Phosphodiesterase 10A and cyclic nucleotide catabolism in the physiopathology of experimental parkinsonism

We describe how dopamine loss can affect the catabolism of the second messenger cAMP and cGMP in the basal ganglia, pointing out that Phosphodiesterases 10A (PDE10A) may play a key role in such process. 10 weeks after dopaminergic lesion in the rat midbrain with 6-OHDA, the cGMP levels are decreased in all dopamine deafferented regions. However, in the same regions: a) &cAMP level show significant increase in the striatum and large variability in the globus pallidus and substantia nigra; b) conversely, cAMP levels are markedly decreased in nucleus accumbens. According to cAMP changes, mRNA and PDE10A expression are down-regulated in the striatum, and in striato-pallidal and striato-nigral projections, while PDE10A is up-regulated in the nucleus accumbens. Therefore, altered cGMP and cAMP steady-states occur in experimental parkinsonism, but only modulation of cAMP catabolism likely relies on dopamine-dependent PDE10A changes. PDE10A downregulation in neurons in the striatum, and in striato-pallidal and striatonigral terminals suggest PDE10A can be involved in dysfunctions of postsynaptic and pre-synaptic modulation of cAMP signaling and synaptic plasticity. Moreover, PDE10A up-regulation in nucleus accumbens secondary to dopamine loss suggests an involvement of PDE10A in mood disorders frequently associated with parkinsonism.