Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-14T04:56:40.611Z Has data issue: false hasContentIssue false
  • English
  • Français

5-HT2A: Its Role in Frontally Mediated Executive Function and Related Psychopathology

Published online by Cambridge University Press:  07 November 2014

Dan J. Stein ,
Sian Hemmings ,
Hanlie Moolman-Smook  and
Kurt Audenaert
Get access Rights & Permissions [Opens in a new window]

Abstract

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.

Type
Pearls in Clinical Neuroscience
Information
CNS Spectrums , Volume 12 , Issue 7 , July 2007 , pp. 512 - 516
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.Barnes, NM, Sharp, T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–1152.CrossRefGoogle ScholarPubMed
2.Celada, P, Puig, M, Amargos-Bosch, M, Adell, A, Artigas, F. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci. 2004;29:252–265.Google ScholarPubMed
3.Roth, BL, Willins, DL, Kristiansen, K, Kroeze, WK. 5-Hydroxytryptamine2-family receptors (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where structure meets function. Pharmacol Ther. 1998;79:231–257.CrossRefGoogle ScholarPubMed
4.Winstanley, CA, Theobald, DE, Dalley, JW, Glennon, JC, Robbins, TW. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology (Berl). 2004;176:376–385.CrossRefGoogle ScholarPubMed
5.Marek, GJ, Carpenter, LL, McDougle, CJ, Price, LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28:402–412.CrossRefGoogle ScholarPubMed
6.Chen, K, Yang, W, Grimsby, J, Shih, JC. The human 5-HT2 receptor is encoded by a multiple intron-exon gene. Brain Res Mol Brain Res. 1992;14:20–26.CrossRefGoogle ScholarPubMed
7.Li, D, Duan, Y, He, L. Association study of serotonin 2A receptor (5-HT2A) gene with schizophrenia and suicidal behavior using systematic meta-analysis. Biochem Biophys Res Commun. 2006;340:1006–1015.CrossRefGoogle ScholarPubMed
8.Van Oekelen, D, Luyten, WH, Leysen, JE. 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci. 2003;72:2429–2449.CrossRefGoogle ScholarPubMed
9.Williams, GV, Rao, SG, Goldman-Rakic, PS. The physiological role of 5-HT2A receptors in working memory. J Neurosci. 2002;22:2843–2854.CrossRefGoogle ScholarPubMed
10.Passetti, F, Dalley, JW, Robbins, TW. Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task. Psychopharmacology (Berl). 2003;165:136–145.CrossRefGoogle ScholarPubMed
11.Gonzalez-Maeso, J, Weisstaub, NV, Zhou, M, et al.Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–452.CrossRefGoogle ScholarPubMed
12.Blier, P, Szabo, ST. Potential mechanisms of action of atypical antipsychotics in treatment-resistant depression and anxiety. J Clin Psychiatry. 2005;66(suppl 8):30–40.Google ScholarPubMed
13.Stockmeier, C, Kellar, K. In vivo regulation of the serotonin-2 receptor in rat brain. Life Sci. 1986;38:117–127.CrossRefGoogle ScholarPubMed
14.Preece, MA, Dalley, JW, Theobald, DE, Robbins, TW, Reynolds, GP. Region specific changes in forebrain 5-hydroxytryptamine1A and 5-hydroxytryptamine2A receptors in isolationreared rats: an in vitro autoradiography study. Neuroscience. 2004;123:725–732.CrossRefGoogle ScholarPubMed
15.Katagiri, H, Kagaya, A, Nakae, S, Morinobu, S, Yamawaki, S. Modulation of serotonin2a receptor function in rats after repeated treatment with dexamethasone and L-type calcium channel antagonist nimodipine. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:1269–1281.CrossRefGoogle ScholarPubMed
16.Meyer, JH, McMain, S, Kennedy, SH, et al.Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry. 2003;160:90–99.CrossRefGoogle ScholarPubMed
17.Bhagwagar, Z, Hinz, R, Taylor, M, Fancy, S, Cowen, P, Grasby, PJ. Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11C]MDL 100,907. Am J Psychiatry. 2006;163:1580–1587.CrossRefGoogle ScholarPubMed
18.Yates, M, Leake, A, Candy, JM, Fairbairn, AF, McKeith, IG, Ferrier, IN. 5HT2 changes in major depression. Biol Psychiatry. 1990;27:489–496.CrossRefGoogle ScholarPubMed
19.Oquendo, MA, Russo, SA, Underwood, MD, et al.Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry. 2006;59:235–243.CrossRefGoogle ScholarPubMed
20.Turecki, G, Brie, R, Dewar, K, et al.Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry. 1999;156:1456–1458.CrossRefGoogle Scholar
21.Meyer, JH, Kapur, S, Eisfeld, B, et al.The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry. 2001;158:78–85.CrossRefGoogle Scholar
22.van Heeringen, C, Audenaert, K, Van Laere, K, et al.Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted suicide. J Affect Disord. 2003;74:149–158.CrossRefGoogle ScholarPubMed
23.Biver, F, Wikler, D, Lotstra, F, Damhaut, P, Goldman, S, Mendlewicz, J. Serotonin 5-HT2 receptor imagingin major depression: focal changes in orbito-insular cortex. Br J Psychiatry. 1997;171:444–448.CrossRefGoogle Scholar
