Levodopa enhances dopamine synthesis and release in dopamine-deafferented striatum leading to improvements in the parkinsonian symptoms; however, long-term use of levodopa can induce unwanted movements or dyskinesias. We hypothesized that increased dopamine synthesis may determine iper-stimulation of D1 receptors as well as an imbalance between synthesis and catabolism of dopamine-dependent cyclic nucleotide cAMP and cGMP, eventually leading to the occurrence of levodopa-induced dyskinesia. We examined cAMP and cGMP signalling in the 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 level of cAMP and cGMP on the severity of levodopa-induced dyskinesias in animals pretreated with zaprinast a phosphodiesterase (PDE) inhibitor of cyclic nucleotide catabolism. 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.