title: Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex.
abstract: Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin-2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.
authors.affiliation: Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; Department of Psychiatry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Electronic address: cxn18@case.edu.
authors.forename: C
authors.initials: C
authors.lastname: Nocjar
authors.affiliation: Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Electronic address: ktlx11@yahoo.com.
authors.forename: K D
authors.initials: KD
authors.lastname: Alex
authors.affiliation: Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA. Electronic address: sonneborn.alex@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Sonneborn
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: atheirabbas@gmail.com.
authors.forename: A I
authors.initials: AI
authors.lastname: Abbas
authors.affiliation: Department of Pharmacology, University of North Carolina-Chapel Hill School of Medicine, 120 Mason Farm Road, 4072 Genetic Medicine Building, Campus Box 7365, Chapel Hill, NC 27599-7365, USA. Electronic address: bryan_roth@med.unc.edu.
authors.forename: B L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Psychiatry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Electronic address: eap6@case.edu.
authors.forename: E A
authors.initials: EA
authors.lastname: Pehek
mesh_terms: D000818:Animals; D002452:Cell Count; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: 5-HT; 5-HT(2A) receptor; 5-HT(2C) receptor; GABA; immunofluorescence; pyramidal
references.citation: Mol Phys. 2014 Jan 1;112(3-4):398-407
references.pmid: 24729635
references.citation: Psychopharmacology (Berl). 2011 Feb;213(2-3):307-20
references.pmid: 21079923
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):735-40
references.pmid: 9435262
references.citation: J Neurosci. 2014 Jun 4;34(23):7931-46
references.pmid: 24899715
references.citation: J Neurosci. 2001 Dec 15;21(24):9856-66
references.pmid: 11739593
references.citation: Neuropsychopharmacology. 2006 Apr;31(4):757-67
references.pmid: 16192987
references.citation: Biochem Pharmacol. 2008 Nov 15;76(10):1276-87
references.pmid: 18812172
references.citation: J Neurochem. 1999 Oct;73(4):1711-7
references.pmid: 10501219
references.citation: Neuron. 2002 Mar 28;34(1):13-25
references.pmid: 11931738
references.citation: Schizophr Res. 2002 Sep 1;57(1):27-34
references.pmid: 12165373
references.citation: Eur J Neurosci. 1999 Aug;11(8):2917-34
references.pmid: 10457188
references.citation: J Pharmacol Exp Ther. 1988 Sep;246(3):924-8
references.pmid: 2843634
references.citation: Brain Res. 1999 Apr 17;825(1-2):161-71
references.pmid: 10216183
references.citation: Cortex. 2013 May;49(5):1195-205
references.pmid: 22789779
references.citation: Psychopharmacology (Berl). 2006 Apr;185(3):274-81
references.pmid: 16521036
references.citation: Cereb Cortex. 2004 Mar;14(3):281-99
references.pmid: 14754868
references.citation: Semin Clin Neuropsychiatry. 2001 Apr;6(2):102-12
references.pmid: 11296310
references.citation: Mol Cell Neurosci. 2004 Apr;25(4):650-63
references.pmid: 15080894
references.citation: J Comp Neurol. 1999 Jun 28;409(2):187-209
references.pmid: 10379914
references.citation: J Neurosci. 1997 Nov 1;17(21):8528-35
references.pmid: 9334425
references.citation: Mol Cell Neurosci. 2008 Jun;38(2):290-9
references.pmid: 18455431
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L471-8
references.pmid: 18621911
references.citation: Neuroscience. 2007 Mar 30;145(3):900-10
references.pmid: 17293055
references.citation: Neuropharmacology. 2005 Dec;49(8):1228-34
references.pmid: 16229866
references.citation: Psychopharmacology (Berl). 1997 Oct;133(4):329-42
references.pmid: 9372531
references.citation: Brain Res. 2010 Feb 2;1312:127-37
references.pmid: 19948151
references.citation: Brain Res Mol Brain Res. 1994 Apr;23(1-2):163-78
references.pmid: 8028479
