal raphe nucleus. J Comp Neurol 435: 450–463PubMedGoogle Scholar
  31. 31.
    Lowry CA, Rodda JE, Lightman SL, Ingram CD (2000) Corticotropin-releasing factor increases in vitro firing rates of serotonergic neurons in the rat dorsal raphe nucleus: evidence for activation of a topographically organized mesolimbocortical serotonergic system. J Neurosci 20: 7728–7736PubMedGoogle Scholar
  32. 32.
    Staub DR, Evans AK, Lowry CA (2006) Evidence supporting a role for corticotropin-releasing factor type 2 (CRF2) receptors in the regulation of subpopulations of serotonergic neurons. Brain Res 1070: 77–89PubMedGoogle Scholar
  33. 33.
    Roche M, Commons KG, Peoples A, Valentino RJ (2003) Circuitry underlying regulation of the serotonergic system by swim stress. J Neurosci 23: 970–977PubMedGoogle Scholar
  34. 34.
    Vandermaelen CP, Aghajanian GK (1983) Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. Brain Res 289: 109–119PubMedGoogle Scholar
  35. 35.
    Kirby LG, Pernar L, Valentino RJ, Beck SG (2003) Distinguishing characteristics of serotonin and non-serotonin-containing cells in the dorsal raphe nucleus: electrophysiological and immunohistochemical studies. Neuroscience 116: 669–683PubMedGoogle Scholar
  36. 36.
    Lu J, Jhou TC, Saper CB (2006) Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci 26: 193–202PubMedGoogle Scholar
  37. 37.
    Hajos M, Gartside SE, Villa AEP, Sharp T (1995) Evidence for a repetitive (burst) firing pattern in a sub-population of 5-hydroxytryptamine neurons in the dorsal and median raphe nuclei of the rat. Neuroscience 69: 189–197PubMedGoogle Scholar
  38. 38.
    Hajos M, Allers KA, Jennings K, Sharp T, Charette G, Sik A, Kocsis B (2007) Neurochemical identification of stereotypic burst-firing neurons in the rat dorsal raphe nucleus using juxtacellular labelling methods. Eur J Neurosci 25: 119–126PubMedGoogle Scholar
  39. 39.
    Kocsis B, Varga V, Dahan L, Sik A (2006) Serotonergic neuron diversity: identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm. Proc Natl Acad Sci USA 103: 1059–1064PubMedGoogle Scholar
  40. 40.
    Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19: 378–383PubMedGoogle Scholar
  41. 41.
    Rutter JJ, Auerbach SB (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J Pharmacol Exp Ther 265: 1319–1324PubMedGoogle Scholar
  42. 42.
    Fuller RW (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 55: 163–167PubMedGoogle Scholar
  43. 43.
    Haigler HJ (1978) Morphine: effects on serotonergic neurons and neurons in areas with a serotonergic input. Eur J Pharmacol 51: 361–376PubMedGoogle Scholar
  44. 44.
    Yarbrough GG, Buxbaum DM, Sanders-Bush E (1973) Biogenic amines and narcotic effects. II. Serotonin turnover in the rat after acute and chronic morphine administration. J Pharmacol Exp Ther 185: 328–335PubMedGoogle Scholar
  45. 45.
    Tao R, Auerbach SB (1994) Increased extracellular serotonin in rat brain after systemic or intraraphe administration of morphine. J Neurochem 63: 517–524PubMedGoogle Scholar
  46. 46.
    Tao R, Auerbach SB (2002) Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. J Pharmacol Exp Ther 303: 549–556PubMedGoogle Scholar
  47. 47.
    Kalen P, Strecker RE, Rosengren E, Bjorklund A (1988) Endogenous release of neuronal serotonin and 5-hydroxyindoleacetic acid in the caudate-putamen of the rat as revealed by intracerebral dialysis coupled to high-performance liquid chromatography with fluorimetric detection. J Neurochem 51: 1422–1435PubMedGoogle Scholar
  48. 48.
    Carboni E, DiChiara G (1989) Serotonin release estimated by transcortical dialysis in freely-moving rats. Neuroscience 32: 637–645PubMedGoogle Scholar
  49. 49.
    Sharp T, Bramwell SR, Clark D, Grahame-Smith DG (1989) In vivo measurements of brain extracellular 5-hydroxytryptamine using microdialysis: changes in relation to 5-hydroxytryptaminergic neuronal activity. J Neurochem 53: 234–240PubMedGoogle Scholar
  50. 50.
    Crespi F (1990) In vivo voltammetry with micro-biosensors for analysis of neurotransmitter release and metabolism. J Neurosci Methods 34: 53–65PubMedGoogle Scholar
  51. 51.
    Tao R, Ma Z, Auerbach SB (2000) Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin. J Pharmacol Exp Ther 294: 571–579PubMedGoogle Scholar
  52. 52.
    de Kock CP, Cornelisse LN, Burnashev N, Lodder JC, Timmerman AJ, Couey JJ, Mansvelder HD, Brussaard AB (2006) NMDA receptors trigger neurosecretion of 5-HT within dorsal raphe nucleus of the rat in the absence of action potential firing. J Physiol 577: 891–905PubMedGoogle Scholar
  53. 53.
    Romero L, Artigas F (1997) Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: Role of somatodendritic autoreceptors. J Neurochem 68: 2593–2603PubMedGoogle Scholar
  54. 54.
    Rutter JJ, Gundlah C, Auerbach SB (1995) Systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation. Synapse 20: 225–233PubMedGoogle Scholar
  55. 55.
    Belin MF, Aguera M, Tappaz M, McRae-Deguerce A, Bobillier P, Pujol JF (1979) GABA-accumulating neurons in the nucleus raphe dorsalis and periaqueductal gray in the rat: a biochemical and radioautographic study. Brain Res 170: 279–297PubMedGoogle Scholar
  56. 56.
    Allers KA, Sharp T (2003) Neurochemical and anatomical identification of fast-and slow-firing neurones in the rat dorsal raphe nucleus using juxtacellular labelling methods in vivo. Neuroscience 122: 193–204PubMedGoogle Scholar
  57. 57.
    Ford B, Holmes CJ, Mainville L, Jones BE (1995) GABAergic neurons in the rat pontomesencephalic tegmentum: codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. J Comp Neurol 363: 177–96PubMedGoogle Scholar
  58. 58.
    Wang QP, Ochiai H, Nakai Y (1992) GABAergic innervation of serotonergic neurons in the dorsal raphe nucleus of the rat studies by electron microscopy double immunostaining. Brain Res Bull 29: 943–948PubMedGoogle Scholar
  59. 59.
    Wang RY, Aghajanian GK (1977) Physiological evidence for habenula as major link between forebrain and midbrain raphe. Science 197: 89–91PubMedGoogle Scholar
  60. 60.
    Ferraro G, Montalbano ME, Sardo P, La Grutta V (1996) Lateral habenular influence on dorsal raphe neurons. Brain Res Bull 41: 47–52PubMedGoogle Scholar
  61. 61.
    Hery F, Ternaux JP (1981) Regulation of release processes in central serotoninergic neurons. J Physiol (Paris) 77: 287–301Google Scholar
  62. 62.
    Nishikawa T, Scatton B (1983) Evidence for a GABAergic inhibitory influence on serotonergic neurons originating from the dorsal raphe. Brain Res 279: 325–329PubMedGoogle Scholar
  63. 63.
    Forchetti CM, Meek JL (1981) Evidence for a tonic GABAergic control of serotonin neurons in the median raphe nucleus. Brain Res 206: 208–212PubMedGoogle Scholar
  64. 64.
    Wirtshafter D, Klitenick MA, Asin KE (1987) Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus. Pharmacol Biochem Behav 27: 45–52PubMedGoogle Scholar
  65. 65.
    Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M (1980) (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283: 92–94PubMedGoogle Scholar
  66. 66.
    Schlicker F, Classen K, Gothert M (1984) GABAB receptor-mediated inhibition of serotonin release in the rat brain. Naunyn-Schmiedeberg’s Arch Pharmacol 26: 99–105Google Scholar
  67. 67.
