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Dopamine D2 receptor-dependent modulation of striatal NO synthase activity

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Abstract

Rationale

Striatal nitric oxide (NO)-producing interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and are regulated by phasic DA transmission. Classic antipsychotic drugs elevate neuronal NO synthase (NOS) expression in the rat striatum. Given that NO signaling potently modulates the membrane excitability of striatal projection neurons, it is plausible that up-regulation of NOS activity after DA D2 receptor blockade contributes to the therapeutic efficacy and/or motor side effects associated with antipsychotic drugs.

Objectives

This study assessed the impact of DA D2 receptor activation on striatal NOS activity in vivo. Characterization of the dopaminergic regulation of striatal NO signaling will be relevant for understanding the mechanism(s) of action of antipsychotic drugs.

Materials and methods

Striatal NO efflux, evoked via electrical stimulation of the substantia nigra (SN) or systemic administration of the DA D1 receptor agonist SKF 81297, was assessed in anesthetized rats using an NO-selective amperometric microsensor.

Results

The facilitatory effect of SN stimulation on striatal NO efflux was attenuated by systemic administration of the DA D2 receptor agonist quinpirole. Conversely, administration of the DA D2 receptor antagonist eticlopride augmented evoked NO efflux. NO efflux induced by systemic administration of SKF 81297 was attenuated by quinpirole and restored by co-administration of quinpirole and eticlopride. The facilitatory effect of SKF 81297 on NO efflux was also significantly attenuated after pretreatment with the non-specific NOS inhibitor methylene blue.

Conclusions

Activation of NO synthesis by phasic DA transmission is down-regulated via a DA D2 receptor-dependent mechanism. DA D2 receptor activation opposes DA D1 receptor activation of NO synthesis at a site postsynaptic to the DA terminal. Further studies examining NO–DA dynamics may have potential to reveal novel therapeutic strategies to treat various brain disorders.

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Abbreviations

DA:

dopamine

eNOS/NOS-3:

endothelial nitric oxide synthase

ETI:

S-(−)-eticlopride HCl

iNOS/NOS-2:

inducible nitric oxide synthase

ITI:

inter-train interval

MB:

methylene blue

nNOS/NOS-1:

neuronal nitric oxide synthase

NO:

nitric oxide

NOS:

nitric oxide synthase

QNP:

(−)-Quinpirole HCl

SKF 81297:

R-(+)-SKF 81297 HBr

SNAP:

(±)S-Nitroso-N-acetyl-penicillamine

SN:

substantia nigra

WPI:

World Precision Instruments

References

  • Akbarian S, Bunney WE Jr, Potkin SG, Wigal SB, Hagman JO, Sandman CA, Jones EG (1993a) Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry 50:169–177

    CAS  Google Scholar 

  • Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG (1993b) Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 50:178–187

    CAS  Google Scholar 

  • Altar CA, Boyar WC, Kim HS (1990) Discriminatory roles for D1 and D2 dopamine receptor subtypes in the in vivo control of neostriatal cyclic GMP. Eur J Pharmacol 181:17–21

    Article  PubMed  CAS  Google Scholar 

  • Ariano MA (1983) Distribution of components of the guanosine 3′,5′-phosphate system in rat caudate-putamen. Neuroscience 10:707–723

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Berretta S, Parthasarathy HB, Graybiel AM (1997) Local release of GABAergic inhibition in the motor cortex induces immediate-early gene expression in indirect pathway neurons of the striatum. J Neurosci 17:4752–4763

    PubMed  CAS  Google Scholar 

  • Bester AM, Harvey BH (2000) Early suppression of striatal cyclic GMP may predetermine the induction and severity of chronic haloperidol-induced vacous chewing movements. Metab Brain Dis 15:275–285

    Article  PubMed  CAS  Google Scholar 

  • Bevan MD, Booth PA, Eaton SA, Bolam JP (1998) Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat. J Neurosci 18:9438–9452

    PubMed  CAS  Google Scholar 

  • Black MD, Selk DE, Hitchcock JM, Wettstein JG, Sorensen SM (1999) On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia. Neuropharmacology 38:1299–1306

    Article  PubMed  CAS  Google Scholar 

  • Black MD, Simmonds J, Senyah Y, Wettstein JG (2002) Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs. Neuropharmacology 42:414–420

    Article  PubMed  CAS  Google Scholar 

  • Boehning D, Snyder SH (2003) Novel neural modulators. Annu Rev Neurosci 26:105–131

