Inhibitory effect of nitric oxide on dopamine transporters: interneuronal communication without receptors.
Previously we observed that Nomega-nitro-L-arginine methyl ester (l-NAME) decreased the striatal dopamine (DA) release in microdialysis experiments and this effect was completely diminished in the presence of the DA uptake inhibitor nomifensine, indicating that the effect was mediated via the DA transporter. The aim of the present work was to study the direct effect of nitrergic compounds on DA uptake. We measured the uptake of [3H]DA in striatal slices and found that the nitric oxide (NO) generator sodium nitroprussid (100 microM) decreased the uptake by 66%. In contrast, the NO synthase inhibitor L-NAME (100 microM) increased the DA uptake by 80%, while the inactive D-NAME had no effect on uptake. Our data indicate that NO exerts an inhibitory effect on DA transporters. Since the production of NO by neuronal NO synthase is closely related to the activation of NMDA receptors, the level of NO around synapses reflects the activity of glutamatergic neurotransmission. The strength of excitatory input, therefore, can be nonsynaptically signaled by NO to the surrounding dopaminergic neurons via the inhibitory tone on transporters. The concomitant elevation of DA concentration around the activated synapse represents the response of dopaminergic system, which can adapt to the changing excitatory activity without receiving glutamatergic input and without expressing glutamate receptors. Thus, the effect of NO on transporters represents a new form of interneuronal communication, a nonsynaptic interaction without receptors.
Kiss
János P
JP
Department of Pharmacology, Institute of Experimental Medicine, P.O. Box 67, Budapest H-1450, Hungary. kiss-j@koki.hu
Zsilla
Gabriella
G
Vizi
E Sylvester
ES
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine