Impact of dopamine–glutamate interactions on striatal neuronal nitric oxide synthase activity
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It is known that dopamine (DA) D1 receptor activation stimulates striatal nitric oxide (NO) synthesis, whereas D2 receptor activation produces the opposite effect. However, the mechanisms involved in the dopaminergic modulation of nitric oxide synthase (NOS) are unknown.
We hypothesized that the effects of DA on striatal NO signaling are dependent on ongoing glutamatergic activation of NOS. Therefore, the current study examined whether intact N-methyl-d-aspartic acid (NMDA) receptor activation is required for the dopaminergic modulation of NOS activity.
We assessed the impact of pharmacological manipulations of D1, D2, and NMDA receptors on NOS activity in the dorsal striatum and motor cortex using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Drugs were administered systemically to conscious animals and NADPH-d staining was quantified in these regions using ex vivo measurements of tissue optical density.
Administration of the neuronal NOS inhibitor N G-propyl-l-arginine (NPA), the D1 receptor antagonist SCH 23390, and the NMDA receptor antagonist 3-phosphonopropyl-piperazine-2-carboxylic acid (CPP) all attenuated staining selectively in the striatum. Administration of the D2 receptor agonist quinpirole decreased NADPH-d staining in both the striatum and cortex. Striatal NADPH-d staining elicited by administration of the D1 receptor agonist SKF 81297 or the D2 receptor antagonist eticlopride was attenuated by NPA, SCH 23390, and CPP pretreatment. Quinpirole pretreatment also abolished the facilitatory effect of SKF 81297.
These studies show for the first time that ongoing NMDA receptor activation is necessary for the modulation of striatal NOS activity by both facilitatory (D1 receptor activation) and inhibitory (D2 receptor activation) dopaminergic signaling mechanisms.
KeywordsDopamine Nitric oxide Nitric oxide synthase NMDA receptor Striatum Cortex
The authors thank Dr. Gloria E. Meredith for the expert advice on performing and quantifying the NADPH-d histochemistry and for the insightful comments on data interpretation and preparation of this manuscript. We are also grateful to Dr. Kuei Tseng for the insightful comments on data interpretation. We would like to thank Alexander Dec and Soleil Leilabadi for their assistance with the histology. This work was supported by the Chicago Medical School and United States Public Health grant NS 047452 (ARW).
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