    Article  PubMed  CAS  Google Scholar 

  • Calabresi P, Centonze D, Gubellini P, Marfia GA, Pisani A, Sancesario G, Bernardi G (2000) Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog Neurobiol 61:231–265

    Article  PubMed  CAS  Google Scholar 

  • Calabresi P, Centonze D, Gubellini P, Marfia GA, Bernardi G (1999a) Glutamate-triggered events inducing corticostriatal long-term depression. J Neurosci 19:6102–6110

    CAS  Google Scholar 

  • Calabresi P, Gubellini P, Centonze D, Sancesario G, Morello M, Giorgi M, Pisani A, Bernardi G (1999b) A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. J Neurosci 19:2489–2499

    CAS  Google Scholar 

  • Cavas M, Navarro JF (2002) Coadministration of -NOARG and tiapride: Effects on catalepsy in male mice. Prog Neuropsychopharmacol Biol Psychiatry 26:69–73

    Article  PubMed  CAS  Google Scholar 

  • Centonze D, Bracci E, Pisani A, Gubellini P, Bernardi G, Calabresi P (2002) Activation of dopamine D1-like receptors excites LTS interneurons of the striatum. Eur J Neurosci 15:2049–2052

    Article  PubMed  Google Scholar 

  • Centonze D, Grande C, Saulle E, Martin AB, Gubellini P, Pavon N, Pisani A, Bernardi G, Moratalla R, Calabresi P (2003) Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity. J Neurosci 23:8506–8512

    PubMed  CAS  Google Scholar 

  • Del Bel EA, Guimaraes FS, Bermúdez-Echeverry M, Gomes MZ, Schiaveto-de-souza A, Padovan-Neto FE, Tumas V, Barion-Cavalcanti AP, Lazzarini M, Nucci-da-Silva LP, de Paula-Souza D (2005) Role of nitric oxide on motor behavior. Cell Mol Neurobiol 25:371–392

    Article  PubMed  Google Scholar 

  • Delgado A, Sierra A, Querejeta E, Valdiosera RF, Aceves J (2000) Inhibitory control of the GABAergic transmission in the rat neostriatum by D2 dopamine receptors. Neuroscience 95:1043–1048

    Article  PubMed  CAS  Google Scholar 

  • Deutsch SI, Rosse RB, Paul SM, Tomasino V, Koetzner L, Morn CB, Mastropaolo J (1996) 7-Nitroindazole and methylene blue, inhibitors of neuronal nitric oxide synthase and NO-stimulated guanylate cyclase, block MK-801-elicited behaviors in mice. Neuropsychopharmacology 15:37–43

    Article  PubMed  CAS  Google Scholar 

  • Di Stefano A, Sozio P, Cacciatore I, Cocco A, Giorgioni G, Costa B, Montali M, Lucacchini A, Martini C, Spoto G, Di Pietrantonio F, Di Matteo E, Pinnen F (2005) Preparation and pharmacological characterization of trans-2-amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes as D2-like dopamine receptor agonists. J Med Chem 48:2646–2654

    Article  PubMed  Google Scholar 

  • French SJ, Ritson GP, Hidaka S, Totterdell S (2005) Nucleus accumbens nitric oxide immunoreactive interneurons receive nitric oxide and ventral subicular afferents in rats. Neuroscience 135:121–131

    Article  PubMed  CAS  Google Scholar 

  • Fujiyama F, Masuko S (1996) Association of dopaminergic terminals and neurons releasing nitric oxide in the rat striatum: an electron microscopic study using NADPH-diaphorase histochemistry and tyrosine hydroxylase immunohistochemistry. Brain Res Bull 40:121–127

    Article  PubMed  CAS  Google Scholar 

  • Gattaz WF, Cramer H, Beckmann H (1984) Haloperidol increases the cerebrospinal fluid concentrations of cyclic GMP in schizophrenic patients. Biol Psychiatry 19:1229–1235

    PubMed  CAS  Google Scholar 

  • Griffith OW, Stuehr DJ (1995) Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol 57:707–734

    Article  PubMed  CAS  Google Scholar 

  • Harvey BH, Bester A (2000) Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. Behav Brain Res 111:203–211

    Article  PubMed  CAS  Google Scholar 

  • Hidaka S, Totterdell S (2001) Ultrastructural features of the nitric oxide synthase-containing interneurons in the nucleus accumbens and their relationship with tyrosine hydroxylase-containing terminals. J Comp Neurol 431:139–154

