title: Enhanced function of prefrontal serotonin 5-HT(2) receptors in a rat model of psychiatric vulnerability.
abstract: Prefrontal serotonin 5-HT(2) receptors have been linked to the pathogenesis and treatment of affective disorders, yet their function in psychiatric vulnerability is not known. Here, we examine the effects of 5-HT(2) receptors in a rat model of psychiatric vulnerability using electrophysiology, gene expression, and behavior. Following the early stress of chronic maternal separation, we found that serotonin has atypical 5-HT(2) receptor-mediated excitatory effects in the adult prefrontal cortex that were blocked by the 5-HT(2A) receptor antagonist MDL 100907. In the absence of a serotonergic agonist, the intrinsic excitability of the prefrontal cortex was not enhanced relative to controls. Yet, in response to stimulation of 5-HT(2) receptors, adult animals with a history of early stress exhibit heightened prefrontal network activity in vitro, enhanced immediate early gene expression in vivo, and potentiated head shake behavior. These changes arise in the absence of any major alteration of prefrontal 5-HT(2A/C) mRNA expression or 5-HT(2) receptor binding. Our microarray results and quantitative PCR validation provide insight into the molecular changes that accompany such enhanced 5-HT(2) receptor function in adult animals following early stress. We observed persistent prefrontal transcriptome changes, with significant enrichment of genes involved in cellular developmental processes, regulation of signal transduction, and G-protein signaling. Specific genes regulated by early stress were validated in an independent cohort, and several altered genes were normalized by chronic blockade of 5-HT(2) receptors in adulthood. Together, our results demonstrate enhanced prefrontal 5-HT(2) receptor function and persistent alterations in prefrontal gene expression in a rat model of psychiatric vulnerability.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Benekareddy
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Goodfellow
authors.forename: Evelyn K
authors.initials: EK
authors.lastname: Lambe
authors.forename: Vidita A
authors.initials: VA
authors.lastname: Vaidya
mesh_terms: D000386:AIDS-Related Complex / Q000235:genetics / Q000378:metabolism; D000662:Amphetamines / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000493:pharmacokinetics; D008426:Maternal Deprivation; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D001523:Mental Disorders / Q000139:chemically induced / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000662:Amphetamines; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D044348:Receptors, Serotonin, 5-HT2; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D014316:Tritium; D012701:Serotonin; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
references.citation: Am J Psychiatry. 2002 Aug;159(8):1265-83
references.pmid: 12153816
references.citation: Eur J Pharmacol. 1999 Jul 28;378(1):23-30
references.pmid: 10478561
references.citation: Neurosci Lett. 1993 Nov 12;162(1-2):81-4
references.pmid: 8121642
references.citation: Ann N Y Acad Sci. 1999 Jun 29;877:383-96
references.pmid: 10415660
references.citation: J Clin Psychopharmacol. 2001 Feb;21(1):53-8
references.pmid: 11199948
references.citation: Pharmacol Biochem Behav. 1995 Jun-Jul;51(2-3):515-9
references.pmid: 7667378
references.citation: J Neurophysiol. 2002 May;87(5):2490-504
references.pmid: 11976386
references.citation: J Neurophysiol. 1999 Dec;82(6):2989-99
references.pmid: 10601434
references.citation: J Neurosci. 2001 Dec 15;21(24):9856-66
references.pmid: 11739593
references.citation: Cereb Cortex. 2004 Mar;14(3):281-99
references.pmid: 14754868
references.citation: Neuropsychopharmacology. 2003 Feb;28(2):402-12
references.pmid: 12589395
references.citation: J Neurophysiol. 2004 Mar;91(3):1171-82
references.pmid: 14602839
references.citation: Neuropsychopharmacology. 2005 Dec;30(12):2192-204
references.pmid: 15920504
references.citation: J Neurosci. 2003 Apr 15;23(8):3373-84
references.pmid: 12716945
references.citation: J Neurosci. 2004 May 19;24(20):4807-17
references.pmid: 15152041
references.citation: Neuroscience. 2007 Mar 30;145(3):900-10
references.pmid: 17293055
references.citation: Curr Neuropharmacol. 2006 Apr;4(2):127-38
references.pmid: 18615130
references.citation: Neuroscience. 2009 Feb 18;158(4):1406-15
references.pmid: 19111907
references.citation: Arch Gen Psychiatry. 1999 Aug;56(8):705-11
references.pmid: 10435604
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Neuropsychopharmacology. 2008 Feb;33(3):574-87
