Regulation of striatal nitric oxide signaling by dopamine and glutamate interactions: Implications for Parkinson's disease.

摘要

Neural networks in the dorsal striatum of the basal ganglia play a major role in the processing of motor information. Dysfunctional neurotransmission within striatal networks is thought to underlie the pathophysiology of several neurological disorders including Parkinson's disease (PD). Previous studies have demonstrated that the pathology associated with PD involves a loss of dopamine (DA) cells in the midbrain and subsequent decreases in striatal DA transmission. However, neuronal dysfunction occurring as a result of DA denervation in the dorsal striatum remains poorly understood. A better understanding of neuroadaptations occurring in the DA-depleted striatum is critical for the development of novel therapies for patients contending with PD.;In recent years, the nitric oxide (NO)-soluble guanylyl cyclase (sGC) signaling pathway has been implicated in the pathology of PD. Striatal aspiny interneurons produce NO via the enzyme neuronal nitric oxide synthase (nNOS). Striatal nNOS interneurons are innervated by afferents from the cortex and midbrain, suggesting that NOS activity may be regulated by glutamate and DA. DA depletion induced by 6-OHDA in rats or in idiopathic PD has been shown to decrease markers of striatal NOS interneurons, mRNA and activity. Elevated levels of striatal sGC and cGMP have also been reported in DA depleted states. These studies suggest that characterization of the complex signaling mechanisms utilized by NOS-containing interneurons in normal and DA depleted striatum will be essential for understanding pathophysiological conditions such as PD.;This thesis tested the hypothesis that excitatory afferents from the frontal cortex stimulate striatal nNOS activation via a NMDA and D1/5 receptor dependent process. Amperometry and microdialysis were used to measure and manipulate striatal NO efflux evoked in response to electrical stimulation of the frontal cortex or pharmacological stimulation of D1/5 receptors. We found that activation of cortical afferents facilitates striatal NO synthesis in a manner that is mediated via NMDA receptor stimulation and potentiated by ongoing DA D1 receptor activation.;The hypothesis that attenuation of striatal sGC activity will restore motor deficits observed following DA depletion was also tested. Immunohistochemical staining of the striatum and substantia nigra of DA depleted rats showed that unilateral 6-OHDA lesions produced a profound loss in striatal DA immunoreactive terminals and midbrain DA cells. Behavioral studies also showed a significant attenuation in stepping behavior following unilateral 6-OHDA lesions. Administration of a sGC inhibitor partially restored deficits in stepping behavior observed in 6-OHDA lesioned rats in a manner that was dependent on the degree of DA depletion in these animals. These studies suggest that characterization of the role of NO-sGC-cGMP signaling in dysfunctional neurotransmission associated with the DA-depleted striatum is critical for: (1) understanding pathophysiological states such as PD, and (2) the development of novel therapeutic tools for the treatment of movement disorders.