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The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression

  • Translational Neurosciences - Original Article
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Abstract

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-d-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.

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References

  • Bamford NS, Zhang H, Schmitz Y, Wu NP, Cepeda C, Levine MS, Schmauss C, Zakharenko SS, Zablow L, Sulzer D (2004) Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron 42:653–663

    Article  PubMed  CAS  Google Scholar 

  • Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K (2010) The Arc of synaptic memory. Exp Brain Res 200:125–140

    Article  PubMed  PubMed Central  Google Scholar 

  • Bruins Slot L, Lestienne F, Grevoz-Barret C, Newman-Tancredi A, Cussac D (2009) F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. Eur J Pharmacol 620:27–35

    Article  PubMed  CAS  Google Scholar 

  • Carlsson A (1975) Dopaminergic autoreceptors. In: Almgren O, Carlsson A, Engel J (eds) Chemical tools in catecholamine research. North-Holland Publishing Company, Amsterdam, p 219

  • Carlsson A (1990) Early psychopharmacology and the rise of modern brain research. J Psychopharmacol 4:120–126

    Article  PubMed  CAS  Google Scholar 

  • Carlsson A, Lindqvist M (1963) Effects on chlorpromazine or haloperidol on formation of 3-methoxy-tyramine and normetanephrine in mouse brain. Acta Pharmacol et Toxicol 20:140

  • Cepeda C, Levine MS (1998) Dopamine and N-methyl-d-aspartate receptor interactions in the neostriatum. Dev Neurosci 20:1–18

    Article  PubMed  CAS  Google Scholar 

  • Cepeda C, Buchwald NA, Levine MS (1993) Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor subtypes activated. Proc Natl Acad Sci USA 90:9576–9580

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cepeda C, Wu N, Andre VM, Cummings DM, Levine MS (2007) The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 81:253–271

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chen G, Greengard P, Yan Z (2004) Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex. Proc Natl Acad Sci USA 101:2596–2600

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  • de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, Saft C, Magnet MK, Sword A, Rembratt Å, Tedroff J, On Behalf of the MermaiHD Study Investigators (2011) The dopaminergic stabilizer pridopidine improves motor function in patients with Huntington’s disease: results from a phase 3, randomized, placebo-controlled study (MermaiHD). Lancet Neurol 10:1049–1057

  • Dyhring T, Nielsen EØ, Sonesson C, Pettersson F, Karlsson J, Svensson P, Christophersen P, Waters N (2010) The dopaminergic stabilizers pridopidine (ACR16) and (−)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties. Eur J Pharmacol 628:19–26

    Article  PubMed  CAS  Google Scholar 

  • El-Sayeh HG, Morganti C (2006) Aripiprazole for schizophrenia. Cochrane Database Syst Rev 2:CD004578

  • Fiorentini C, Busi C, Spano P, Missale C (2010) Dimerization of dopamine D1 and D3 receptors in the regulation of striatal function. Curr Opin Pharmacol 10(1):87–92

    Article  PubMed  CAS  Google Scholar 

  • Flores-Hernández J, Cepeda C, Hernández-Echeagaray E, Calvert CR, Jokel ES, Fienberg AA, Greengard P, Levine MS (2002) Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. J Neurophysiol 88:3010–3020

    Article  PubMed  Google Scholar 

  • Fumagalli F, Frasca A, Racagni G, Riva MA (2009) Antipsychotic drugs modulate Arc expression in the rat brain. Eur Neuropsychopharmacol 19:109–115

    Article  PubMed  CAS  Google Scholar 

  • Gao K, Ganocy SJ, Gajwani P, Muzina DJ, Kemp DE, Calabrese JR (2008) A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence. J Clin Psychiatry 69:302–309

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Islas C, Hablitz JJ (2003) Dopamine enhances EPSCs in layer II–III pyramidal neurons in rat prefrontal cortex. J Neurosci 23:867–875

    PubMed  CAS  Google Scholar 

  • Gronier B, Waters S, Ponten H (2013) The dopaminergic stabilizer pridopidine increases neuronal activity of presumed pyramidal neurons in the prefrontal cortex. J Neural Transm 120(9):1281–1294

    Article  PubMed  CAS  Google Scholar 

  • Kamińska K, Gołembiowska K, Rogóż Z (2013) Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex. Pharmacol Rep 65(5):1144–1151

    Article  PubMed  Google Scholar 

  • Kawashima T, Okuno H, Nonaka M, Adachi-Morishima A, Kyo N, Okamura M, Takemoto-Kimura S, Worley PF, Bito H (2009) Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signalling in activated neurons. Proc Natl Acad Sci USA 106:316–321

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Korb E, Finkbeiner S (2011) Arc in synaptic plasticity: from gene to behaviour. Trends Neurosci 34(11):591–598

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U, Kuhl D (1995) Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci USA 92:5734–5738

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433–445

    Article  PubMed  CAS  Google Scholar 

  • Maggio R, Millan MJ (2010) Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Curr Opin Pharmacol 10(1):100–107

    Article  PubMed  CAS  Google Scholar 

  • Nakahara T, Kuroki T, Hashimoto K, Hondo H, Tsutsumi T, Motomura K, Ueki H, Hirano M, Uchimura H (2000) Effect of atypical antipsychotics on phencyclidine-induced expression of Arc in rat brain. NeuroReport 11:551–555

