Psychopharmacology

, Volume 191, Issue 3, pp 793–803 | Cite as

Dopamine D2 receptor-dependent modulation of striatal NO synthase activity

  • Stephen Sammut
  • Kristina E. Bray
  • Anthony R. West
Original Investigation

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.

Keywords

Schizophrenia Nitric oxide Antipsychotic drugs Basal ganglia 

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

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Stephen Sammut
    • 1
  • Kristina E. Bray
    • 1
  • Anthony R. West
    • 1
  1. 1.Department of NeuroscienceThe Chicago Medical School at Rosalind Franklin University of Medicine and ScienceNorth ChicagoUSA

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