Investigation on phosphodiesterase 10A control over D1-mediated facilitation of GABA release in the striato-nigral projections under normal and dopamine-depleted condictions in murine midbrain slices.

In the present study, we investigated the interplay between D1 receptors and phosphodiesterase (PDE) 10A in the modulation of the GABAergic transmission to substantia nigra pars reticulata (SNpr) neurons, using mouse slices. we found that PDE10A inhibitors (papaverine), alone or in combination with the D1 receptor agonist SKF 38393, did not change spontaneous IPSCs (sIPSCs) frequency or amplitude in the substantia nigra pars reticulata (SNpr). An increase in frequency, but not in amplitude, of sIPSCs was only observed when SKF 38393 and PDE10A inhibitor was associated to perfusion with higher extracellular K+. On the other hand, the amplitude of the evoked IPSCs (eIPSCs) of the striato-nigral projection to SNpr, was increased in response to co-administration of SKF 38393 and papaverine in normal extracellular potassium. We next investigated the effects produced by dopamine (DA) depletion in the striatum. Under this condition, SKF 38393 alone increased either sIPSCs frequency and eIPSC amplitude. We found reduced PDE10A levels and higher cAMP-dependent phosphorylation in response to D1R stimulation in the striatum of DA-depleted mice. Perfusion with papaverine had no effect on the SKF 38393-induced changes of IPSCs in slices of DA-depleted mice. These findings reveal a dynamic interplay between PDE10A activity, level of neuronal network depolarization and degree of dopaminergic tone in the ability of D1 receptors to facilitate the GABAergic transmission to SNpr neurons from the direct nigro-striatal pathway.