24.Yatham, LN, Liddle, PF, Shiah, IS, et al.Brain serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen Psychiatry. 2000;57:850–858.CrossRefGoogle ScholarPubMed
25.Mintun, MA, Sheline, YI, Moerlein, SM, Vlassenko, AG, Huang, Y, Snyder, AZ. Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biol Psychiatry. 2004;55:217–224.CrossRefGoogle ScholarPubMed
26.Stockmeier, CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res. 2003;37:357–373.CrossRefGoogle ScholarPubMed
27.Amat, J, Paul, E, Zarza, C, Watkins, LR, Maier, SF. Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci. 2006;26:13264–13272.CrossRefGoogle ScholarPubMed
28.Yatham, LN, Liddle, PF, Dennie, J, et al.Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone. Arch Gen Psychiatry. 1999;56:705–711.CrossRefGoogle ScholarPubMed
29.Yatham, LN, Liddle, PF, Shiah, IS, et al.Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry. 2001;178:448–453.CrossRefGoogle Scholar
30.El Mansari, M, Blier, P. Responsiveness of 5-HT1A and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition. J Psychiatry Neurosci. 2005;30:268–274.Google Scholar
31.Polesskaya, OO, Sokolov, BP. Differential expression of the C and T alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res. 2002;67:812–822.CrossRefGoogle Scholar
32.Parsons, MJ, D'Souza, UM, Arranz, MJ, Kerwin, RW, Makoff, AJ. The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry. 2004;56:406–410.CrossRefGoogle ScholarPubMed
33.Kouzmenko, AP. No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia. Hum Hered. 2007;49:103–105.CrossRefGoogle Scholar
34.Bray, NJ, Buckland, PR, Hall, H, Owen, MJ, O'Donovan, MC. The serotonin-2A receptor gene locus does not contain common polymorphism-affecting mRNA levels in adult brain. Mol Psychiatry. 2004;9:109–114.CrossRefGoogle Scholar
35.Bjork, JM, Moeller, FG, Dougherty, DM, Swann, AC, Machado, MA, Hanis, CL. Serotonin 2a receptor T102C polymorphism and impaired impulse control. Am J Med Genet. 2002;114:336–339.CrossRefGoogle ScholarPubMed
36.Hemmings, SM, Kinnear, CJ, Lochner, C, et al.Genetic correlates in trichotillomania—a case-control association study in the South African Caucasian population. Isr J Psychiatry Relat Sci. 2006;43:93–101.Google ScholarPubMed
37.Bonnier, B, Gorwood, P, Hamon, P, Sarfati, Y, Boni, C, Hardy-Bayle, MC. Association of 5-HT2A receptor gene polymorphism with major affective disorders: the case of a subgroup of bipolar disorder with low suicide risk. Biol Psychiatry. 2002;51:762–765.CrossRefGoogle ScholarPubMed
38.Berggård, C, Damberg, M, Longato-Stadler, E, Hallman, J, Oreland, L, Garpenstrand, H. The serotonin 2A-1438 G/A receptor polymorphism in a group of Swedish male criminals. Neurosci Lett. 2003;347:196–198.CrossRefGoogle Scholar
39.Ricca, V, Nacmias, B, Boldrini, M, et al.Psychopathological traits and 5-HT2A receptor promoter polymorphism (-1438 G/A) in patients suffering from anorexia nervosa and bulimia nervosa. Neurosci Lett. 2004;365:92–96.CrossRefGoogle Scholar
40.Nomura, M, Nomura, Y. Psychological, neuroimaging, and biochemical studies on functional association between impulsive behavior and the 5-HT2A receptor gene polymorphism in humans. Ann N Y Acad Sci. 2006;1086:134–143.CrossRefGoogle ScholarPubMed
41.De Luca, V, Likhodi, O, Kennedy, JL, Wong, AH. Parent-of-origin effect and genomic imprinting of the HTR2A receptor gene T102C polymorphism in psychosis. Psychiatry Res. 2007;151:243–248.CrossRefGoogle ScholarPubMed
42.Gerard, MS, Higley, JD. Evolutionary underpinnings of excessive alcohol consumption. Addiction. 2002;97:415–425.Google Scholar
43.Peremans, K, Audenaert, K, Hoybergs, Y, et al.The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive-aggressive dog, as measured with 1231-5-IR91150SPECT. Eur J Nucl Med Mol Imaging. 2005;32:708–716.CrossRefGoogle Scholar
44.Kendler, KS. Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry. 2006;163:1138–1146.CrossRefGoogle ScholarPubMed
45.Lerer, B, Segman, RH, Tan, EC, et al.Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype. Int J Neuropsychopharmacol. 2005;8:411–425.CrossRefGoogle ScholarPubMed
46.Arranz, MJ, Munro, J, Sham, P, et al.Meta-analysis of studies-on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res. 1998;32:93–99.CrossRefGoogle ScholarPubMed
47.Papakostas, GI, Fava, M. A meta-analysis of clinical trials comparing the serotonin (5HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. Eur Psychiatry. In press.Google Scholar
48.Stein, DJ, Newman, TK, Savitz, J, Ramesar, R. Warriors versus worriers: the role of COMT gene variants. CNS Spectr. 2006;11:745–748.CrossRefGoogle ScholarPubMed
49.Alex, KD, Pehek, EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113:296–320.CrossRefGoogle ScholarPubMed
50.Harvey, BH, Naciti, C, Brand, L, Stein, DJ. Endocrine, cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats. Brain Res. 2003;983:97–107.CrossRefGoogle ScholarPubMed