references.pmid: 17460614
references.citation: J Neurosci. 2007 Feb 7;27(6):1467-73
references.pmid: 17287521
references.citation: Neuroreport. 1995 Apr 19;6(6):901-4
references.pmid: 7612879
references.citation: Prog Brain Res. 2000;126:413-31
references.pmid: 11105660
references.citation: Int J Neuropsychopharmacol. 2009 Jul;12(6):761-72
references.pmid: 19102816
references.citation: J Child Psychol Psychiatry. 2007 Mar-Apr;48(3-4):224-44
references.pmid: 17355397
references.citation: Cereb Cortex. 2004 Oct;14(10):1100-9
references.pmid: 15115744
references.citation: J Membr Biol. 1997 Mar 1;156(1):73-85
references.pmid: 9070466
references.citation: Science. 2006 Jul 28;313(5786):536-40
references.pmid: 16873667
references.citation: Brain Res. 1996 Jan 15;706(2):259-66
references.pmid: 8822365
references.citation: J Physiol. 2001 Apr 1;532(Pt 1):143-63
references.pmid: 11283231
references.citation: Neurosci Biobehav Rev. 2005;29(8):1335-46
references.pmid: 16095695
references.citation: J Psychiatry Neurosci. 2004 Jul;29(4):252-65
references.pmid: 15309042
references.citation: South Med J. 2008 Jun;101(6):612-7
references.pmid: 18475223
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Neuroscience. 2000;98(2):295-300
references.pmid: 10854760
references.citation: J Pharmacol Exp Ther. 1997 Aug;282(2):699-706
references.pmid: 9262333
references.citation: Am J Psychiatry. 2001 Jan;158(1):78-85
references.pmid: 11136637
references.citation: Brain Res. 1996 Nov 11;739(1-2):57-69
references.pmid: 8955925
references.citation: Hum Psychopharmacol. 2000 Aug;15(6):397-415
references.pmid: 12404302
references.citation: J Neurochem. 1996 Sep;67(3):1145-52
references.pmid: 8752121
references.citation: Neuron. 1994 Mar;12(3):529-40
references.pmid: 7512349
references.citation: Neuron. 2006 Feb 16;49(4):547-62
references.pmid: 16476664
references.citation: Brain Res Bull. 2001 Nov 15;56(5):441-51
references.pmid: 11750789
references.citation: Neuropsychopharmacology. 2007 Jul;32(7):1504-19
references.pmid: 17164818
references.citation: J Neurosci. 2001 Jul 1;21(13):4609-24
references.pmid: 11425889
references.citation: J Neurosci. 1997 Apr 15;17(8):2785-95
references.pmid: 9092600
references.citation: J Psychiatr Res. 2003 Sep-Oct;37(5):357-73
references.pmid: 12849929
references.citation: Psychopharmacology (Berl). 2007 Mar;190(4):497-506
references.pmid: 17124620
references.citation: Br J Pharmacol. 1990 Feb;99(2):221-2
references.pmid: 1691671
references.citation: J Clin Psychiatry. 2005 Oct;66(10):1321-5
references.pmid: 16259547
references.citation: Dev Psychopathol. 2001 Summer;13(3):419-49
references.pmid: 11523842
references.citation: Nucl Recept Signal. 2003;1:e012
references.pmid: 16604184
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):55-60
references.pmid: 12551726
references.citation: Arch Gen Psychiatry. 2000 Sep;57(9):850-8
references.pmid: 10986548
references.citation: Neural Dev. 2009 May 18;4:17
references.pmid: 19450252
references.citation: Psychiatry Res. 1992 Dec;45(4):227-37
references.pmid: 1292040
references.citation: Metab Brain Dis. 2004 Jun;19(1-2):3-14
references.pmid: 15214501
references.citation: Neuroscience. 1997 Jan;76(2):441-8
references.pmid: 9015328
references.citation: Neurochem Int. 2006 Apr;48(5):350-7
references.pmid: 16423427
references.citation: Neuroscience. 2004;123(3):725-32
references.pmid: 14706784
references.citation: Nat Neurosci. 2010 May;13(5):622-9
references.pmid: 20383137
references.citation: Neuropharmacology. 2000 Jan 28;39(3):463-70
references.pmid: 10698012
references.citation: Biol Psychiatry. 1999 May 1;45(9):1085-98
references.pmid: 10331101
references.citation: Nat Neurosci. 2000 Oct;3(10):1027-34
references.pmid: 11017176
references.citation: J Neurosci. 2004 Jun 16;24(24):5603-10
references.pmid: 15201333
references.citation: Front Neurosci. 2010 Aug 13;4:
references.pmid: 20802802
references.citation: Neuropharmacology. 2007 Jun;52(8):1671-7
references.pmid: 17493641
references.citation: Brain Res Dev Brain Res. 1991 Jan 15;58(1):51-8
references.pmid: 2015654
references.citation: J Neurosci. 2003 Apr 1;23(7):2779-88
references.pmid: 12684464
references.citation: Synapse. 2001 Apr;40(1):1-10
references.pmid: 11170216
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):416-8
references.pmid: 19166896
references.citation: Cereb Cortex. 2005 Jan;15(1):1-14
references.pmid: 15238448
references.citation: J Clin Psychopharmacol. 2008 Apr;28(2):156-65
references.pmid: 18344725
references.citation: Neuron. 2009 Jun 11;62(5):655-69
references.pmid: 19524525