title: Imbalances in prefrontal cortex CC-Homer1 versus CC-Homer2 expression promote cocaine preference.
abstract: Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmission in vivo and support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward.
authors: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106-9660, USA.
authors: Alexis W
authors: AW
authors: Ary
authors: Kevin D
authors: KD
authors: Lominac
authors: Melissa G
authors: MG
authors: Wroten
authors: Amy R
authors: AR
authors: Williams
authors: Rianne R
authors: RR
authors: Campbell
authors: Osnat
authors: O
authors: Ben-Shahar
authors: Georg
authors: G
authors: von Jonquieres
authors: Matthias
authors: M
authors: Klugmann
authors: Karen K
authors: KK
authors: Szumlinski
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D000072233:Homer Scaffolding Proteins; D007266:Inhibition, Psychological; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming
chemical_list: D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606625:Homer2 protein, mouse; D034741:RNA, Small Interfering; D013549:Sweetening Agents; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D013395:Sucrose; D003042:Cocaine
references: J Neurochem. 1990 Dec;55(6):2091-7
references: 1977889
references: J Neurosci. 2013 Jan 9;33(2):495-506a
references: 23303930
references: Genome Biol. 2007;8(2):206
references: 17316461
references: Psychopharmacology (Berl). 2000 Aug;151(2-3):99-120
references: 10972458
references: Neurosci Lett. 2009 Mar 13;452(2):167-71
references: 19118598
references: Ann N Y Acad Sci. 2010 Feb;1187:35-75
references: 20201846
references: J Neurosci. 2003 Apr 15;23(8):3531-7
references: 12716962
references: Eur J Neurosci. 2003 Sep;18(6):1645-51
references: 14511343
references: Curr Opin Pharmacol. 2009 Feb;9(1):59-64
references: 19157986
references: Alcohol Clin Exp Res. 2012 Sep;36(9):1623-33
references: 22432643
references: Neurosci Biobehav Rev. 2003 Oct;27(6):555-79
references: 14599436
references: Mol Psychiatry. 2011 Oct;16(10):974-86
references: 21519339
references: J Neurosci. 2010 Jun 9;30(23):7984-92
references: 20534846
references: J Neurosci. 2009 Oct 28;29(43):13603-12
references: 19864572
references: Psychopharmacology (Berl). 2003 Jul;168(1-2):66-74
references: 12442201
references: Neuropharmacology. 2013 Mar;66:302-10
references: 22659088
references: Eur J Neurosci. 2004 Sep;20(6):1639-46
references: 15355331
references: Synapse. 2009 Jul;63(7):598-609
references: 19306440
references: Brain Res. 2007 Dec 12;1184:295-305
references: 17950706
references: Genes Brain Behav. 2005 Jul;4(5):273-88
references: 16011574
references: J Pharmacol Exp Ther. 2002 Nov;303(2):608-15
references: 12388642
references: Addict Biol. 2008 Sep;13(3-4):310-25
references: 18331369
references: Neuropsychopharmacology. 2006 Apr;31(4):768-77
references: 16160706
references: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6055-60
references: 17389377
references: Mol Cell Neurosci. 2005 Feb;28(2):347-60
references: 15691715
references: Addict Biol. 2012 Jul;17(4):746-57
references: 22339852
references: J Neurosci. 2005 Dec 14;25(50):11586-94
references: 16354916
references: Nat Rev Neurosci. 2011 Oct 20;12(11):652-69
references: 22011681
references: J Neurosci. 1996 Feb 15;16(4):1550-60
references: 8778304
references: J Neurosci. 2008 Jun 4;28(23):6046-53
references: 18524910
references: Neuron. 2004 Aug 5;43(3):401-13
references: 15294147
references: J Neurosci. 2006 Aug 16;26(33):8492-501
references: 16914674
references: Nature. 1977 Apr 21;266(5604):730-2
references: 559941
references: J Pharmacol Exp Ther. 2005 Jul;314(1):139-47
references: 15769865
references: Neuropsychopharmacology. 2008 May;33(6):1365-78
references: 17568396
references: J Neurosci. 2007 Jun 6;27(23):6249-60
references: 17553998
references: J Neurosci. 2010 Jan 6;30(1):210-7
references: 20053903
references: Biochem Pharmacol. 2008 Jan 1;75(1):218-65
references: 17706608
references: Neuropsychopharmacology. 2007 Aug;32(8):1760-73
references: 17251912
references: Neuroscience. 1993 Feb;52(3):605-20
references: 8450962
references: J Neurosci. 2000 Oct 1;20(19):7238-45
references: 11007880
references: Behav Brain Res. 1998 Dec;97(1-2):115-27
references: 9867237
references: Neurobiol Aging. 2003 Jan-Feb;24(1):37-48
references: 12493549
references: J Comp Neurol. 1992 Jun 8;320(2):145-60
references: 1377716
references: J Neurosci. 2001 Nov 15;21(22):9043-52
references: 11698615
references: Biochem Pharmacol. 2008 Jan 1;75(1):112-33
references: 17765204
references: Nat Neurosci. 2003 Jul;6(7):743-9
references: 12778052
references: J Neurosci. 2005 Jul 27;25(30):7054-61
references: 16049182
references: Neuropsychopharmacology. 2012 Feb;37(3):707-22
references: 22030712
references: Behav Pharmacol. 2008 Sep;19(5-6):485-500
references: 18690104
references: Psychopharmacology (Berl). 1989;98(3):357-62
references: 2546170
references: Neurosci Biobehav Rev. 2010 Nov;35(2):185-211
references: 20109488
references: Neuropharmacology. 2009;56 Suppl 1:177-85
references: 18565549
references: Neuroscience. 2009 Mar 3;159(1):414-26
references: 19105975
references: Psychopharmacology (Berl). 2003 Jul;168(1-2):44-56
references: 12652346
references: Biol Psychiatry. 2010 Jan 1;67(1):81-4
references: 19717140
references: Genes Brain Behav. 2011 Feb;10(1):111-26
references: 20807241
references: J Neurosci. 2008 Aug 20;28(34):8560-7
references: 18716215
references: Brain Res. 2011 Sep 21;1413:60-71
references: 21855055
references: J Neurosci. 2009 Jul 8;29(27):8655-68
references: 19587272
references: Mol Pharmacol. 2007 Sep;72(3):612-21
references: 17584991
references: Alcohol Clin Exp Res. 2008 Apr;32(4):617-31
references: 18341649