Skip to main content
Log in

Stress-related Serotonergic Systems: Implications for Symptomatology of Anxiety and Affective Disorders

  • Original Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Previous studies have suggested that serotonergic neurons in the midbrain raphe complex have a functional topographic organization. Recent studies suggest that stimulation of a bed nucleus of the stria terminalis-dorsal raphe nucleus pathway by stress- and anxiety-related stimuli modulates a subpopulation of serotonergic neurons in the dorsal part of the dorsal raphe nucleus (DRD) and caudal part of the dorsal raphe nucleus (DRC) that participates in facilitation of anxiety-like responses. In contrast, recent studies suggest that activation of a spinoparabrachial pathway by peripheral thermal or immune stimuli excites subpopulations of serotonergic neurons in the ventrolateral part of the dorsal raphe nucleus/ventrolateral periaqueducal gray (DRVL/VLPAG) region and interfascicular part of the dorsal raphe nucleus (DRI). Studies support a role for serotonergic neurons in the DRVL/VLPAG in inhibition of panic-like responses, and serotonergic neurons in the DRI in antidepressant-like effects. Thus, data suggest that while some subpopulations of serotonergic neurons in the dorsal raphe nucleus play a role in facilitation of anxiety-like responses, others play a role in inhibition of anxiety- or panic-like responses, while others play a role in antidepressant-like effects. Understanding the anatomical and functional properties of these distinct serotonergic systems may lead to novel therapeutic strategies for the prevention and/or treatment of affective and anxiety disorders. In this review, we describe the anatomical and functional properties of subpopulations of serotonergic neurons in the dorsal raphe nucleus, with a focus on those implicated in symptoms of anxiety and affective disorders, the DRD/DRC, DRVL/VLPAG, and DRI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abrams JK, Johnson PL, Hay-Schmidt A, Mikkelsen JD, Shekhar A, Lowry CA (2005) Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs. Neuroscience 133:983–997

    Article  PubMed  CAS  Google Scholar 

  • Amaral DG, Cowan WM (1980) Subcortical afferents to the hippocampal formation in the monkey. J Comp Neurol 189:573–591

    Article  PubMed  CAS  Google Scholar 

  • Amat J, Tamblyn JP, Paul ED, Bland ST, Amat P, Foster AC, Watkins LR, Maier SF (2004) Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala. Neuroscience 129:509–519

    Article  PubMed  CAS  Google Scholar 

  • 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 8:365–371

    Article  PubMed  CAS  Google Scholar 

  • Azmitia EC, Gannon PJ (1986) The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. In: Fahn S et al (eds) Myoclonus. Raven Press, New York, pp 407–468

    Google Scholar 

  • Azmitia EC Jr, Segal M (1978) An autoradiographic analysis of the differential ascending projection of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:651–668

    Article  Google Scholar 

  • Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H, Mann JJ, Arango V (2006) Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 31:814–824

    Article  PubMed  CAS  Google Scholar 

  • Bach-Mizrachi H, Underwood MD, Tin A, Ellis SP, Mann JJ, Arango V (2008) Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. Mol Psychiatry 13:507–513

    Article  PubMed  CAS  Google Scholar 

  • Bago M, Marson L, Dean C (2002) Serotonergic projections to the rostroventrolateral medulla from midbrain and raphe nuclei. Brain Res 945:249–258

    Article  PubMed  CAS  Google Scholar 

  • Banasr M, Hery M, Brezun JM, Daszuta A (2001) Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus. Eur J Neurosci 14:1417–1424

    Article  PubMed  CAS  Google Scholar 

  • Bang SJ, Jensen P, Dymecki SM, Commons KG (2012) Projections and interconnections of genetically defined serotonin neurons in mice. Eur J Neurosci 35:85–96

    Article  PubMed  Google Scholar 

  • Baratta MV, Zarza CM, Gomez DM, Campeau S, Watkins LR, Maier SF (2009) Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress. Eur J Neurosci 30:1111–1116

    Article  PubMed  Google Scholar 

  • Barton DA, Esler MD, Dawood T, Lambert EA, Haikerwal D, Brenchley C, Socratous F, Hastings J, Guo L, Wiesner G, Kaye DM, Bayles R, Schlaich MP, Lambert GW (2008) Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy. Arch Gen Psychiatry 65:38–46

