We have uncovered an important role of the sGC-cGMP signaling pathway in the regulation of normal corticostriatal transmission and basal ganglia dysfunction induced by chronic DA depletion. We found that systemic administration of the selective sGC inhibitor ODQ decreased corticostriatal transmission in naïve rats in a manner that was reversed by intrastriatal infusion of a cGMP analogue. Moreover, ODQ administration markedly reversed the abnormal elevation in cGMP levels and reduced the increase in spontaneous firing observed in the DA-depleted striatum. These effects of ODQ were also associated with a normalization of the characteristic increase in metabolic activity observed in the STN following nigrostriatal DA cell loss. Moreover, the effects of systemically delivered ODQ on STN hyperactivity were replicated in studies using intrastriatal microinjections of this drug, indicating that striatal sGC inhibition leads to downregulation of striatopallidal output. The effects of ODQ on neuronal hyperactivity in the striatum and the STN were found to be behaviorally relevant as a similar systemic treatment transiently attenuated the reduction in forelimb use observed in 6-OHDA-lesioned rats and mice chronically treated with MPTP. These observations, along with previous studies 
, provide strong evidence that an upregulation of sGC-cGMP signaling in the DA-depleted striatum may contribute to the enduring changes in neuronal excitability and locomotor activity observed in parkinsonian animals. Furthermore, our data demonstrate for the first time that pharmacological attenuation of striatal sGC-cGMP signaling represents a promising novel non-dopaminergic therapeutic approach for restoring basal ganglia dysfunction and subduing motor symptoms associated with PD.
Presently, little is known as to how attenuation of striatal sGC-cGMP signaling may rescue dysfunctional basal ganglia output and behavioral abnormalities associated with experimental parkinsonism. However, converging evidence now indicates that striatal sGC-cGMP signaling plays a key role in the regulation of MSN excitability 
, short and long-term corticostriatal synaptic plasticity 
, and neuronal synchrony 
. The current studies examining the effects of ODQ on cortically-evoked striatal synaptic potentials in naïve rats indicate that tonic cGMP signaling also facilitates corticostriatal transmission within striatal networks. Taken together with previous studies 
, these findings show that transient elevations in intracellular cGMP markedly increase striatal MSN excitability and facilitate corticostriatal excitatory synaptic transmission. Notably, acute D2 (but not D1) receptor blockade mimics the facilitatory effect of DA depletion on striatal sGC activity 
and MSN activity 
. Thus, despite that striatal MSNs from both the direct and indirect output pathways express high levels of all components of the sGC-cGMP second messenger cascade 
, the above studies suggest that alterations in cGMP signaling observed after striatal DA-depletion could result from a preferential upregulation of cGMP synthesis in D2 receptor-expressing striatopallidal neurons of the indirect pathway 
Importantly, intrastriatal infusion of ODQ was sufficient to normalize the increased metabolic activity observed in the STN of 6-OHDA-lesioned rats. This finding is of great translational value as STN hyperactivity is one of the pathophysiological hallmarks of parkinsonism that has been repeatedly reported in animal models and in PD. In addition to the indirect pathway (i.e., striatopallidal neurons), there are other afferents known to contribute to the STN hyperactivity such as the excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem. However, the above outcomes from studies employing intrastriatal ODQ infusions point to a primary role of the indirect pathway in mediating both the STN hyperactivity and the ODQ-dependent reversal of this pathophysiological state induced following DA depletion.
At the cellular level, even less is known regarding how alterations in striatal sGC-cGMP signaling contribute to dysregulation of corticostriatal-striatopallidal transmission observed in the DA-depleted striatum. Given the current findings and previous reports 
, it is possible that inhibition of the sGC-cGMP signaling pathway reduces the abnormal increase in intrinsic excitability observed in striatal MSNs following chronic DA depletion. Indeed, under DA-depleted conditions pharmacological downregulation of sGC-cGMP signaling (i.e., following ODQ administration) may preferentially affect striatopallidal neurons because they are likely to exhibit increased cyclic nucleotide production and PKA/PKG/DARPP-32 activation as a result of decreased D2 receptor-mediated suppression of adenylate cyclase and sGC activity 
. This prediction is consistent with previous studies showing that drugs that augment cAMP (i.e., the adenylate cyclase activator forskolin) or cGMP (i.e., the phosphodiesterase inhibitor zaprinast) levels in MSNs increase the excitatory impact of corticostriatal transmission on these cells 
. Activation of the sGC-cGMP signaling pathway is also known to stimulate presynaptic facilitation of glutamate release 
, and to increase surface expression of AMPA receptors at postsynaptic sites 
. Taken together, these observations indicate that concurrent downregulation of pre- and postsynaptic sGC-cGMP signaling at corticostriatal synapses may be sufficient to normalize the abnormally augmented corticostriatal-striatopallidal transmission observed following DA depletion.
Unveiling the role of non-dopaminergic neural systems in the pathophysiology of experimental parkinsonism has great translational value, as this will open new avenues for treating PD and other debilitating neurological disorders. For instance, given the results of the current study, it is very likely that drugs designed to stimulate metabolism of excessive cGMP (and possibly cAMP) via activation of one or more of the numerous isoforms of phosphodiesterases expressed in the striatum 
will maximize the specificity of this novel treatment approach. In support of this, in the current study we demonstrated that a second messenger-based therapy (i.e., sGC inhibition and decreased cGMP signaling) is effective for reversing basal ganglia dysfunction and akinesia induced following DA depletion. These observations should lead to a broader understanding of how cyclic nucleotide signaling cascades can be modulated as an approach for treating motor symptoms associated with PD and related neurological disorders. Future studies will have to determine whether an enduring reversal of parkinsonian symptoms can be achieved with a treatment regimen designed to chronically downregulate striatal sGC-cGMP signaling. Moreover, novel studies examining the potential utility of combination therapy using low doses of L-DOPA and inhibitors of sGC-cGMP-PKG signaling are also warranted.