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Selective Overexpression of Dopamine D3 Receptors in the Striatum Disrupts Motivation but not Cognition

Published:December 06, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.11.023

      Background

      Evidence indicating an increase in dopamine D2 receptor (D2R) density and occupancy in patients with schizophrenia comes from positron emission tomography studies using ligands that bind both D2Rs and dopamine D3 receptors (D3Rs), questioning the role of D3Rs in the pathophysiology of the disease. Dopamine D3 receptor positron emission tomography ligands have recently been developed and antagonists with preferential affinity for D3R versus D2R are undergoing clinical evaluation. To determine if an increase in D3Rs in the striatum could produce phenotypes relevant to schizophrenia, we generated a transgenic model of striatal D3R overexpression.

      Methods

      A bi-transgenic system was used to generate mice with increased D3Rs selectively in the striatum. Mice with overexpression of D3R were subjected to an extensive battery of behavioral tests, including several relevant to schizophrenia. Ligand binding and quantitative reverse transcription polymerase chain reaction methods were used to quantify the effect of D3R overexpression on dopamine D1 receptors (D1Rs) in the striatum.

      Results

      Mice with overexpression of D3R show no abnormalities in basic behavioral functions or cognitive tests but do display a deficit in incentive motivation. This was associated with a reduction in striatal D1R ligand binding, driven by a downregulation at the level of transcription. Both motivation and D1R expression were rescued by switching off the transgene in adulthood.

      Conclusions

      Overexpression of D3Rs in the striatum of mice does not elicit cognitive deficits but disrupts motivation, suggesting that changes in D3Rs may be involved in the negative symptoms of schizophrenia. These data imply that it will be important to evaluate the effects of D3R antagonists on motivational symptoms, which are not improved by currently available antipsychotic medications.