    Article  PubMed  CAS  Google Scholar 

  • Natesan S, Svensson KA, Reckless GE, Nobrega JN, Barlow KB, Johansson AM, Kapur S (2006) The dopamine stabilizers (S)-(−)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(−)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J Pharmacol Exp Ther 318:810–818

    Article  PubMed  CAS  Google Scholar 

  • Pei Q, Tordera R, Sprakes M, Sharp T (2004) Glutamate receptor activation is involved in 5-HT2 agonist-induced Arc gene expression in the rat cortex. Neuropharmacology 46:331–339

    Article  PubMed  CAS  Google Scholar 

  • Pettersson F, Pontén H, Waters N, Waters S, Sonesson C (2010) Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16). J Med Chem 53:2510–2520

    Article  PubMed  CAS  Google Scholar 

  • Ponten H, Dyhring T, Edling M, Pettersson F, Sonesson C, Svanberg B, Swanson L, Tedroff J, Waters S, Waters N (2009) ACR325: a dopaminergic stabiliser that displays state-dependent effects in vivo. Eur Neuropsychopharmacol 19(Suppl 3):S276

    Article  Google Scholar 

  • Ponten H, Kullingsjö J, Lagerkvist S, Martin P, Pettersson F, Sonesson C, Waters S, Waters N (2010) In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 644:88–95

    Article  PubMed  CAS  Google Scholar 

  • Robbins MJ, Critchlow HM, Lloyd A, Cilia J, Clarke JD, Bond B, Jones DN, Maycox PR (2008) Differential expression of IEG mRNA in rat brain following acute treatment with clozapine or haloperidol: a semi-quantitative RT-PCR study. J. Psychopharmacol. 22:536–542

    Article  PubMed  CAS  Google Scholar 

  • Seamans JK, Durstewitz D, Christie BR, Stevens CF, Sejnowski TJ (2001) Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci USA 98:301–306

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Serres F, Rodriguez M, Rivet J-M, Galizzi J-P, Lockhart B, Sharp T, Millan MJ (2012) Blockade of Π± 2-adrenoceptors induces Arc gene expression in rat brain in a glutamate receptor-dependent manner: a combined qPCR, in situ hybridisation and immunocytochemistry study. Neuropharmacology 63:992–1001

    Article  PubMed  CAS  Google Scholar 

  • Silverstone PH, Lalies MD, Hudson AL (2012) Quetiapine and buspirone both elevate cortical levels of noradrenaline and dopamine in vivo, but do not have synergistic effects. Front Psychiatry 3:82. doi:10.3389/fpsyt.2012.00082

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sonesson C, Swanson L, Waters N (2005) New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission. World Intellectual Property Organization patent WO 2005/121087

  • Sonesson C, Andersson B, Waters S, Waters N, Tedroff J (2001) New modulators of dopamine neurotransmission. World Intellectual Property Organization patent WO 2001/46145

  • Stahl SM (2001) Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1, “Goldilocks” actions at dopamine receptors. J Clin Psychiatry 62:841–842

    Article  PubMed  CAS  Google Scholar 

  • Steward O, Worley PF (2001) Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation. Neuron 30:227–240

    Article  PubMed  CAS  Google Scholar 

  • Surmeier DJ, Ding J, Day M, Wang Z, Shen W (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 30:228–235

    Article  PubMed  CAS  Google Scholar 

  • The Huntington Study Group HART Investigators (2013) A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord. doi:10.1002/mds.25362

  • Tseng KY, O’Donnell P (2004) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 24:5131–5139

    Article  PubMed  CAS  Google Scholar 

  • Wang J, O’Donnell P (2001) D1 dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb Cortex 11:452–462

    Article  PubMed  CAS  Google Scholar 

  • Waters S, Martin P, Pettersson F, Ponten H, Sonesson C, Swanson L, Waters N (2006) Pharmacology of the dopaminergic stabilizer and glutamate enhancer ACR325 Society for Neuroscience Annual Conference, Atlanta, USA. Abstract Viewer/Itinerary Planner: Program No. 828.18

  • Yamagata K, Suzuki K, Sugiura H, Kawashima N, Okuyama S (2000) Activation of an effector immediate-early gene Arc by methamphetamine. Ann N Y Acad Sci 914:22–32

    Article  PubMed  CAS  Google Scholar 

  • Yin HH, Lovinger DM (2006) Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling. Proc Natl Acad Sci USA 103:8251–8256

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by NeuroSearch Sweden AB and Integrative Research Laboratories Sweden AB. Teva Pharmaceutical Industries, Ltd. reviewed the manuscript before submission.

Conflict of interest

S. Waters, M. Edling, H. Ponten, B. Svanberg, D. Klamer and N. Waters were all employees of NeuroSearch Sweden AB, Gothenburg, Sweden when the study was performed.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 431, 405 30, Gōteborg, Sweden

    Susanna Waters, Henrik Ponten & Daniel Klamer

  2. Integrative Research Laboratories AB, A Wallgrens Backe 20, 413 46, Göteborg, Sweden

    Susanna Waters, Boel Svanberg & Nicholas Waters

  3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Box 431, 405 30, Gōteborg, Sweden

    Malin Edling

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  1. Susanna Waters
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  2. Henrik Ponten
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  6. Nicholas Waters
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Correspondence to Susanna Waters.

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Waters, S., Ponten, H., Edling, M. et al. The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression. J Neural Transm 121, 1337–1347 (2014). https://doi.org/10.1007/s00702-014-1231-1

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  • DOI: https://doi.org/10.1007/s00702-014-1231-1

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