    Article  PubMed  CAS  Google Scholar 

  • Beck SG, Pan YZ, Akanwa AC, Kirby LG (2004) Median and dorsal raphe neurons are not electrophysiologically identical. J Neurophysiol 91:994–1005

    Article  PubMed  Google Scholar 

  • Beitz AJ (1982) The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7:133–159

    Article  PubMed  CAS  Google Scholar 

  • Beyer CE, Cremers TI (2008) Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin? Eur J Pharmacol 580:350–354

    Article  PubMed  CAS  Google Scholar 

  • Bobillier P, Seguin S, Dugueurce A, Lewis BD, Pujol JF (1979) The efferent connections of the nucleus raphe centralis superior in the rat as revealed by autoradiography. Brain Res 166:1–8

    Article  PubMed  CAS  Google Scholar 

  • Bonkale WL, Turecki G, Austin MC (2006) Increased tryptophan hydroxylase immunoreactivity in the dorsal raphe nucleus of alcohol-dependent, depressed suicide subjects is restricted to the dorsal subnucleus. Synapse 60:81–85

    Article  PubMed  CAS  Google Scholar 

  • Bouwknecht JA, Spiga F, Staub DR, Hale MW, Shekhar A, Lowry CA (2007) Differential effects of exposure to low-light or high-light open-field on anxiety-related behaviors: relationship to c-Fos expression in serotonergic and non-serotonergic neurons in the dorsal raphe nucleus. Brain Res Bull 72:32–43

    Article  PubMed  CAS  Google Scholar 

  • Brezun JM, Daszuta A (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89:999–1002

    Article  PubMed  CAS  Google Scholar 

  • Brioni JD, O’Neill AB, Kim DJ, Decker MW (1993) Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur J Pharmacol 238:1–8

    Article  PubMed  CAS  Google Scholar 

  • Cheeta S, Irvine EE, Kenny PJ, File SE (2001a) The dorsal raphe nucleus is a crucial structure mediating nicotine’s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology 155:78–85

    Article  PubMed  CAS  Google Scholar 

  • Cheeta S, Tucci S, File SE (2001b) Antagonism of the anxiolytic effect of nicotine in the dorsal raphe nucleus by dihydro-beta-erythroidine. Pharmacol Biochem Behav 70:491–496

    Article  PubMed  CAS  Google Scholar 

  • Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF (2010) 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339–345

    Article  PubMed  CAS  Google Scholar 

  • Commons KG (2008) Evidence for topographically organized endogenous 5-HT-1A receptor-dependent feedback inhibition of the ascending serotonin system. Eur J Neurosci 27:2611–2618

    Article  PubMed  Google Scholar 

  • Commons KG, Connolley KR, Valentino RJ (2003) A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders. Neuropsychopharmacology 28:206–215

    Article  PubMed  CAS  Google Scholar 

  • Cooper MA, Grober MS, Nicholas CR, Huhman KL (2009) Aggressive encounters alter the activation of serotonergic neurons and the expression of 5-HT1A mRNA in the hamster dorsal raphe nucleus. Neuroscience 161:680–690

    Article  PubMed  CAS  Google Scholar 

  • Crawford LK, Craige CP, Beck SG (2010) Increased intrinsic excitability of lateral wing serotonin neurons of the dorsal raphe: a mechanism for selective activation in stress circuits. J Neurophysiol 103(5):2652–2663

    Article  PubMed  CAS  Google Scholar 

  • Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in cell bodies of brain stem neurons. Acta Physiol Scand 62:5–55

    Google Scholar 

  • Day HE, Greenwood BN, Hammack SE, Watkins LR, Fleshner M, Maier SF, Campeau S (2004) Differential expression of 5HT-1A, alpha(1b) adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol 474:364–378

    Article  PubMed  CAS  Google Scholar 

  • Deakin JFW, Graeff FG (1991) 5-HT and mechanisms of defence. J Psychopharmacol 5:305–315

