title: Elevated Expression of Serotonin 5-HT(2A) Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine.
abstract: The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT(2A) receptors (5-HT(2A)R) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT(2A)R in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT(2A)R linked to a synthetic marker peptide (Flag) was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT(2A)R-Flag). This viral vector (2 μl; 10(9-10) transducing units/ml) was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer's solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip), both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p < 0.05). Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT(2A)R protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT(2A)R in the VTA and suggest that the 5-HT(2A)R receptor in the VTA plays a role in regulation of responsiveness to cocaine.
authors: Center for Addiction Research, University of Texas Medical Branch Galveston, TX, USA ; Department of Pharmacology and Toxicology, University of Texas Medical Branch Galveston, TX, USA.
authors: David V
authors: DV
authors: Herin
authors: Marcy J
authors: MJ
authors: Bubar
authors: Patricia K
authors: PK
authors: Seitz
authors: Mary L
authors: ML
authors: Thomas
authors: Gilbert R
authors: GR
authors: Hillman
authors: Yevgeniya I
authors: YI
authors: Tarasenko
authors: Ping
authors: P
authors: Wu
authors: Kathryn A
authors: KA
authors: Cunningham
keywords: 5-HT2A receptor; AAV; cocaine; locomotor activity; psychostimulants; serotonin; ventral tegmental area; virally mediated gene transfer
references: Neuroscience. 2003;116(1):107-17
references: 12535944
references: Psychopharmacology (Berl). 1994 Jun;115(1-2):110-4
references: 7862881
references: J Pharmacol Exp Ther. 2004 Sep;310(3):1246-54
references: 15131246
references: Psychopharmacology (Berl). 2011 Feb;213(2-3):307-20
references: 21079923
references: J Pharmacol Exp Ther. 2000 Feb;292(2):610-7
references: 10640298
references: J Virol. 1998 Mar;72(3):2224-32
references: 9499080
references: Brain Res. 1996 Mar 25;713(1-2):99-107
references: 8724980
references: Neuroscience. 2007 Apr 25;146(1):286-97
references: 17367945
references: Neuropsychopharmacology. 2002 Oct;27(4):576-86
references: 12377394
references: J Comp Neurol. 1979 Sep 1;187(1):85-98
references: 489779
references: J Comp Neurol. 1999 Jun 28;409(2):187-209
references: 10379914
references: J Neurosci. 2003 Aug 20;23(20):7569-76
references: 12930795
references: Pharmacol Biochem Behav. 1998 Mar;59(3):595-611
references: 9512061
references: Neuropharmacology. 2011 Sep;61(3):468-77
references: 21402085
references: Brain Res. 2005 Nov 30;1063(2):105-13
references: 16274677
references: Mol Pharmacol. 1994 May;45(5):826-36
references: 8190100
references: J Chem Neuroanat. 2001 Sep;22(3):185-203
references: 11522440
references: Neuropsychopharmacology. 2002 Sep;27(3):430-41
references: 12225700
references: Prog Brain Res. 2008;172:319-46
references: 18772040
references: Eur J Pharmacol. 1976 Nov;40(1):45-56
references: 1033072
references: Pharmacol Biochem Behav. 1991 Dec;40(4):775-80
references: 1816565
references: Mol Cell Neurosci. 2001 May;17(5):855-71
references: 11358483
references: Brain Res. 1993 Jun 25;615(1):113-20
references: 7689908
references: Trends Pharmacol Sci. 2006 Feb;27(2):105-12
references: 16406129
references: Lancet. 2007 Jun 23;369(9579):2097-105
references: 17586305
references: J Neurochem. 1986 Aug;47(2):529-40
references: 2942638
references: Psychopharmacology (Berl). 2006 Jan;183(4):482-9
references: 16261316
references: Gene Ther. 2002 Feb;9(4):245-55
references: 11896463
references: Prog Neuropsychopharmacol Biol Psychiatry. 2004 May;28(3):547-57
references: 15093963
references: Circulation. 2000 Dec 5;102(23):2836-41
references: 11104741
references: Science. 1997 Aug 8;277(5327):812-4
references: 9242609
references: J Neurosci. 1994 Nov;14(11 Pt 1):6744-53
references: 7965075
references: J Neurosci. 2001 Oct 1;21(19):7781-7