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):45-56
references.pmid: 17180162
references.citation: J Neurosci. 2002 Aug 15;22(16):6846-55
references.pmid: 12177182
references.citation: Neuropsychopharmacology. 2015 Jul;40(8):1957-68
references.pmid: 25666313
references.citation: Neuropsychopharmacology. 2002 Sep;27(3):430-41
references.pmid: 12225700
references.citation: Brain Res. 1988 Jun 21;453(1-2):315-28
references.pmid: 3401769
references.citation: J Clin Invest. 2013 Dec;123(12):4986-91
references.pmid: 24292660
references.citation: Mol Pharmacol. 1998 Jul;54(1):94-104
references.pmid: 9658194
references.citation: Behav Brain Res. 2003 Nov 30;146(1-2):105-19
references.pmid: 14643464
references.citation: Trends Pharmacol Sci. 2008 Sep;29(9):454-64
references.pmid: 18676031
references.citation: J Pharmacol Exp Ther. 1990 Jan;252(1):171-8
references.pmid: 2137174
references.citation: Neuropharmacology. 2009 Feb;56(2):507-13
references.pmid: 18977370
references.citation: Neuropsychopharmacology. 2006 Feb;31(2):265-77
references.pmid: 15999145
references.citation: Prog Brain Res. 2000;126:413-31
references.pmid: 11105660
references.citation: Br J Pharmacol. 1999 Sep;128(1):13-20
references.pmid: 10498829
references.citation: J Int Neuropsychol Soc. 2006 Mar;12(2):248-60
references.pmid: 16573858
references.citation: Psychopharmacology (Berl). 2002 May;161(3):263-70
references.pmid: 12021829
references.citation: J Biol Chem. 2002 Mar 29;277(13):11441-9
references.pmid: 11801601
references.citation: Neuroscience. 2012 Aug 30;218:138-53
references.pmid: 22626650
references.citation: Cereb Cortex. 2004 Oct;14(10):1100-9
references.pmid: 15115744
references.citation: Brain Cogn. 2012 Nov;80(2):237-49
references.pmid: 22935543
references.citation: J Neurosci. 2000 Aug 15;20(16):6225-31
references.pmid: 10934272
references.citation: Neuropsychopharmacology. 2005 Dec;30(12):2180-91
references.pmid: 15841107
references.citation: J Biol Chem. 2004 Jan 23;279(4):2945-54
references.pmid: 14602721
references.citation: Psychopharmacology (Berl). 2012 Jan;219(2):401-10
references.pmid: 22101355
references.citation: Neurobiol Dis. 2010 Aug;39(2):169-80
references.pmid: 20394819
references.citation: J Comp Neurol. 2000 Feb 14;417(3):337-48
references.pmid: 10683608
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):1120-6
references.pmid: 11082448
references.citation: Mol Pharmacol. 2002 Dec;62(6):1339-43
references.pmid: 12435801
references.citation: Neuropsychopharmacology. 2002 Jun;26(6):716-28
references.pmid: 12007742
references.citation: Ann N Y Acad Sci. 1998 Dec 15;861:111-20
references.pmid: 9928247
references.citation: J Psychiatry Neurosci. 2004 Jul;29(4):252-65
references.pmid: 15309042
references.citation: J Neurosci. 2009 Jun 3;29(22):7124-36
references.pmid: 19494135
references.citation: J Comp Physiol Psychol. 1971 Nov;77(2):212-20
references.pmid: 5000659
references.citation: J Pharmacol Exp Ther. 2000 Jan;292(1):76-87
references.pmid: 10604933
references.citation: Cortex. 2013 Jul-Aug;49(7):1790-800
references.pmid: 23206529
references.citation: Cereb Cortex. 1996 May-Jun;6(3):470-81
references.pmid: 8670672
references.citation: Brain Res. 1985 Nov 4;346(2):231-49
references.pmid: 4052777
references.citation: J Neurosci. 2002 Apr 1;22(7):2843-54
references.pmid: 11923449
references.citation: J Nerv Ment Dis. 1998 Dec;186(12):737-45
references.pmid: 9865811
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: BMC Neurosci. 2012 Mar 07;13:25
references.pmid: 22397586
references.citation: Neuropsychologia. 1987;25(2):359-65
references.pmid: 3601041
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):793-807
references.pmid: 15378039
references.citation: Arch Int Pharmacodyn Ther. 1982 Apr;256(2):301-5
references.pmid: 7103617
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1997 Oct;356(4):446-54
references.pmid: 9349630
references.citation: Brain Res Mol Brain Res. 1999 Aug 25;71(2):358-63
references.pmid: 10521592