    Article  PubMed  CAS  Google Scholar 

  • Dhingra NK, Raju TR, Meti BL (1997) Selective reduction of monoamine oxidase A and B in the frontal cortex of subordinate rats. Brain Res 758:237–240

    Article  PubMed  CAS  Google Scholar 

  • Di Giovanni G, Di Matteo V, Pierucci M, Esposito E (2008) Serotonin-dopamine interaction: electrophysiological evidence. Prog Brain Re 172:45–71

    Article  CAS  Google Scholar 

  • Donner NC, Johnson PL, Fitz SD, Kellen KE, Shekhar A, Lowry CA (2012) Elevated tph2 mRNA expression in a rat model of chronic anxiety. Depression and Anxiety (in press)

  • Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387

    Article  PubMed  CAS  Google Scholar 

  • Esler M, Lambert E, Alvarenga M, Socratous F, Richards J, Barton D, Pier C, Brenchley C, Dawood T, Hastings J, Guo L, Haikerwal D, Kaye D, Jennings G, Kalff V, Kelly M, Wiesner G, Lambert G (2007) Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor. Stress 10:295–304

    Article  PubMed  CAS  Google Scholar 

  • Evans AK, Heerkens JL, Lowry CA (2009) Acoustic stimulation in vivo and corticotropin-releasing factor in vitro increase tryptophan hydroxylase activity in the rat caudal dorsal raphe nucleus. Neurosci Lett 455:36–41

    Article  PubMed  CAS  Google Scholar 

  • Gardner KL, Thrivikraman KV, Lightman SL, Plotsky PM, Lowry CA (2005) Early life experience alters behavior during social defeat: focus on serotonergic systems. Neuroscience 136:181–191

    Article  PubMed  CAS  Google Scholar 

  • Gasser PJ, Lowry CA, Orchinik M (2006) Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 26:8758–8766

    Article  PubMed  CAS  Google Scholar 

  • Gasser PJ, Orchinik M, Raju I, Lowry CA (2009) Distribution of organic cation transporter 3, a corticosterone-sensitive monoamine transporter, in the rat brain. J Comp Neurol 512:529–555

    Article  PubMed  CAS  Google Scholar 

  • Graeff FG (1990) Brain defense systems and anxiety. In: Roth M, Burrows GD, Noyes R (eds) Handbook of anxiety, vol 3. Elsevier, Amsterdam, pp 307–354

    Google Scholar 

  • Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF (1996) Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 54:129–141

    Article  PubMed  CAS  Google Scholar 

  • Grahn RE, Will MJ, Hammack SE, Maswood S, McQueen MB, Watkins LR, Maier SF (1999) Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor. Brain Res 826:35–43

    Article  PubMed  CAS  Google Scholar 

  • Gray TS, Magnuson DJ (1992) Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat. Peptides 13:451–460

    Article  PubMed  CAS  Google Scholar 

  • Groenewegen HJ (1988) Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography. Neuroscience 24:379–431

    Article  PubMed  CAS  Google Scholar 

  • Guiard BP, El Mansari M, Merali Z, Blier P (2008) Functional interactions between dopamine, serotonin and norepinephrine neurons: an in vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 11:625–639

    PubMed  CAS  Google Scholar 

  • Haghighi F, Bach-Mizrachi H, Huang YY, Arango V, Shi S, Dwork AJ, Rosoklija G, Sheng HT, Morozova I, Ju J, Russo JJ, Mann JJ (2008) Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression. Mol Psychiatry 13:813–820

    Article  PubMed  CAS  Google Scholar 

  • Hale MW, Lowry CA (2011) Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits. Psychopharmacology 213:243–264

    Article  PubMed  CAS  Google Scholar 

  • Hale MW, Hay-Schmidt A, Mikkelsen JD, Poulsen B, Bouwknecht JA, Evans AK, Stamper CE, Shekhar A, Lowry CA (2008) Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex. Neuroscience 157:733–748

    Article  PubMed  CAS  Google Scholar 

  • Hale MW, Stamper CE, Staub DR, Lowry CA (2010) Urocortin 2 increases c-Fos expression in serotonergic neurons projecting to the ventricular/periventricular system. Exp Neurol 224:271–281

