Abstract
There is considerable evidence supporting the involvement of serotonin-2C (5-HT2C) receptors in the pathophysiology of depression. First, 5-HT2C receptors play an important role in the regulation of monoamine transmission. Second, abnormalities in expression and functioning of 5-HT2C receptors have been observed in depressed patients and in animal models of depression. Third, a large body of evidence indicates that 5-HT2C receptors mediate certain behavioral functions that are disturbed in depression. Finally, some compounds acting on 5-HT2C receptors are effective in the treatment of depression. This chapter aims to summarize these four lines of evidence for the involvement of 5-HT2C receptors in pathophysiology and treatment of depression.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113:296–320.
Alex KD, Yavanian GJ, McFarlane HG, et al (2005) Modulation of dopamine release by striatal 5-HT2C receptors. Synapse 55:242–251.
American Psychiatric Association (2000). Diagnostic and statistical manual (DSM) IV.
Berendsen HH, Broekkamp CL (1997) Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine. Psychopharmacology 133:275–282.
Blackburn TP, Baxter GS, Kennett GA, et al (1993) BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties. Psychopharmacology 110:257–264.
Blier P, Pineyro G, el Mansari M, et al (1998) Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Ann N Y Acad Sci 861:204–216.
Bockaert J, Claeysen S, Becamel C, et al (2006) Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 326: 553–572.
Boothman LJ, Allers KA, Rasmussen K, et al (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 139:998–1004.
Boothman L, Raley J, Denk F, et al (2006) In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism. Br J Pharmacol 149:861–869.
Burns CM, Chu H, Rueter SM, et al (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308.
Cervo L, Samanin R (1995) 5-HT1A receptor full and partial agonists and 5-HT2C (but not 5-HT3) receptor antagonists increase rates of punished responding in rats. Pharmacol Biochem Behav 52:671–676.
Chenu F, El Mansari M, Blier P (2009) Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area. Int J Neuropsychopharmacol 12:475–485.
Cremers TI, Giorgetti M, Bosker FJ, et al (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29:1782–1789.
Cremers TI, Rea K, Bosker FJ, et al (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32:1550–1557.
Cussac D, Newman-Tancredi A, Duqueyroix D, et al (2002) Differential activation of Gq/11 and Gi(3) proteins at 5-hydroxytryptamine(2C) receptors revealed by antibody capture assays: influence of receptor reserve and relationship to agonist-directed trafficking. Mol Pharmacol 62:578–589.
Di Giovanni G, Di Matteo V, Di Mascio M, et al (2000) Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin (2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse 35:53–61.
Di Giovanni G, Di Matteo V, La Grutta V, et al (2001) m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103:111–116.
Di Mascio M, Di Giovanni G, Di Matteo V, et al (1999) Decreased chaos of midbrain dopaminergic neurons after serotonin denervation. Neuroscience 92:237–243.
Di Matteo V, Di Giovanni G, Di Mascio M, et al (2000) Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors. Brain Res 865:85–90.
Dremencov E (2009) Aiming at new targets for the treatment of affective disorders. Curr Drug Targets 10:1049.
Dremencov E, Gur E, Lerer B, et al (2002) Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hypothalamus. Prog Neuropsychopharmacol Biol Psychiatry 26:1029–1034.
Dremencov E, Gur E, Lerer B, et al (2003) Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 27:729–739.
Dremencov E, Gispan-Herman I, Rosenstein M, et al (2004) The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression. Prog Neuropsychopharmacol Biol Psychiatry 28:141–147.
Dremencov E, Newman ME, Kinor N, et al (2005) Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment. Neuropharmacology 48:34–42.
Dremencov E, Weizmann Y, Kinor N, et al (2006) Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response. Curr Drug Targets 7:165–175.
Dremencov E, El Mansari M, Blier P (2007a) Distinct electrophysiological effect of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons. Psychopharmacology 194:63–72.
Dremencov E, El Mansari M, Blier P (2007b) Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain. Biol Psychiatry 61: 671–678.
Dremencov E, El Mansari M, Blier P (2009) Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 34:223–229.
Englander MT, Dulawa SC, Bhansali P, et al (2005) How stress and fluoxetine modulate serotonin 2C receptor pre-mRNA editing. J Neurosci 25:648–651.
Fone KC, Shalders K, Fox ZD, et al (1996) Increased 5-HT2C receptor responsiveness occurs on rearing rats in social isolation. Psychopharmacology 123:346–352.
Gleeson S, Ahlers ST, Mansbach RS, et al (1989) Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes. J Pharmacol Exp Ther 250:809–817.
Goodwin GM, Emsley R, Rembry S, et al (2009) Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 70:1128–1137.