    Article  PubMed  CAS  Google Scholar 

  • Hyland BI, Reynolds JNJ, Hay J, Perk CG, Miller R (2002) Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114:475–492

    Article  PubMed  CAS  Google Scholar 

  • Kaster MP, Rosa AO, Santos AR, Rodrigues AL (2005) Involvement of nitric oxide-cGMP pathway in the antidepressant-like effects of adenosine in the forced swimming test. Int J Neuropsychopharmacol 8:601–606

    Article  PubMed  CAS  Google Scholar 

  • Kawaguchi Y (1993) Physiological, morphological, and histochemical characterization of three classes of interneurons in rat neostriatum. J Neurosci 13:4908–4923

    PubMed  CAS  Google Scholar 

  • Kawaguchi Y (1997) Neostriatal cell subtypes and their functional roles. Neurosci Res 27:1–8

    Article  PubMed  CAS  Google Scholar 

  • Kubota Y, Mikawa S, Kawaguchi Y (1993) Neostriatal GABAergic interneurones contain NOS, calretinin or parvalbumin. Neuroreport 5:205–208

    Article  PubMed  CAS  Google Scholar 

  • Lau YS, Petroske E, Meredith GE, Wang JQ (2003) Elevated neuronal nitric oxide synthase expression in chronic haloperidol-treated rats. Neuropharmacology 45:986–994

    Article  PubMed  CAS  Google Scholar 

  • Lauer M, Johannes S, Fritzen S, Senitz D, Riederer P, Reif A (2005) Morphological abnormalities in nitric-oxide-synthase-positive striatal interneurons of schizophrenic patients. Neuropsychobiology 52:111–117

    Article  PubMed  CAS  Google Scholar 

  • Lavin A, Nogueira L, Lapish CC, Wightman RM, Phillips PEM, Seamans JK (2005) Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling. J Neurosci 25:5013–5023

    Article  PubMed  CAS  Google Scholar 

  • Liou YJ, Tsai SJ, Hong CJ, Liao DL (2003) Association analysis for the CA repeat polymorphism of the neuronal nitric oxide synthase (NOS1) gene and schizophrenia. Schizophr Res 65:57–59

    Article  PubMed  Google Scholar 

  • Luo D, Das S, Vincent SR (1995) Effects of methylene blue and LY83583 on neuronal nitric oxide synthase and NADPH-diaphorase. Eur J Pharmacol 290:247–251

    Article  PubMed  CAS  Google Scholar 

  • Mayer B, Brunner F, Schmidt K (1993) Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 45:367–374

    Article  PubMed  CAS  Google Scholar 

  • Morello M, Reiner A, Sancesario G, Karle EJ, Bernardi G (1997) Ultrastructural study of nitric oxide synthase-containing striatal neurons and their relationship with parvalbumin-containing neurons in rats. Brain Res 776:30–39

    Article  PubMed  CAS  Google Scholar 

  • Morris BJ, Simpson CS, Mundell S, Maceachern K, Johnston HM, Nolan AM (1997) Dynamic changes in NADPH-diaphorase staining reflect activity of nitric oxide synthase: evidence for a dopaminergic regulation of striatal nitric oxide release. Neuropharmacology 36:1589–1599

    Article  PubMed  CAS  Google Scholar 

  • Ohta K, Rosner G, Graf R (1997) Nitric oxide generation from sodium nitroprusside and hydroxylamine in brain. Neuroreport 8:2229–2235

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York

    Google Scholar 

  • Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP, Wienker T, Topner T, Fritzen S, Walter U, Schmitt A, Fallgatter AJ, Lesch KP (2006) A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11:286–300

    Article  PubMed  CAS  Google Scholar 

  • Rivera A, Alberti I, Martin AB, Narvaez JA, de la Calle A, Moratalla R (2002) Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype. Eur J Neurosci 16:2049–2058

    Article  PubMed  Google Scholar 

  • Salin P, Kerkerian-Le GL, Heidet V, Epelbaum J, Nieoullon A (1990) Somatostatin-immunoreactive neurons in the rat striatum: effects of corticostriatal and nigrostriatal dopaminergic lesions. Brain Res 521:23–32