    Article  PubMed  CAS  Google Scholar 

  • Hale MW, Dady KF, Evans AK, Lowry CA (2011a) Evidence for in vivo thermosensitivity of serotonergic neurons in the rat dorsal raphe nucleus and raphe pallidus nucleus implicated in thermoregulatory cooling. Exp Neurol 277:271–281

    Google Scholar 

  • Hale MW, Shekhar A, Lowry CA (2011b) Development by environment interactions controlling tryptophan hydroxylase expression. J Chem Neuroanat 41:219–226

    Article  PubMed  CAS  Google Scholar 

  • Hammack SE, Richey KJ, Schmid MJ, LoPresti ML, Watkins LR, Maier SF (2002) The role of corticotropin-releasing hormone in the dorsal raphe nucleus in mediating the behavioral consequences of uncontrollable stress. J Neurosci 22:1020–1026

    PubMed  CAS  Google Scholar 

  • 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 23:1019–1025

    PubMed  CAS  Google Scholar 

  • Hammack SE, Richey KJ, Watkins LR, Maier SF (2004) Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress. Behav Neurosci 118:443–448

    Article  PubMed  Google Scholar 

  • Herbert H (1992) Evidence for projections from medullary nuclei onto serotonergic and dopaminergic neurons in the midbrain dorsal raphe nucleus of the rat. Cell Tissue Res 270:149–156

    Article  PubMed  CAS  Google Scholar 

  • Herbert J, Saper CB (1992) Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat. J Comp Neurol 315:34–52

    Article  PubMed  CAS  Google Scholar 

  • Hollis JH, Evans AK, Bruce KP, Lightman SL, Lowry CA (2006) Lipopolysaccharide has indomethacin-sensitive actions on Fos expression in topographically organized subpopulations of serotonergic neurons. Brain Behav Immun 20:569–577

    Article  PubMed  CAS  Google Scholar 

  • Holstege G (1995) The basic, somatic, and emotional components of the motor system in mammals. In: Paxinos G (ed) The rat nervous system. Academic Press, San Diego, pp 137–154

    Google Scholar 

  • Holstege G, Meiners L, Tan K (1985) Projections of the bed nucleus of the stria terminalis to the mesencephalon, pons, and medulla oblongata in the cat. Exp Brain Res 58:379–391

    Article  PubMed  CAS  Google Scholar 

  • Hurley KM, Herbert H, Moga MM, Saper CB (1991) Efferent projections of the infralimbic cortex of the rat. J Comp Neurol 308:249–276

    Article  PubMed  CAS  Google Scholar 

  • Jensen P, Farago AF, Awatramani RB, Scott MM, Deneris ES, Dymecki SM (2008) Redefining the serotonergic system by genetic lineage. Nat Neurosci 11:417–419

    Article  PubMed  CAS  Google Scholar 

  • Johnson PL, Hollis JH, Moratalla R, Lightman SL, Lowry CA (2005) Acute hypercarbic gas exposure reveals functionally distinct subpopulations of serotonergic neurons in rats. J Psychopharmacol 19:327–341

    Article  PubMed  CAS  Google Scholar 

  • Johnson PL, Shekhar A (2006) Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci 26:7093–7104

    Article  PubMed  CAS  Google Scholar 

  • Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A (2007) Neural pathways underlying lactate-induced panic. Neuropsychopharmacology 33:2093–2107

    Article  PubMed  CAS  Google Scholar 

  • Johnson PL, Lowry CA, Truitt W, Shekhar A (2008) Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic. J Psychopharmacol 22:642–645

    Article  PubMed  CAS  Google Scholar 

  • Johnson PL, Fitz SD, Hollis JH, Moratalla R, Lightman SL, Shekhar A, Lowry CA (2010) Induction of c-Fos in ‘panic/defence’-related brain circuits following brief hypercarbic gas exposure. J Psychopharmacol 25:26–36

    Article  PubMed  CAS  Google Scholar 

  • 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 755:229–245

    Article  PubMed  CAS  Google Scholar 

  • Kelly KJ, Donner NC, Hale MW, Lowry CA (2011) Swim stress activates serotonergic and nonserotonergic neurons in specific subdivisions of the rat dorsal raphe nucleus in a temperature-dependent manner. Neuroscience 197:251–268

