Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms

An important role for the reactive gas nitric oxide (NO) in regulating striatal dopaminergic neurotransmission was identified shortly after initial observations indicated that this unorthodox neurotransmitter mediates many of the influences of glutamatergic neurotransmission in the cerebellum, cortex, and hippocampus. While the precise actions of NO on striatal presynaptic and postsynaptic elements remain to be fully characterized, the recent application of sophisticated anatomical, neurochemical, and electrophysiological approaches to the study of nitrergic signaling has revealed that NO exerts a powerful influence both on tonic extracellular dopamine (DA) levels and phasic DA neuron spike activity via the modulation of intrinsic striatal mechanisms and striatonigral feedback loops. Although the nature of the NO-mediated modulatory influence on DA neurotransmission was initially clouded by seemingly conflicting neurochemical observations, a growing body of literature and understanding of the diverse signaling mechanisms and effector pathways utilized by NO indicates that NO exerts a primary facilitatory influence over tonic and phasic dopaminergic neurotransmission under physiological conditions. A review of neurochemical and electrophysiological studies examining the influence of endogenous and exogenous NO on DA neurotransmission indicates that NO signaling exerts multiple effects on local striatal circuits and projection neurons involved in regulating basal ganglia output and nigrostriatal DA neuron activity. In addition to summarizing these influences, the current review focuses on the mechanisms utilized by striatal NO signaling pathways involved in modulating DA transmission at the level of the terminal and cell body and attempts to integrate these observations into a functional model of NO-dependent regulation of basal ganglia systems.