    Innis RB, Aghajanian GK (1987) Pertussis toxin blocks 5-HT1A and GABAB receptor-mediated inhibition of serotonergic neurons. Eur J Pharmacol 143: 195–204PubMedGoogle Scholar
  68. 68.
    Waldmeier PC, Wicki P, Feldtrauer JJ, Baumann PA (1988) Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol 337: 289–295Google Scholar
  69. 69.
    Abellan MT, Jolas T, Aghajanian GK, Artigas F (2000) Dual control of dorsal raphe serotonergic neurons by GABA(B) receptors. Electrophysiological and microdialysis studies. Synapse 36: 21–34PubMedGoogle Scholar
  70. 70.
    Fiske E, Gronli J, Bjorvatn B, Ursin R, Portas CM (2006) The effect of GABA(A) antagonist bicuculline on dorsal raphe nucleus and frontal cortex extracellular serotonin: a window on SWS and REM sleep modulation. Pharmacol Biochem Behav 83: 314–21PubMedGoogle Scholar
  71. 71.
    Rueter LE, Jacobs BL (1996) A microdialysis examination of serotonin release in the rat forebrain induced by behavioral/environmental manipulations. Brain Res 739: 57–69PubMedGoogle Scholar
  72. 72.
    Rueter LE, Fornal CA, Jacobs BL (1997) A critical review of 5-HT brain microdialysis and behavior. Rev Neurosci 8: 117–137PubMedGoogle Scholar
  73. 73.
    Wirtshafter D, Stratford TR, Pitzer MR (1993) Studies on the behavioral activation produced by stimulation of GABAB receptors in the median raphe nucleus. Behav Brain Res 59: 83–93PubMedGoogle Scholar
  74. 74.
    Nusser Z, Sieghart W, Somogyi P (1998) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci 18: 1693–1703PubMedGoogle Scholar
  75. 75.
    Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6: 215–229PubMedGoogle Scholar
  76. 76.
    Mody I (2001) Distinguishing between GABA(A) receptors responsible for tonic and phasic conductances. Neurochem Res 26: 907–913PubMedGoogle Scholar
  77. 77.
    Reisine TD, Soubrie P, Artaud F, Glowinski J (1982) Involvement of lateral habenula-dorsal raphe neurons in the differential regulation striatal and nigral serotonergic transmission in cats. J Neurosci 2: 1062–1071PubMedGoogle Scholar
  78. 78.
    Lemos JC, Pan YZ, Ma X, Lamy C, Akanwa AC, Beck SG (2006) Selective 5-HT receptor inhibition of glutamatergic and GABAergic synaptic activity in the rat dorsal and median raphe. Eur J Neurosci 24: 3415–3430PubMedGoogle Scholar
  79. 79.
    Nitz D, Siegel JM (1996) GABA release in posterior hypothalamus across sleep-wake cycle. Am J Physiol 271: R1707–R1712PubMedGoogle Scholar
  80. 80.
    Maloney KJ, Mainville L, Jones BE (1999) Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery. J Neurosci 19: 3057–3072PubMedGoogle Scholar
  81. 81.
    Sakai K, Crochet S (2000) Serotonergic dorsal raphe neurons cease firing by disfacilitation during paradoxical sleep. Neuroreport 11: 3237–3241PubMedGoogle Scholar
  82. 82.
    McBain CJ, Fisahn A (2001) Interneurons unbound. Nat Rev Neurosci 2: 11–23PubMedGoogle Scholar
  83. 83.
    Buzsaki G (2001) Hippocampal GABAergic interneurons: a physiological perspective. Neurochem Res 26: 899–905PubMedGoogle Scholar
  84. 84.
    Liu R, Jolas T, Aghajanian G (2000) Serotonin 5-HT(2) receptors activate local GABA inhibitory inputs to serotonergic neurons of the dorsal raphe nucleus. Brain Res 873: 34–45PubMedGoogle Scholar
  85. 85.
    Boothman L, Raley J, Denk F, Hirani E, Sharp T (2006) In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism. Br J Pharmacol 149: 861–869PubMedGoogle Scholar
  86. 86.