    Article  PubMed  CAS  Google Scholar 

  • Kiyasova V, Gaspar P (2011) Development of raphe serotonin neurons from specification to guidance. Eur J Neurosci 34:1553–1562

    Article  PubMed  Google Scholar 

  • Kiyasova V, Fernandez SP, Laine J, Stankovski L, Muzerelle A, Doly S, Gaspar P (2011) A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei. J Neurosci 31:2756–2768

    Article  PubMed  CAS  Google Scholar 

  • Köhler C, Chan-Palay V, Steinbusch H (1982) The distribution and origin of serotonin-containing fibers in the septal area: a combined immunohistochemical and fluorescent retrograde tracing study in the rat. J Comp Neurol 209:91–111

    Article  PubMed  Google Scholar 

  • Köhler C, Steinbusch H (1982) Identification of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain. Neuroscience 7:951–975

    Article  PubMed  Google Scholar 

  • Krout KE, Belzer RE, Loewy AD (2002) Brainstem projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 448:53–101

    Article  PubMed  Google Scholar 

  • Le Francois B, Czesak M, Steubl D, Albert PR (2008) Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55:977–985

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, Fitz S, Johnson PL, Shekhar A (2008) Repeated stimulation of CRF receptors in the BNST of rats selectively induces social but not panic-like anxiety. Neuropsychopharmacology 33(1):2586–2594

    Article  PubMed  CAS  Google Scholar 

  • Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799

    PubMed  CAS  Google Scholar 

  • Ljubic-Thibal V, Morin A, Diksic M, Hamel E (1999) Origin of the serotonergic innervation to the rat dorsolateral hypothalamus: retrograde transport of cholera toxin and upregulation of tryptophan hydroxylase mRNA expression following selective nerve terminals lesion. Synapse 32:177–186

    Article  PubMed  CAS  Google Scholar 

  • Lopez de Lara C, Brezo J, Rouleau G, Lesage A, Dumont M, Alda M, Benkelfat C, Turecki G (2007) Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol Psychiatry 62:72–80

    Article  PubMed  CAS  Google Scholar 

  • Lowry CA, Hale MW (2010) Serotonin and the neurobiology of anxious states. In: Mûller CP, Jacobs BL (eds) Handbook of the behavioral neurobiology of serotonin. Elsevier, Amsterdam, pp 379–398

    Chapter  Google Scholar 

  • Lowry CA, Johnson PL, Hay-Schmidt A, Mikkelsen J, Shekhar A (2005) Modulation of anxiety circuits by serotonergic systems. Stress 8:233–246

    Article  PubMed  CAS  Google Scholar 

  • Lowry CA, Hollis JH, de Vries A, Pan B, Brunet LR, Hunt JR, Paton JF, van Kampen E, Knight DM, Evans AK, Rook GA, Lightman SL (2007) Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience 146:756–772

    Article  PubMed  CAS  Google Scholar 

  • Lowry CA, Evans AK, Gasser PJ, Hale MW, Staub DR, Shekhar A (2008a) Topographical organization and chemoarchitecture of the dorsal raphe nucleus and the median raphe nucleus. In: Monti JM, Pandi-Perumal BL, Jacobs BL, Nutt DL (eds) Serotonin and sleep: molecular functional and clinical aspects. Birkhauser, Switzerland, pp 25–68

    Chapter  Google Scholar 

  • Lowry CA, Hale MW, Evans AK, Heerkens J, Staub DR, Gasser PJ, Shekhar A (2008b) Serotonergic systems, anxiety, and affective disorder: focus on the dorsomedial part of the dorsal raphe nucleus. Ann NY Acad Sci 1148:86–94

    Article  PubMed  Google Scholar 

  • Luiten PG, ter Horst GJ, Karst H, Steffens AB (1985) The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res 329:374–378

    Article  PubMed  CAS  Google Scholar 

  • MacGillivray L, Lagrou LM, Reynolds KB, Rosebush PI, Mazurek MF (2010) Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity. Neuroscience 171:407–420