      Key Words

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      References

        • Simpson E.H.
        • Kellendonk C.
        • Kandel E.
        A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia.
        Neuron. 2010; 65: 585-596
        • Howes O.D.
        • Kambeitz J.
        • Kim E.
        • Stahl D.
        • Slifstein M.
        • Abi-Dargham A.
        • Kapur S.
        The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
        Arch Gen Psychiatry. 2012; 69: 776-786
        • Seeman P.
        • Lee T.
        Antipsychotic drugs: Direct correlation between clinical potency and presynaptic action on dopamine neurons.
        Science. 1975; 188: 1217-1219
        • Creese I.
        • Burt D.R.
        • Snyder S.H.
        Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.
        Science. 1976; 192: 481-483
        • Schwartz J.C.
        • Diaz J.
        • Pilon C.
        • Sokoloff P.
        Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions.
        Brain Res Brain Res Rev. 2000; 31: 277-287
        • Weinberger DR
        • Laruelle M
        Neurochemical and neuropharmacological imaging in schizophrenia.
        in: Davis K.L. Charney D. Coyle J.T. Nemeroff C.B. Neuropharmacology: The Fifth Generation of Progress. Lippincott, Williams, and Wilkins, Philadelphia2001
        • Sibley D.R.
        Cloning of a ‘D3’ receptor subtype expands dopamine receptor family.
        Trends Pharmacol Sci. 1991; 12: 7-9
        • Prante O.
        • Dorfler M.
        • Gmeiner P.
        Dopamine receptor subtype-selective drugs: D2-like receptors.
        in: Neve K.A. The Dopamine Receptors, 2nd ed. Humana Press, New York2010: 101-136
        • Gallezot J.D.
        • Beaver J.D.
        • Gunn R.N.
        • Nabulsi N.
        • Weinzimmer D.
        • Singhal T.
        • et al.
        Affinity and selectivity of [(1)(1)C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo.
        Synapse. 2012; 66: 489-500
        • Tziortzi A.C.
        • Searle G.E.
        • Tzimopoulou S.
        • Salinas C.
        • Beaver J.D.
        • Jenkinson M.
        • et al.
        Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy.
        Neuroimage. 2011; 54: 264-277
        • Searle G.
        • Beaver J.D.
        • Comley R.A.
        • Bani M.
        • Tziortzi A.
        • Slifstein M.
        • et al.
        Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist.
        Biol Psychiatry. 2010; 68: 392-399
        • Graff-Guerrero A.
        • Mizrahi R.
        • Agid O.
        • Marcon H.
        • Barsoum P.
        • Rusjan P.
        • et al.
        The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: A clinical [11C]-(+)-PHNO PET study.
        Neuropsychopharmacology. 2009; 34: 1078-1086
        • Kung M.P.
        • Kung H.F.
        • Chumpradit S.
        • Foulon C.
        In vitro binding of a novel dopamine D3 receptor ligand: [125I]trans-7-OH-PIPAT-A.
        Eur J Pharmacol. 1993; 235: 165-166
        • Gurevich E.V.
        • Bordelon Y.
        • Shapiro R.M.
        • Arnold S.E.
        • Gur R.E.
        • Joyce J.N.
        Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study.
        Arch Gen Psychiatry. 1997; 54: 225-232
        • Kellendonk C.
        • Simpson E.H.
        • Polan H.J.
        • Malleret G.
        • Vronskaya S.
        • Winiger V.
        • et al.
        Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.
        Neuron. 2006; 49: 603-615
        • Mayford M.
        • Bach M.E.
        • Huang Y.Y.
        • Wang L.
        • Hawkins R.D.
        • Kandel E.R.
        Control of memory formation through regulated expression of a CaMKII transgene.
        Science. 1996; 274: 1678-1683
        • Schaeren-Wiemers N.
        • Gerfin-Moser A.
        A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: In situ hybridization using digoxigenin-labelled cRNA probes.
        Histochemistry. 1993; 100: 431-440
        • Biezonski D.K.
        • Meyer J.S.
        Effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: Implications for MDMA neurotoxicity.
        J Neurochem. 2010; 112: 951-962
        • Simpson E.H.
        • Kellendonk C.
        • Ward R.D.
        • Richards V.
        • Lipatova O.
        • Fairhurst S.
        • et al.
        Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia.
        Biol Psychiatry. 2011; 69: 928-935
        • Muller P.Y.
        • Janovjak H.
        • Miserez A.R.
        • Dobbie Z.
        Processing of gene expression data generated by quantitative real-time RT-PCR.
        Biotechniques. 2002; 32 (1376, 1378–1379): 1372-1374
        • Pittenger C.
        • Fasano S.
        • Mazzocchi-Jones D.
        • Dunnett S.B.
        • Kandel E.R.
        • Brambilla R.
        Impaired bidirectional synaptic plasticity and procedural memory formation in striatum-specific cAMP response element-binding protein-deficient mice.
        J Neurosci. 2006; 26: 2808-2813
        • Bach M.E.
        • Simpson E.H.
        • Kahn L.
        • Marshall J.J.
        • Kandel E.R.
        • Kellendonk C.
        Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning.
        Proc Natl Acad Sci U S A. 2008; 105: 16027-16032
        • Drew M.R.
        • Simpson E.H.
        • Kellendonk C.
        • Herzberg W.G.
        • Lipatova O.
        • Fairhurst S.
        • et al.
        Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing.
        J Neurosci. 2007; 27: 7731-7739
        • Cazorla M.
        • Shegda M.
        • Ramesh B.
        • Harrison N.L.
        • Kellendonk C.
        Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels.
        J Neurosci. 2012; 32: 2398-2409
        • Surmeier D.J.
        • Eberwine J.
        • Wilson C.J.
        • Cao Y.
        • Stefani A.
        • Kitai S.T.