    Hajos M, Richards CD, Szekely AD, Sharp T (1998) An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience 87: 95–108PubMedGoogle Scholar
  87. 87.
    Hajos M, Hajos-Korcsok E, Sharp T (1999) Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat. Br J Pharmacol 126: 1741–1750PubMedGoogle Scholar
  88. 88.
    Casanovas JM, Hervas I, Artigas F (1999) Postsynaptic 5-HT1A receptors control 5-HT release in the rat medial prefrontal cortex. Neuroreport 10: 1441–1445PubMedGoogle Scholar
  89. 89.
    Celada P, Puig M, Casanovas JM, Guillazo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21: 9917–9929PubMedGoogle Scholar
  90. 90.
    Varga V, Szekely AD, Csillag A, Sharp T, Hajos M (2001) Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones. Neuroscience 106: 783–792PubMedGoogle Scholar
  91. 91.
    Boothman LJ, Allers KA, Rasmussen K, Sharp T (2003) Evidence that central 5-HT2A and 5-HT2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat. Br J Pharmacol 139: 998–1004PubMedGoogle Scholar
  92. 92.
    Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mork A, Honig G, Bogeso KP, Westerink BH, den Boer H, Wikstrom HV, Tecott LH (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29: 1782–1789PubMedGoogle Scholar
  93. 93.
    Bissiere S, Humeau Y, Luthi A (2003) Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nat Neurosci 6: 587–592PubMedGoogle Scholar
  94. 94.
    Marowsky A, Yanagawa Y, Obata K, Vogt KE (2005) A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function. Neuron 48: 1025–1037PubMedGoogle Scholar
  95. 95.
    Grahn RE, Maswood S, McQueen MB, Watkins LR, Maier SF (1999) Opioid-dependent effects of inescapable shock on escape behavior and conditioned fear responding are mediated by the dorsal raphe nucleus. Behav Brain Res 99: 153–167PubMedGoogle Scholar
  96. 96.
    Behzadi G, Kalen P, Parvopassu F, Wiklund L (1990) Afferents to the median raphe nucleus of the rat: retrograde cholera toxin and wheat germ conjugated horseradish peroxidase tracing, and selective D-[3H]aspartate labeling of possible excitatory amino acid inputs. Neuroscience 37: 77–100PubMedGoogle Scholar
  97. 97.
    Commons KG, Beck SG, Bey VW (2005) Two populations of glutamatergic axons in the rat dorsal raphe nucleus defined by the vesicular glutamate transporters 1 and 2. Eur J Neurosci 21: 1577–1586PubMedGoogle Scholar
  98. 98.
    Kalen P, Karlson M, Wiklund L (1985) Possible excitatory amino acid afferents to nucleus raphe dorsalis of the rat investigated with retrograde wheat germ agglutinin and D-[3H]aspartate tracing. Brain Res 360: 285–297PubMedGoogle Scholar
  99. 99.
    Aghajanian GK, Wang RY (1977) Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique. Brain Res 122: 229–242PubMedGoogle Scholar
  100. 100.
    Nishikawa T, Scatton B (1985) Inhibitory influence of GABA on central serotonergic transmission. Involvement of the habenulo-raphe pathways in the GABAergic inhibition of ascending cerebral serotonergic neurons. Brain Res 331: 81–90PubMedGoogle Scholar
  101. 101.
    Hermann DM, Luppi PH, Peyron C, Hinckel P, Jouvet M (1997) Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of choleratoxin (subunit b). J Chem Neuroanat 13: 1–21PubMedGoogle Scholar
  102. 102.
    Li YW, Bayliss DA (1998) Presynaptic inhibition by 5-HT1B receptors of glutamatergic synaptic inputs onto serotonergic caudal raphe neurones in rat. J Physiol 510: 121–34PubMedGoogle Scholar
  103. 103.
    Pan ZZ, Williams JT (1989) GABA-and glutamate-mediated synaptic potentials in rat dorsal raphe neurons in vitro. J Neurophysiol 61: 719–726PubMedGoogle Scholar
  104. 104.
    Hall RA, Kessler M, Lynch G (1994) Kainate binding to the AMPA receptor in rat brain. Neurochem Res 19: 777–782PubMedGoogle Scholar
  105. 105.