    Article  PubMed  CAS  Google Scholar 

  • Maier SF, Watkins LF (1998) Stressor controllability, anxiety, and serotonin. Cognitive Therapy Res 22:595–613

    Article  Google Scholar 

  • 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 29:829–841

    Article  PubMed  CAS  Google Scholar 

  • Maier SF, Busch CR, Maswood S, Grahn RE, Watkins LR (1995a) The dorsal raphe nucleus is a site of action mediating the behavioral effects of the benzodiazepine receptor inverse agonist DMCM. Behav Neurosci 109:759–766

    Article  PubMed  CAS  Google Scholar 

  • Maier SF, Grahn RE, Watkins LR (1995b) 8-OH-DPAT microinjected in the region of the dorsal raphe nucleus blocks and reverses the enhancement of fear conditioning and interference with escape produced by exposure to inescapable shock. Behav Neurosci 109:404–412

    Article  PubMed  CAS  Google Scholar 

  • McDevitt RA, Hiroi R, Mackenzie SM, Robin NC, Cohn A, Kim JJ, Neumaier JF (2011) Serotonin 1B autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression-like behavior. Biol Psychiatry 69:780–787

    Article  PubMed  CAS  Google Scholar 

  • Mikkelsen JD, Hay-Schmidt A, Larsen PJ (1997) Central innervation of the rat ependyma and subcommissural organ with special reference to ascending serotoninergic projections from the raphe nuclei. J Comp Neurol 384:556–568

    Article  PubMed  CAS  Google Scholar 

  • Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260

    Article  PubMed  CAS  Google Scholar 

  • Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA, Eckelman W, Herscovitch P, Charney DS, Drevets WC (2004) Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 24:589–591

    Article  PubMed  CAS  Google Scholar 

  • Nguyen T, Chin WC, O’Brien JA, Verdugo P, Berger AJ (2001) Intracellular pathways regulating ciliary beating of rat brain ependymal cells. J Physiol 531:131–140

    Article  PubMed  CAS  Google Scholar 

  • Pasquier DA, Reinoso-Suarez F (1978) The topographic organization of hypothalamic and brain stem projections to the hippocampus. Brain Res Bull 3:373–389

    Article  PubMed  CAS  Google Scholar 

  • Paul ED, Hale MW, Lukkes JL, Valentine MJ, Sarchet DM, Lowry CA (2011) Repeated social defeat increases reactive emotional coping behavior and alters functional responses in serotonergic neurons in the rat dorsal raphe nucleus. Physiol Behav 104:272–282

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego

    Google Scholar 

  • Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP (2004) Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 9:879–889

    Article  PubMed  CAS  Google Scholar 

  • Petit J-M, Luppi P-H, Peyron C, Rampon C, Jouvet M (1995) VIP-like immunoreactive projections from the dorsal raphe and caudal linear nuclei to the bed nucleus of the stria terminalis demonstrated by a double immunohistochemical method in the rat. Neurosci Lett 193:77–80

    Article  PubMed  CAS  Google Scholar 

  • Peyron C, Petit J-M, Rampon C, Jouvet M, Luppi P-H (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience 82:443–468

    Article  PubMed  CAS  Google Scholar 

  • Porrino LJ, Goldman-Rakic PS (1982) Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP. J Comp Neurol 205:63–76

    Article  PubMed  CAS  Google Scholar 

  • Rizvi TA, Ennis M, Behbehani MM, Shipley MT (1991) Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J Comp Neurol 303:121–131

    Article  PubMed  CAS  Google Scholar 

  • Rozeske RR, Evans AK, Frank MG, Watkins LR, Lowry CA, Maier SF (2011) Uncontrollable, but not controllable, stress desensitizes 5-HT1A receptors in the dorsal raphe nucleus. J Neurosci 31:14107–14115

    Article  PubMed  CAS  Google Scholar 

  • Saper CB, Loewy AD (1980) Efferent connections of the parabrachial nucleus in the rat. Brain Res 197:291–317

    Article  PubMed  CAS  Google Scholar 

  • Simpson KL, Fisher TM, Waterhouse BD, Lin RC (1998) Projection patterns from the raphe nuclear complex to the ependymal wall of the ventricular system in the rat. J Comp Neurol 399:61–72