Green AR, Heal DJ, Goodwin GM (1986) The effects of electroconvulsive therapy and antidepressant drugs on monoamine receptors in rodent brain--similarities and differences. Ciba Found Symp 123:246–267.
Griebel G, Misslin R, Pawlowski M, et al (1991) m-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice. Neuroreport 2:627–629.
Gurevich I, Tamir H, Arango V, et al (2002) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34:349–356.
Hrdina PD, Vu TB (1993) Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study. Synapse 14:324–331.
Hrdina PD, Demeter E, Vu TB, et al (1993) 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: increase in 5-HT2 sites in cortex and amygdala. Brain Res 614:37–44.
Hyttel J (1982) Citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6:277–295.
Kaplan HI, Sadock BJ (1995) Comprehensive textbook of psychiatry. VI, 2804, Baltimore, MD: Williams & Wilkins, p I-122.
Kennett GA, Wood MD, Glen A, et al (1994) In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 111: 797–802.
Kennett GA, Bailey F, Piper DC, et al (1995) Effect of SB 200646A, a 5-HT2C/5-HT2B receptor antagonist, in two conflict models of anxiety. Psychopharmacology 118: 178–182.
Martin JR, Ballard TM, Higgins GA (2002) Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacol Biochem Behav 71:615–625.
McGrew L, Chang MS, Sanders-Bush E (2002) Phospholipase D activation by endogenous 5-hydroxytryptamine 2C receptors is mediated by Galpha13 and pertussis toxin-insensitive Gbetagamma subunits. Mol Pharmacol 62:1339–1343.
McKeith IG, Marshall EF, Ferrier IN, et al (1987) 5-HT receptor binding in post-mortem brain from patients with affective disorder. J Affect Disord 13:67–74.
Mikuni M, Meltzer HY (1984) Reduction of serotonin-2 receptors in rat cerebral cortex after subchronic administration of imipramine, chlorpromazine, and the combination thereof. Life Sci 34:87–92.
Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110:135–370.
Millan MJ, Gobert A, Lejeune F, et al (2003) The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306:954–964.
Mongeau R, Blier P, de Montigny C (1997) The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments. Brain Res Brain Res Rev 23:145–195.
Moreau JL, Bos M, Jenck F, et al (1996) 5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats. Eur Neuropsychopharmacol 6:169–175.
Niswender CM, Copeland SC, Herrick-Davis K, et al (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472–9478.
Rajkumar R, Pandey DK, Mahesh R, et al (2009) 1-(m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT(2A) receptors: proposal of a modified rodent antidepressant assay. Eur J Pharmacol 608:32–41.
Redrobe JP, Bourin M (1997) Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test. Eur J Pharmacol 325:129–135.
Rocha B, Rigo M, Di Scala G, et al (1994) Chronic mianserin or eltoprazine treatment in rats: effects on the elevated plus-maze test and on limbic 5-HT2C receptor levels. Eur J Pharmacol 262:125–131.
Rosenzweig-Lipson S, Sabb A, Stack G, et al (2007) Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology 192:159–170.
Sotty F, Folgering JH, Brennum LT, et al (2009) Relevance of dorsal raphe nucleus firing in serotonin 5-HT(2C) receptor blockade-induced augmentation of SSRIs effects. Neuropharmacology 57:18–24.
Stahl SM, Fava M, Trivedi MH, et al (2010) Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry 71:616–626.
Stefanski R, Ladenheim B, Lee SH, et al (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135.
Theile JW, Morikawa H, Gonzales RA, et al (2009) Role of 5-hydroxytryptamine2C receptors in Ca2 + -dependent, ethanol potentiation of GABA release onto ventral tegmental area dopamine neurons. J Pharmacol Exp Ther 329:625–633.
Tremblay P, Blier P (2006) Catecholaminergic strategies for the treatment of major depression. Curr Drug Targets 7:149–158.
van Mill JG, Hoogendijk WJ, Vogelzangs N, et al (2010) Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry 71:239–246.
Westphal RS, Backstrom JR, Sanders-Bush E (1995) Increased basal phosphorylation of the constitutively active serotonin 2C receptor accompanies agonist-mediated desensitization. Mol Pharmacol 48:200–205.
World Health Organization (2002) The world health report 2002.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Dremencov, E., Folgering, J.H.A., Hogg, S., Tecott, L., Cremers, T.I.F.H. (2011). The Role of 5-HT2C Receptors in the Pathophysiology and Treatment of Depression. In: Di Giovanni, G., Esposito, E., Di Matteo, V. (eds) 5-HT2C Receptors in the Pathophysiology of CNS Disease. The Receptors, vol 22. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-941-3_12
Download citation
DOI: https://doi.org/10.1007/978-1-60761-941-3_12
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-940-6
Online ISBN: 978-1-60761-941-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)