references.citation: Neuroscience. 1991;40(2):399-412
references.pmid: 1851255
references.citation: Curr Top Med Chem. 2006;6(18):1971-85
references.pmid: 17017968
references.citation: Therapie. 2005 Sep-Oct;60(5):441-60
references.pmid: 16433010
references.citation: J Neurosci. 2000 Feb 1;20(3):1208-15
references.pmid: 10648725
references.citation: Neuroscience. 1999;91(2):599-606
references.pmid: 10366017
references.citation: Psychopharmacology (Berl). 2004 Nov;176(3-4):376-85
references.pmid: 15232674
references.citation: Arch Gen Psychiatry. 2001 Apr;58(4):345-52
references.pmid: 11296095
references.citation: J Neurochem. 2014 Nov;131(4):432-43
references.pmid: 25073477
references.citation: ScientificWorldJournal. 2010 Sep 14;10:1870-85
references.pmid: 20852829
references.citation: Front Neurosci. 2009 Dec 15;3(3):337-43
references.pmid: 20198150
references.citation: Psychopharmacology (Berl). 2003 Jan;165(2):136-45
references.pmid: 12420150
references.citation: J Neurochem. 2010 Jun;113(6):1504-15
references.pmid: 20345755
references.citation: Neurosci Lett. 1998 Dec 24;258(3):179-82
references.pmid: 9885960
references.citation: Biol Psychiatry. 2008 Dec 15;64(12):1026-34
references.pmid: 18823880
references.citation: Brain Res Bull. 2001 Nov 15;56(5):441-51
references.pmid: 11750789
references.citation: Neuropharmacology. 2000;39(1):123-32
references.pmid: 10665825
references.citation: Br J Pharmacol. 2001 Sep;134(2):386-92
references.pmid: 11564657
references.citation: Brain Res Brain Res Rev. 2000 Mar;31(2-3):302-12
references.pmid: 10719157
references.citation: Neuron. 2005 Mar 3;45(5):651-60
references.pmid: 15748841
references.citation: J Neurosci. 2010 Dec 1;30(48):16082-90
references.pmid: 21123555
references.citation: Pharmacol Biochem Behav. 2002 Apr;71(4):533-54
references.pmid: 11888546
references.citation: Neuropsychopharmacology. 2014 Jan;39(2):370-82
references.pmid: 23939424
references.citation: J Neurosci. 2014 Aug 27;34(35):11519-25
references.pmid: 25164650
references.citation: Psychopharmacology (Berl). 1999 Mar;143(1):89-96
references.pmid: 10227084
references.citation: Trends Pharmacol Sci. 2005 Dec;26(12):625-30
references.pmid: 16269190
references.citation: Ann N Y Acad Sci. 1998 Dec 15;861:121-7
references.pmid: 9928248
references.citation: J Pharmacol Exp Ther. 2011 Oct;339(1):99-105
references.pmid: 21737536
references.citation: Neuropsychopharmacology. 1999 Jan;20(1):92-6
references.pmid: 9885788
references.citation: Neuroscience. 2007 Jun 8;146(4):1677-88
references.pmid: 17467185
references.citation: Neuron. 1995 Mar;14(3):477-85
references.pmid: 7695894
references.citation: Psychopharmacology (Berl). 2003 May;167(3):304-14
references.pmid: 12677356
references.citation: Brain Res. 1990 Jul 30;524(1):139-43
references.pmid: 2400925
references.citation: Pharmacol Ther. 2007 Feb;113(2):296-320
references.pmid: 17049611
references.citation: Neuroscience. 1999;92(2):601-11
references.pmid: 10408609
references.citation: Mol Pharmacol. 2010 Nov;78(5):818-26
references.pmid: 20699324
references.citation: Physiol Behav. 1998 Jun 1;64(3):373-80
references.pmid: 9748107
references.citation: Nature. 1997 May 15;387(6630):303-8
references.pmid: 9153397
references.citation: Synapse. 1997 Sep;27(1):79-82
references.pmid: 9268067
references.citation: Neuropsychopharmacology. 2010 Sep;35(10):2037-48
references.pmid: 20520599
references.citation: Mol Psychiatry. 2014 Oct;19(10):1106-14
references.pmid: 24166413
references.citation: Neurochem Res. 2006 Feb;31(2):167-76
references.pmid: 16673176
references.citation: J Comp Neurol. 1995 Jan 16;351(3):357-73
references.pmid: 7706547
references.citation: J Pharmacol Exp Ther. 2001 Oct;299(1):83-9
references.pmid: 11561066
references.citation: Pharmacol Ther. 1998 Sep;79(3):231-57
references.pmid: 9776378
references.citation: J Pharmacol Exp Ther. 2003 Aug;306(2):734-43
references.pmid: 12721337
references.citation: J Neurosci. 2010 Feb 10;30(6):2211-22
