Lowered cAMP and cGMP signalling in the brain during levodopa‐induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms

Abstract

Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa-induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level increased in the cortex and striatum but decreased in the globus pallidus of both hemispheres, whereas the cGMP decreased below baseline levels in the contralateral cortico-striatal-pallidal regions. In dyskinetic animals chronic levodopa treatment led to an absolute decrease in cAMP and cGMP levels in cortico-striatal-pallidal regions of both hemispheres. Pretreatment with zaprinast reduced the severity of levodopa-induced dyskinesias, and partly prevented the decrease in cyclic nucleotides compared with pretreatment with saline-levodopa. In conclusion, using a rat model of hemiparkinsonism, we observed a significant reduction in the levels of cyclic nucleotides in both hemispheres at the peak of levodopa-induced dyskinesias. We propose that such a decrease in cyclic nucleotides may partly result from increased catabolism through PDE overactivity.

Nitric oxide regulates synaptic transmission between spiny projection neurons

“…Striatal dopamine depletion is associated with impairments in both striatal NO signaling and GABAergic transmission in axon collaterals of SPNs (14,19). To study the role of dopamine in the regulation of striatal NO signaling and VGAT levels in SPNs, cGMP levels or VGAT labeling was measured in the striata from 6-hydroxydopamine lesioned mice (Fig.…”

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…Moreover, L-DOPA did not affect the NO/sGC/cGMP pathway in the mouse MPTP PD model, being capable only of up-regulating the expression and activity of nNOS and GC in normal animal to the level seen in MPTP-treated mice [177]. Moreover, Giorgi and colleagues [196] observed very low levels of cGMP in the corticostriatal-pallidal loop at the peak of LIDs in rats with experimental hemi-parkinsonism. Interestingly, especially for the possible new treatment applications, pretreatment of the dyskinetic animals with an unselective PDE inhibitor before L-DOPA treatment effectively reduced the severity of the dyskinesias, and partly prevented the decrease of cGMP levels in the GP, putamen and the sensorymotor cortex [196].…”

“…Moreover, Giorgi and colleagues [196] observed very low levels of cGMP in the corticostriatal-pallidal loop at the peak of LIDs in rats with experimental hemi-parkinsonism. Interestingly, especially for the possible new treatment applications, pretreatment of the dyskinetic animals with an unselective PDE inhibitor before L-DOPA treatment effectively reduced the severity of the dyskinesias, and partly prevented the decrease of cGMP levels in the GP, putamen and the sensorymotor cortex [196]. These findings have recently been confirmed by Picconi and co-workers [187] using more specific inhibitors for the PDE that specifically acts on cGMP metabolism.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Thus, in the dyskinetic 6-OHDA-lesioned rat killed in the on-state, levels of cAMP and cyclic guanosine monophosphate (cGMP) were reduced in the cortex, striatum, and GP compared with L-DOPA-naive 6-OHDA-lesioned rats (Giorgi et al, 2008). Subchronic administration of the phosphodiesterase type 5 (PDE5) inhibitor zaprinast partly reversed, although did not normalize, those changes in cyclic nucleotide levels and alleviated established LI-AIMs (Giorgi et al, 2008).…”