    Tolle TR, Berthele A, Zieglgansberger W, Seeburg PH, Wisden W (1993) The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray. J Neurosci 13: 5009–5028PubMedGoogle Scholar
  106. 106.
    Sommer B, Burnashev N, Verdoorn TA, Keinanen K, Sakmann B, Seeburg PH (1992) A glutamate receptor channel with high affinity for domoate and kainate. EMBO J 11: 1651–166PubMedGoogle Scholar
  107. 107.
    Bettler B, Mulle C (1995) Review: neurotransmitter receptors. II. AMPA and kainate receptors. Neuropharmacology 34: 123–139PubMedGoogle Scholar
  108. 108.
    Partin KM, Patneau DK, Winters CA, Mayer ML, Buonanno A (1993) Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron 11: 1069–1082PubMedGoogle Scholar
  109. 109.
    Wong LA, Mayer ML (1993) Differential modulation by cyclothiazide and concanavalin A of desensitization at native alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-and kainate-preferring glutamate receptors. Mol Pharmacol 44: 504–510PubMedGoogle Scholar
  110. 110.
    Westerink BHC, Santiago M, Devries JB (1992) The release of dopamine from nerve terminals and dendrites of nigrostriatal neurons induced by excitatory amino acids in the conscious rat. Naunyn-Schmiedeberg’s Arch Pharmacol 345: 523–529Google Scholar
  111. 111.
    Pollard H, Charriaut-Marlangue C, Cantagrel S, Represa A, Robain O, Moreau J, Ben-Ari Y (1994) Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 63: 7–18PubMedGoogle Scholar
  112. 112.
    Schwarcz R, Hokfelt T, Fuxe K, Jonson G, Goldstein M, Terenius L (1979) Ibotenic acid-induced neuronal degeneration: A morphological and neurochemical study. Exp Brain Res 37: 199–216PubMedGoogle Scholar
  113. 113.
    Buller AL, Larson HC, Schneider BE, Beaton JA, Morrisett RA, Monaghan DT (1994) The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. J Neurosci 14: 5471–5484PubMedGoogle Scholar
  114. 114.
    Pallotta M, Segieth J, Whitton PS (1998) N-methyl-d-aspartate receptors regulate 5-HT release in the raphe nuclei and frontal cortex of freely moving rats: differential role of 5-HT1A autoreceptors. Brain Res 783: 173–178PubMedGoogle Scholar
  115. 115.
    Stanford IM, Cooper AJ (1999) Presynaptic mu and delta opioid receptor modulation of GABAA IPSCs in the rat globus pallidus in vitro. J Neurosci 19: 4796–4803PubMedGoogle Scholar
  116. 116.
    Vertes RP, Kocsis B (1997) Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81: 893–926PubMedGoogle Scholar
  117. 117.
    Tamminga CA (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12: 21–36PubMedGoogle Scholar
  118. 118.
    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47: 351–354PubMedGoogle Scholar
  119. 119.
    Wang T, O’Connor WT, Ungerstedt U, French ED (1994) N-Methyl-d-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666: 255–262PubMedGoogle Scholar
  120. 120.
    Bristow LJ, Hutson PH, Thorn L, Tricklebank MD (1993) The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents. Br J Pharmacol 108: 1156–1153PubMedGoogle Scholar
  121. 121.
    Hernandez L, Auerbach S, Hoebel BG (1988) Phencyclidine (PCP) injected in the nucleus accumbens increases extracellular dopamine and serotonin as measured by microdialysis. Life Sci 42: 1713–1723PubMedGoogle Scholar
  122. 122.
    Martin P, Carlsson ML, Hjorth S (1998) Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 9: 2985–2988PubMedGoogle Scholar
  123. 123.
    Grant KA, Colombo G, Grant J, Rogawski MA (1996) Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. Neuropharmacology 35: 1709–1719PubMedGoogle Scholar
  124. 124.
    Ellison G (1995) The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res Rev 20: 250–267PubMedGoogle Scholar
  125. 125.