    Article  PubMed  CAS  Google Scholar 

  • Sammut S, Dec A, Mitchell D, Linardakis J, Ortiguela M, West AR (2006) Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism. Neuropsychopharmacology 31:493–505

    Article  PubMed  CAS  Google Scholar 

  • Sancesario G, Morello M, Reiner A, Giacomini P, Massa R, Schoen S, Bernardi G (2000) Nitrergic neurons make synapses on dual-input dendritic spines of neurons in the cerebral cortex and the striatum of the rat: implication for a postsynaptic action of nitric oxide. Neuroscience 99:627–642

    Article  PubMed  CAS  Google Scholar 

  • Shinkai T, Ohmori O, Hori H, Nakamura J (2002) Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia. Mol Psychiatry 7:560–563

    Article  PubMed  CAS  Google Scholar 

  • Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ (2006a) Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396

    Article  CAS  Google Scholar 

  • Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, Schmidt CJ (2006b) Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 51:374–385

    Article  CAS  Google Scholar 

  • Starr MS, Starr BS (1995) Do NMDA receptor-mediated changes in motor behaviour involve nitric oxide? Eur J Pharmacol 272:211–217

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Vincent SR (1994) Nitric oxide: a radical neurotransmitter in the central nervous system. Prog Neurobiol 42:129–160

    Article  PubMed  CAS  Google Scholar 

  • Volke V, Wegener G, Vasar E, Rosenberg R (1999) Methylene blue inhibits hippocampal nitric oxide synthase activity in vivo. Brain Res 826:303–305

    Article  PubMed  CAS  Google Scholar 

  • Vuillet J, Kerkerian L, Kachidian P, Bosler O, Nieoullon A (1989) Ultrastructural correlates of functional relationships between nigral dopaminergic or cortical afferent fibers and neuropeptide Y-containing neurons in the rat striatum. Neurosci Lett 100:99–104

    Article  PubMed  CAS  Google Scholar 

  • Vuillet J, Dimova R, Nieoullon A, Goff LK-L (1992) Ultrastructural relationships between choline acetyltransferase- and neuropeptide Y-containing neurons in the rat striatum. Neuroscience 46:351–360

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Pickel VM (2002) Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate–putamen nucleus. J Comp Neurol 442:392–404

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Kai L, Day M, Ronesi J, Yin HH, Ding J, Tkatch T, Lovinger DM, Surmeier DJ (2006) Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons. Neuron 50:443–452

    Article  PubMed  CAS  Google Scholar 

  • West AR, Galloway MP (1997) Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms. Neuropharmacology 36:1571–1581

    Article  PubMed  CAS  Google Scholar 

  • West AR, Grace AA (2004) The nitric oxide–guanylyl cyclase signaling pathway modulates membrane activity states and electrophysiological properties of striatal medium spiny neurons recorded in vivo. J Neurosci 24:1924–1935

    Article  PubMed  CAS  Google Scholar 

  • West AR, Galloway MP, Grace AA (2002) Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms. Synapse 44:227–245

    Article  PubMed  CAS  Google Scholar 

  • Wolin MS, Cherry PD, Rodenburg JM, Messina EJ, Kaley G (1990) Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion. J Pharmacol Exp Ther 254:872–876

    PubMed  CAS  Google Scholar 

  • Xing G, Chavko M, Zhang LX, Yang S, Post RM (2002) Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophr Res 58:21–30

    Article  PubMed  Google Scholar 

  • Zhang X (2004) Real time and in vivo monitoring of nitric oxide by electrochemical sensors—from dream to reality. Front Biosci 9:3434–3446

    PubMed  CAS  Google Scholar 

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Acknowledgment

The authors thank Dr. Marjorie A. Ariano and Dr. Chris Nelson for their valuable assistance and comments regarding this manuscript. We are also grateful to Mr. John Linardakis and Ms. Anupama Topgi for assistance with the histology. This work was supported by the Chicago Medical School, NARSAD, Parkinson’s Disease Foundation and United States Public Health grant NS 047452 (ARW).

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  1. Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA

    Stephen Sammut, Kristina E. Bray & Anthony R. West

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  1. Stephen Sammut
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  2. Kristina E. Bray
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  3. Anthony R. West
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Correspondence to Anthony R. West.

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Sammut, S., Bray, K.E. & West, A.R. Dopamine D2 receptor-dependent modulation of striatal NO synthase activity. Psychopharmacology 191, 793–803 (2007). https://doi.org/10.1007/s00213-006-0681-z

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