Phasic Dopaminergic Transmission Increases NO Efflux in the Rat Dorsal Striatum via a Neuronal NOS and a Dopamine D1/5 Receptor-Dependent Mechanism

Dysfunctional neurotransmission within striatal networks is believed to underlie the pathophysiology of several neurological and psychiatric disorders. Nitric oxide (NO)-producing interneurons have been shown to play a critical role in modulating striatal synaptic transmission. These interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and may be regulated by DA receptor activation. In the current study, striatal NO efflux was measured in anesthetized male rats using an NO-selective electrochemical microsensor and the role of DA in modulating NO synthase (NOS) activity was assessed during electrical or chemical (bicuculline) stimulation of the substantia nigra (SN). Electrical stimuli were patterned to approximate the natural single spike or burst firing activity of midbrain DA neurons. Electrical stimulation of the SN at low frequencies induced modest increases in striatal NO efflux. In contrast, train stimulation of the SN robustly increased NO efflux in a stimulus intensity-dependent manner. NO efflux evoked by SN stimulation was similar in chloral hydrate- and urethane-anesthetized rats. The facilitatory effect of train stimulation on striatal NO efflux was transient and attenuated by systemic administration of the neuronal NOS inhibitor 7-nitroindazole and the nonselective NOS inhibitor methylene blue. Moreover, the increase in NO efflux observed during chemical and train stimulation of the SN was attenuated following systemic administration of the DA D1/5 receptor antagonist SCH 23390. SCH 23390 also blocked NO efflux induced by systemic administration of the D1/5 agonist SKF 81297. These results indicate that neuronal NOS is activated in vivo by nigrostriatal DA cell burst firing via a DA D1/5-like receptor-dependent mechanism.

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