    Article  PubMed  CAS  Google Scholar 

  • Singewald N, Kaehler ST, Philippu A (1999) Noradrenaline release in the locus coeruleus of conscious rats is triggered by drugs, stress and blood pressure changes. NeuroReport 10:1583–1587

    Article  PubMed  CAS  Google Scholar 

  • Singewald N, Salchner P, Sharp T (2003) Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry 53:275–283

    Article  PubMed  CAS  Google Scholar 

  • Sink KS, Walker DL, Freeman SM, Flandreau EI, Ressler KJ, Davis M (2012) Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry. doi:10.1038/mp.2011.188

    PubMed  Google Scholar 

  • Spannuth BM, Hale MW, Evans AK, Lukkes JL, Campeau S, Lowry CA (2011) Investigation of a central nucleus of the amygdala/dorsal raphe nucleus serotonergic circuit implicated in fear-potentiated startle. Neuroscience 179:104–119

    Article  PubMed  CAS  Google Scholar 

  • Sperling R, Commons KG (2011) Shifting topographic activation and 5-HT1A receptor-mediated inhibition of dorsal raphe serotonin neurons produced by nicotine exposure and withdrawal. Eur J Neurosci 33:1866–1875

    Article  PubMed  Google Scholar 

  • 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 1044:176–189

    Article  PubMed  CAS  Google Scholar 

  • Staub DR, Evans AK, Lowry CA (2006) Evidence supporting a role for corticotropin-releasing factor type 2 (CRF(2)) receptors in the regulation of subpopulations of serotonergic neurons. Brain Res 1070:77–89

    Article  PubMed  CAS  Google Scholar 

  • Stezhka VV, Lovick TA (1997) Projections from dorsal raphe nucleus to the periaqueductal grey matter: studies in slices of rat midbrain maintained in vitro. Neurosci Lett 230:57–60

    Article  PubMed  CAS  Google Scholar 

  • Szabo ST, de Montigny C, Blier P (1999) Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers. Br J Pharmacol 126:568–571

    Article  PubMed  CAS  Google Scholar 

  • Underwood MD, Arango V, Bakalian MJ, Ruggiero DA, Mann JJ (1999) Dorsal raphe nucleus serotonergic neurons innervate the rostral ventrolateral medulla in rat. Brain Res 824:45–55

    Article  PubMed  CAS  Google Scholar 

  • 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 23:7155–7159

    PubMed  CAS  Google Scholar 

  • Van Bockstaele EJ, Biswas A, Pickel VM (1993) Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens. Brain Res 624:188–198

    Article  PubMed  Google Scholar 

  • Vandermaelen CP, Aghajanian GK (1983) Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. Brain Res 289:109–119

    Article  PubMed  CAS  Google Scholar 

  • Vertes RP, Fass B (1988) Projections between the interpeduncular nucleus and basal forebrain in the rat as demonstrated by the anterograde and retrograde transport of WGA-HRP. Exp Brain Res 73:23–31

    Article  PubMed  CAS  Google Scholar 

  • Vertes RP, Fortin WJ, Crane AM (1999) Projections of the median raphe nucleus in the rat. J Comp Neurol 407:555–582

    Article  PubMed  CAS  Google Scholar 

  • Wyss JM, Swanson LW, Cowan WM (1979) A study of subcortical afferents to the hippocampal formation in the rat. Neuroscience 4:463–476

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16

    Article  PubMed  CAS  Google Scholar 

  • Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M (2004) SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 9:1030–1036

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The project described was supported by R01MH086539 (CAL) and R01MH065702 (AS/CAL) from the National Institute of Mental Health and Grant No. 0845550 (CAL) from the National Science Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, or the National Science Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christopher A. Lowry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hale, M.W., Shekhar, A. & Lowry, C.A. Stress-related Serotonergic Systems: Implications for Symptomatology of Anxiety and Affective Disorders. Cell Mol Neurobiol 32, 695–708 (2012). https://doi.org/10.1007/s10571-012-9827-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-012-9827-1

Keywords

Navigation