    Willetts J, Balster RL, Leander JD (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 11: 423–428PubMedGoogle Scholar
  126. 126.
    French ED (1994) Phencyclidine and the midbrain dopamine system: electrophysiology and behavior. Neurotoxicol Teratol 16: 355–362PubMedGoogle Scholar
  127. 127.
    Soloviev MM, Abutidze K, Mellor I, Streit P, Grishin EV, Usherwood PN, Barnard EA (1998) Plasticity of agonist binding sites in hetero-oligomers of the unitary glutamate receptor subunit XenU1. J Neurochem 71: 991–1001PubMedGoogle Scholar
  128. 128.
    Barnard EA (1997) Ionotropic glutamate receptors: new types and new concepts. Trends Pharmacol Sci 18: 141–148PubMedGoogle Scholar
  129. 129.
    Rothman RB, Reid AA, Monn JA, Jacobson AE, Rice KC (1989) The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. Mol Pharmacol 36: 887–896PubMedGoogle Scholar
  130. 130.
    Yamakura T, Chavez-Noriega LE, Harris RA (2000) Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine. Anesthesiology 92: 1144–1153PubMedGoogle Scholar
  131. 131.
    Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD (2001) Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade. Neuropharmacology 40: 847–55PubMedGoogle Scholar
  132. 132.
    Lee JJ, Croucher MJ (2003) Actions of Group I and Group II metabotropic glutamate receptor ligands on 5-hydroxytryptamine release in the rat cerebral cortex in vivo: differential roles in the regulation of central serotonergic neurotransmission. Neuroscience 117: 671–679PubMedGoogle Scholar
  133. 133.
    Feinberg I, Campbell IG, Schoepp DD, Anderson K (2002) The selective group mGlu2/3 receptor agonist LY379268 suppresses REM sleep and fast EEG in the rat. Pharmacol Biochem Behav 73: 467–474PubMedGoogle Scholar
  134. 134.
    Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4: 131–144PubMedGoogle Scholar
  135. 135.
    Varga V, Kekesi A, Juhasz G, Kocsis B (1998) Reduction of the extracellular level of glutamate in the median raphe nucleus associated with hippocampal theta activity in the anaesthetized rat. Neuroscience 84: 49–57PubMedGoogle Scholar
  136. 136.
    Lucas G, Debonnel G (2002) 5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphe nucleus 5-HT neuronal activity. Eur J Neurosci 16: 817–822PubMedGoogle Scholar
  137. 137.
    Conductier G, Dusticier N, Lucas G, Cote F, Debonnel G, Daszuta A, Dumuis A, Nieoullon A, Hen R, Bockaert J, Compan V (2006) Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse. Eur J Neurosci 24: 1053–1062PubMedGoogle Scholar
  138. 138.
    Ge JA, Barnes NM (1996) 5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo. Br J Pharmacol 117: 1475–1480PubMedGoogle Scholar
  139. 139.
    Miller JD, Morin LP, Schwartz WJ, Moore RY (1996) New insights into the mammalian circadian clock. Sleep 19: 641–667PubMedGoogle Scholar
  140. 140.
    Liu R, Ding Y, Aghajanian GK (2002) Neurokinins activate local glutamatergic inputs to serotonergic neurons of the dorsal raphe nucleus. Neuropsychopharmacology 27: 329–340PubMedGoogle Scholar
  141. 141.
    Valentino RJ, Bey V, Pernar L, Commons KG (2003) Substance P Acts through local circuits within the rat dorsal raphe nucleus to alter serotonergic neuronal activity. J Neurosci 23: 7155–7159PubMedGoogle Scholar
  142. 142.
    Stout SC, Owens MJ, Nemeroff CB (2001) Neurokinin(1) receptor antagonists as potential antidepressants. Annu Rev Pharmacol Toxicol 41: 877–906PubMedGoogle Scholar
  143. 143.
    Jolas T, Aghajanian GK (1996) Neurotensin excitation of serotonergic neurons in the dorsal raphe nucleus of the rat in vitro. Eur J Neurosci 8: 153–161PubMedGoogle Scholar
  144. 144.