references: 11567068
references: Neuroscience. 2002;113(1):23-35
references: 12123681
references: Brain Res Bull. 2000 Apr;51(6):499-505
references: 10758340
references: Neuropsychopharmacology. 1999 Jun;20(6):556-64
references: 10327425
references: J Neurochem. 1999 Sep;73(3):1033-42
references: 10461892
references: J Pharmacol Exp Ther. 1995 Dec;275(3):1638-46
references: 8531139
references: PLoS One. 2011;6(6):e20508
references: 21687728
references: Addict Biol. 2010 Jul;15(3):227-49
references: 20456287
references: Brain Res. 2000 Jan 24;853(2):377-80
references: 10640637
references: Biol Psychiatry. 2005 Mar 15;57(6):617-23
references: 15780848
references: Behav Neurosci. 2009 Apr;123(2):382-96
references: 19331461
references: Brain Res Bull. 1982 Jul-Dec;9(1-6):321-53
references: 6816390
references: Mol Ther. 2005 Jun;11(6):843-8
references: 15922954
references: Brain Res. 1998 May 18;793(1-2):169-75
references: 9630611
references: Pharmacol Biochem Behav. 2002 Apr;71(4):533-54
references: 11888546
references: Eur J Neurosci. 2007 Jan;25(1):106-18
references: 17241272
references: J Neurosci. 1990 Jan;10(1):303-10
references: 2299396
references: Trends Pharmacol Sci. 2005 Dec;26(12):625-30
references: 16269190
references: Behav Neurosci. 2007 Dec;121(6):1224-33
references: 18085876
references: Behav Neurosci. 2005 Oct;119(5):1173-83
references: 16300424
references: Psychopharmacology (Berl). 2005 Apr;178(4):505-13
references: 15765263
references: Drug Alcohol Depend. 2006 Feb 28;81(3):275-82
references: 16146672
references: Brain Res Bull. 1989 Apr;22(4):725-35
references: 2736398
references: J Neurosci. 2001 Sep 15;21(18):7397-403
references: 11549750
references: Brain Res Rev. 2007 Nov;56(1):27-78
references: 17574681
references: Neuroscience. 2007 Jun 8;146(4):1677-88
references: 17467185
references: J Pharmacol Exp Ther. 2001 Apr;297(1):357-63
references: 11259563
references: Pharmacol Ther. 2007 Feb;113(2):296-320
references: 17049611
references: Science. 2006 Dec 22;314(5807):1866-8
references: 17185580
references: Pharmacol Biochem Behav. 1999 Jun;63(2):237-43
references: 10371652
references: J Neurosci. 2013 Jan 23;33(4):1615-30
references: 23345234
references: Eur J Pharmacol. 1992 Nov 13;223(1):65-74
references: 1362159
references: Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):11-26
references: 14965241
references: Front Mol Neurosci. 2011 Dec 26;4:57
references: 22207836
references: Pharmacol Biochem Behav. 2002 Apr;71(4):745-56
references: 11888566
references: Neuropharmacology. 2004 Mar;46(4):504-10
references: 14975674
references: Behav Brain Res. 2008 Dec 16;195(1):39-53
references: 18639587
references: Psychopharmacology (Berl). 1997 Mar;130(1):41-58
references: 9089847
references: J Pharmacol Exp Ther. 1976 Dec;199(3):649-61
references: 994022
references: J Neurochem. 1994 Nov;63(5):1701-13
references: 7931325
references: Behav Pharmacol. 2011 Jun;22(3):248-61
references: 21499079
references: J Comp Neurol. 2000 Nov 13;427(2):220-34
references: 11054690
references: J Physiol. 1992 May;450:455-68
references: 1331427
references: Brain Res. 2003 May 16;972(1-2):216-21
references: 12711095
references: J Neurochem. 2007 Mar;100(6):1449-57
references: 17241127
references: Eur J Neurosci. 2003 Jul;18(2):403-11
references: 12887422
references: J Neurochem. 2004 Oct;91(2):318-26
references: 15447665
references: Drug Alcohol Depend. 2006 Feb 1;81(2):117-27
references: 16054778
references: Hum Gene Ther. 1999 Jan 20;10(2):201-13
references: 10022545
references: Psychopharmacology (Berl). 2011 Feb;213(2-3):321-35
references: 20814782
references: Brain Res. 2000 May 12;864(2):176-85
references: 10802024
references: Neuroscience. 1999;91(2):587-97
references: 10366016
references: Neuropharmacology. 2003 Mar;44(3):342-53
references: 12604093
references: Neuroscience. 2002;111(1):163-76
references: 11955720
references: ACS Chem Neurosci. 2013 Jan 16;4(1):110-21
references: 23336050
references: Brain Res. 1994 Aug 22;654(2):324-30
references: 7987681