references.pmid: 20147548
references.citation: Trends Pharmacol Sci. 2001 May;22(5):229-32
references.pmid: 11339973
references.citation: Nat Med. 2001 May;7(5):541-7
references.pmid: 11329053
references.citation: Mol Pharmacol. 1999 May;55(5):863-72
references.pmid: 10220565
references.citation: Behav Neurosci. 1997 Oct;111(5):920-36
references.pmid: 9383514
references.citation: Exp Brain Res. 2013 Oct;230(4):395-406
references.pmid: 23864045
references.citation: Neuroscience. 1995 Dec;69(3):903-13
references.pmid: 8596658
references.citation: Nat Neurosci. 2010 May;13(5):622-9
references.pmid: 20383137
references.citation: Schizophr Bull. 2007 Nov;33(6):1284-90
references.pmid: 17656637
references.citation: Nucleic Acids Res. 2010 Jun;38(10):e118
references.pmid: 20185571
references.citation: Neuropsychopharmacology. 2001 Mar;24(3):319-29
references.pmid: 11166521
references.citation: J Neurochem. 1986 Dec;47(6):1754-60
references.pmid: 3021903
references.citation: Eur J Pharmacol. 2004 Sep 13;498(1-3):59-69
references.pmid: 15363976
references.citation: Neuropsychologia. 1974 Jul;12(3):323-30
references.pmid: 4421777
references.citation: Neuropsychopharmacology. 2004 Sep;29(9):1637-47
references.pmid: 15127084
references.citation: J Neural Transm (Vienna). 1998;105(4-5):365-96
references.pmid: 9720968
references.citation: Exp Neurol. 2009 Sep;219(1):239-48
references.pmid: 19500571
references.citation: Am J Physiol. 1999 Feb;276(2):C395-403
references.pmid: 9950767
references.citation: J Comp Neurol. 1996 Apr 08;367(3):431-43
references.pmid: 8698902
references.citation: Neuropharmacology. 1984 Oct;23(10):1223-5
references.pmid: 6521858
references.citation: Dialogues Clin Neurosci. 2004 Jun;6(2):185-97
references.pmid: 22033633
references.citation: J Comp Neurol. 1997 Jan 27;377(4):465-99
references.pmid: 9007187
references.citation: Life Sci. 2003 Apr 18;72(22):2429-49
references.pmid: 12650852
references.citation: Neuroscience. 1987 Apr;21(1):97-122
references.pmid: 2955249
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: Ann N Y Acad Sci. 1998 Dec 15;861:38-48
references.pmid: 9928237
references.citation: J Neurosci. 2007 Nov 7;27(45):12123-31
references.pmid: 17989278
references.citation: Annu Rev Med. 2009;60:355-66
references.pmid: 19630576
references.citation: J Neuroendocrinol. 2005 Oct;17(10):672-8
references.pmid: 16159380
references.citation: Neurotox Res. 2008 Oct;14(2-3):185-9
references.pmid: 19073425
references.citation: Neuron. 1996 Apr;16(4):815-23
references.pmid: 8607999
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: J Comp Neurol. 1994 Mar 1;341(1):95-116
references.pmid: 8006226
references.citation: J Pharmacol Exp Ther. 1992 Mar;260(3):1361-5
references.pmid: 1347569
references.citation: Neuropsychopharmacology. 2011 Feb;36(3):638-51
references.pmid: 21048700
references.citation: Psychopharmacology (Berl). 1994 Oct;116(2):143-51
references.pmid: 7862943
references.citation: Expert Opin Ther Targets. 2004 Feb;8(1):15-23
references.pmid: 14996615
references.citation: Cereb Cortex. 2008 Jan;18(1):178-88
references.pmid: 17517682
references.citation: Pharmacol Rev. 1994 Jun;46(2):157-203
references.pmid: 7938165
references.citation: Synapse. 2001 Oct;42(1):12-26
references.pmid: 11668587
references.citation: Behav Brain Res. 2011 Aug 1;221(1):63-74
references.pmid: 21376088
references.citation: Psychopharmacology (Berl). 1996 Jun;125(4):285-345
references.pmid: 8826538
references.citation: Cereb Cortex. 2002 Dec;12(12):1254-68
references.pmid: 12427677
references.citation: Biol Psychiatry. 2011 Apr 15;69(8):754-61
references.pmid: 21292242
references.citation: Neuroscience. 2002;111(1):163-76
references.pmid: 11955720
references.citation: ACS Chem Neurosci. 2013 Jan 16;4(1):110-21
references.pmid: 23336050
references.citation: J Biol Chem. 2008 Jun 20;283(25):17194-204
references.pmid: 18442977
references.citation: J Comp Neurol. 1997 Jul 28;384(2):233-47
references.pmid: 9215720