Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization.
BACKGROUND
All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; however, there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Recent data suggest that D2Rs form dimers in-vitro and in-vivo, and we hypothesized that schizophrenia, as well as preclinical models of schizophrenia, would demonstrate altered dimerization of D2Rs, even though the overall number of D2Rs was unaltered.


METHODS
We measured the expression of D2Rs dimers and monomers in patients with schizophrenia using Western blots, and then in striatal tissue from rats exhibiting the amphetamine-induced sensitized state (AISS). We further examined the interaction between D2Rs and the dopamine transporter (DAT) by co-immunoprecipitation, and measured the expression of dopamine D2High receptors with ligand binding assays in rat striatum slices with or without acute amphetamine pre-treatment.


RESULTS
We observed significantly enhanced expression of D2Rs dimers (277.7 ± 33.6%) and decreased expression of D2Rs monomers in post-mortem striatal tissue of schizophrenia patients. We found that amphetamine facilitated D2Rs dimerization in both the striatum of AISS rats and in rat striatal neurons. Furthermore, amphetamine-induced D2Rs dimerization may be associated with the D2R-DAT protein-protein interaction as an interfering peptide that disrupts the D2R-DAT coupling, blocked amphetamine-induced up-regulation of D2Rs dimerization.


CONCLUSIONS
Given the fact that amphetamine induces psychosis and that the AISS rat is a widely accepted animal model of psychosis, our data suggest that D2R dimerization may be important in the pathophysiology of schizophrenia and may be a promising new target for novel antipsychotic drugs.
Wang
Min
M
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Pei
Lin
L
Fletcher
Paul J
PJ
Kapur
Shitij
S
Seeman
Philip
P
Liu
Fang
F
D000368:Aged; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D004298:Dopamine
J Neural Transm Suppl. 1983;18:165-79
6192208
Synapse. 2007 May;61(5):263-7
17318886
Nat Rev Drug Discov. 2002 Oct;1(10):808-20
12360258
Nature. 2000 Jan 20;403(6767):274-80
10659839
Science. 2002 Oct 25;298(5594):846-50
12399596
FEBS Lett. 1998 Dec 28;441(3):383-6
9891976
Brain Res Rev. 2008 Aug;58(2):415-52
18222544
Cell. 2002 Oct 18;111(2):219-30
12408866
Schizophr Bull. 2009 May;35(3):549-62
19325164
Nat Chem Biol. 2009 Sep;5(9):608-9
19690532
Ann Nucl Med. 2002 Nov;16(7):437-46
12508833
Biochem Biophys Res Commun. 1996 Oct 3;227(1):200-4
8858125
Biochem Pharmacol. 2005 May 15;69(10):1451-61
15857609
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):654-9
17194762
Biochemistry. 2003 Sep 23;42(37):11023-31
12974638
Mol Pharmacol. 2000 Mar;57(3):446-52
10692483
J Neurochem. 1994 Nov;63(5):1589-95
7931316
J Neurochem. 1984 Jul;43(1):221-35
6726248
Eur J Pharmacol. 1992 Oct 1;227(2):139-46
1358662
J Biol Chem. 1999 Jul 9;274(28):19894-900
10391935
Mol Biol Cell. 2004 Feb;15(2):696-705
14617818
J Biol Chem. 2007 Jul 20;282(29):21285-300
17395585
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8
15716360
Cell Signal. 2007 Sep;19(9):1928-38
17561373
Synapse. 2003 Sep 15;49(4):209-15
12827639
Synapse. 2006 Sep 15;60(4):319-46
16786561
Nat Chem Biol. 2008 Feb;4(2):126-31
18193048
EMBO J. 2007 Apr 18;26(8):2127-36
17380124
Biochem J. 2008 Jun 1;412(2):245-56
18307412
J Neurochem. 2008 Jul;106(1):83-95
18346199
Neuropsychopharmacology. 2003 Aug;28(8):1433-9
12838271
Science. 2000 Apr 7;288(5463):154-7
10753124
J Neurosci. 2002 Oct 1;22(19):8476-86
12351722
J Biol Chem. 2004 Aug 20;279(34):35671-8
15159403
J Neurosci. 1998 Mar 15;18(6):1979-86
9482784
Biochem Pharmacol. 1975 Apr 15;24(8):847-52
1125084
J Biol Chem. 2001 Aug 10;276(32):30308-14
11373283
Schizophr Res. 2009 Apr;109(1-3):191-2
19171464
Arch Gen Psychiatry. 2005 Apr;62(4):371-8
15809404
Ann N Y Acad Sci. 2004 Oct;1025:279-87
15542728
J Biol Chem. 2002 May 17;277(20):18091-7
11872740
Mol Pharmacol. 2002 Sep;62(3):507-13
12181426
Annu Rev Pharmacol Toxicol. 1993;33:639-77
8494354
Prog Neuropsychopharmacol Biol Psychiatry. 2007 Nov 15;31(8):1556-71
17884274
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7673-5
10884398
J Neural Transm (Vienna). 2009 Aug;116(8):983-7
19002553
Schizophr Res. 2000 Aug 3;44(2):151-5
10913747
J Biol Chem. 2001 Jun 22;276(25):22621-9
11278324
EMBO J. 2009 Aug 5;28(15):2195-208
19590495
J Biol Chem. 2002 Nov 29;277(48):46010-9
12297500