        Dopamine receptor subtypes colocalize in rat striatonigral neurons.
        Proc Natl Acad Sci U S A. 1992; 89: 10178-10182
        • Surmeier D.J.
        • Song W.J.
        • Yan Z.
        Coordinated expression of dopamine receptors in neostriatal medium spiny neurons.
        J Neurosci. 1996; 16: 6579-6591
        • Aleman A.
        • Hijman R.
        • de Haan E.H.
        • Kahn R.S.
        Memory impairment in schizophrenia: A meta-analysis.
        Am J Psychiatry. 1999; 156: 1358-1366
        • Fioravanti M.
        • Carlone O.
        • Vitale B.
        • Cinti M.E.
        • Clare L.
        A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia.
        Neuropsychol Rev. 2005; 15: 73-95
        • Spieker E.A.
        • Astur R.S.
        • West J.T.
        • Griego J.A.
        • Rowland L.M.
        Spatial memory deficits in a virtual reality eight-arm radial maze in schizophrenia.
        Schizophr Res. 2012; 135: 84-89
        • Goldman-Rakic P.S.
        Working memory dysfunction in schizophrenia.
        J Neuropsychiatry Clin Neurosci. 1994; 6: 348-357
        • Lee J.
        • Park S.
        Working memory impairments in schizophrenia: A meta-analysis.
        J Abnorm Psychol. 2005; 114: 599-611
        • Park S.
        • Holzman P.S.
        Schizophrenics show spatial working memory deficits.
        Arch Gen Psychiatry. 1992; 49: 975-982
        • Gold J.M.
        • Bish J.A.
        • Iannone V.N.
        • Hobart M.P.
        • Queern C.A.
        • Buchanan R.W.
        Effects of contextual processing on visual conditional associative learning in schizophrenia.
        Biol Psychiatry. 2000; 48: 406-414
        • Kemali D.
        • Maj M.
        • Galderisi S.
        • Monteleone P.
        • Mucci A.
        Conditional associative learning in drug-free schizophrenic patients.
        Neuropsychobiology. 1987; 17: 30-34
        • Rushe T.M.
        • Woodruff P.W.
        • Murray R.M.
        • Morris R.G.
        Episodic memory and learning in patients with chronic schizophrenia.
        Schizophr Res. 1999; 35: 85-96
        • Salamone J.D.
        Will the last person who uses the term ‘reward’ please turn out the lights? Comments on processes related to reinforcement, learning, motivation and effort.
        Addict Biol. 2006; 11: 43-44
        • Aberman J.E.
        • Ward S.J.
        • Salamone J.D.
        Effects of dopamine antagonists and accumbens dopamine depletions on time-constrained progressive-ratio performance.
        Pharmacol Biochem Behav. 1998; 61: 341-348
        • Cousins M.S.
        • Salamone J.D.
        Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure.
        Pharmacol Biochem Behav. 1994; 49: 85-91
        • Salamone J.D.
        • Arizzi M.N.
        • Sandoval M.D.
        • Cervone K.M.
        • Aberman J.E.
        Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: Contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task.
        Psychopharmacology (Berl). 2002; 160: 371-380
        • Kosaka J.
        • Takahashi H.
        • Ito H.
        • Takano A.
        • Fujimura Y.
        • Matsumoto R.
        • et al.
        Decreased binding of [11C]NNC112 and [11C]SCH23390 in patients with chronic schizophrenia.
        Life Sci. 2010; 86: 814-818
        • Abi-Dargham A.
        • Xu X.
        • Thompson J.L.
        • Gil R.
        • Kegeles L.S.
        • Urban N.
        • et al.
        Increased prefrontal cortical D(1) receptors in drug naive patients with schizophrenia: A PET study with [(1)(1)C]NNC112.
        J Psychopharmacol. 2012; 26: 794-805
        • Napolitano F.
        • Bonito-Oliva A.
        • Federici M.
        • Carta M.
        • Errico F.
        • Magara S.
        • et al.
        Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine.
        J Neurosci. 2010; 30: 11043-11056
        • van Tol H.H.
        • Riva M.
        • Civelli O.
        • Creese I.
        Lack of effect of chronic dopamine receptor blockade on D2 dopamine receptor mRNA level.
        Neurosci Lett. 1990; 111: 303-308
        • Bouthenet M.L.
        • Souil E.
        • Martres M.P.
        • Sokoloff P.
        • Giros B.
        • Schwartz J.C.
        Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: Comparison with dopamine D2 receptor mRNA.
        Brain Res. 1991; 564: 203-219
        • Guillin O.
        • Diaz J.
        • Carroll P.
        • Griffon N.
        • Schwartz J.C.
        • Sokoloff P.
        BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.
        Nature. 2001; 411: 86-89
        • Sokoloff P.
        • Diaz J.
        • Le Foll B.
        • Guillin O.
        • Leriche L.
        • Bezard E.
        • Gross C.
        The dopamine D3 receptor: A therapeutic target for the treatment of neuropsychiatric disorders.
        CNS Neurol Disord Drug Targets. 2006; 5: 25-43
        • Fiorentini C.
        • Busi C.
        • Gorruso E.
        • Gotti C.
        • Spano P.
        • Missale C.
        Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization.
        Mol Pharmacol. 2008; 74: 59-69
        • Berridge K.C.
        The debate over dopamine’s role in reward: The case for incentive salience.
        Psychopharmacology (Berl). 2007; 191: 391-431
        • Flagel S.B.
        • Clark J.J.
        • Robinson T.E.
        • Mayo L.
        • Czuj A.
        • Willuhn I.
        • et al.
        A selective role for dopamine in stimulus-reward learning.
        Nature. 2011; 469: 53-57
      1. Adham N, Gyertyan I, Kiss B, Pasztor G, Gupta S, Szombathelyi Z, et al. (2007): Antidepressant activity of RGH-188, a potential antipsychotic with D3/D2 antagonist/partial agonist properties in a chronic mild stress-induced anhedonia model. Presented at the Society for Neuroscience Annual Meeting, November 12–17, San Diego, California. San Diego, CA: Society for Neuroscience.