    Jolas T, Aghajanian GK (1997) Neurotensin and the serotonergic system. Prog Neurobiol 52: 455–468PubMedGoogle Scholar
  145. 145.
    Price ML, Kirby LG, Valentino RJ, Lucki I (2002) Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming. Psychopharmacology (Berl) 162: 406–414Google Scholar
  146. 146.
    Pernar L, Curtis AL, Vale WW, Rivier JE, Valentino RJ (2004) Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions. J Neurosci 24: 1305–1311PubMedGoogle Scholar
  147. 147.
    Staub DR, Spiga F, Lowry CA (2005) Urocortin 2 increases c-Fos expression in topographically organized subpopulations of serotonergic neurons in the rat dorsal raphe nucleus. Brain Res 1044: 176–189PubMedGoogle Scholar
  148. 148.
    Hammack SE, Schmid MJ, LoPresti ML, Der-Avakian A, Pellymounter MA, Foster AC, Watkins LR, Maier SF (2003) Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress. J Neurosci 23: 1019–1025PubMedGoogle Scholar
  149. 149.
    Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29: 829–841PubMedGoogle Scholar
  150. 150.
    Juckel G, Gallinat J, Riedel M, Sokullu S, Schulz C, Moller HJ, Muller N, Hegerl U (2003) Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity. Schizophr Res 64: 115–124PubMedGoogle Scholar
  151. 151.
    Korosi A, Veening JG, Kozicz T, Henckens M, Dederen J, Groenink L, van der Gugten J, Olivier B, Roubos EW (2006) Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain. Brain Res 1072: 46–54PubMedGoogle Scholar
  152. 152.
    Senkowski D, Linden M, Zubragel D, Bar T, Gallinat J (2003) Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder. Biol Psychiatry 53: 304–314PubMedGoogle Scholar
  153. 153.
    Stutzmann GE, McEwen BS, LeDoux JE (1998) Serotonin modulation of sensory inputs to the lateral amygdala: dependency on corticosterone. J Neurosci 18: 9529–9538PubMedGoogle Scholar
  154. 154.
    Stutzmann GE, LeDoux JE (1999) GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: a mechanism for modulation of sensory inputs related to fear conditioning. J Neurosci 19: RC8PubMedGoogle Scholar
  155. 155.
    Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37: 577–582PubMedGoogle Scholar
  156. 156.
    Liu QS, Pu L, Poo MM (2005) Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437: 1027–1031PubMedGoogle Scholar
  157. 157.
    Carlezon WA, Jr Nestler, EJ (2002) Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse? Trends Neurosci 25: 610–615PubMedGoogle Scholar
  158. 158.
    Nugent FS, Penick EC, Kauer JA (2007) Opioids block long-term potentiation of inhibitory synapses. Nature 446: 1086–1090PubMedGoogle Scholar
  159. 159.
    Melis M, Camarini R, Ungless MA, Bonci A (2002) Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J Neurosci 22: 2074–2082PubMedGoogle Scholar
  160. 160.
    Tao R, Ma Z, Auerbach SB (1998) Alteration in regulation of serotonin release in rat dorsal raphe nucleus after prolonged exposure to morphine. J Pharmacol Exp Ther 286: 481–488PubMedGoogle Scholar
  161. 161.
    Jolas T, Nestler EJ, Aghajanian GK (2000) Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe nucleus: association with an up-regulation of the cyclic AMP pathway. Neuroscience 95: 433–443PubMedGoogle Scholar
  162. 162.
    Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29: 547–569PubMedGoogle Scholar
  163. 163.
    Grahn RE, Watkins LR, Maier SF (2000) Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus. Behav Brain Res 112: 33–41PubMedGoogle Scholar
  164. 164.
    Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8: 365–371PubMedGoogle Scholar
  165. 165.
    Bandler R, Shipley MT (1994) Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci 17: 379–389PubMedGoogle Scholar
  166. 166.
    Fields HL (2000) Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 122: 245–253PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2008

Authors and Affiliations

  • Sidney B. Auerbach
    • 1
  1. 1.Department of Cell Biology and Neuroscience, RutgersThe State University of New JerseyPiscatawayUSA

Personalised recommendations