Tolerance to paradoxical increase in motor activity caused by inhibition of phosphodiesterase 10a in a model of hypodopaminergy

Abstract

Introduction. Phosphodiesterases (PDEs) are a group of enzymes that hydrolyze the phosphodiester bond in cyclic nucleotides. PDE10A is mainly present in the medium-sized spiny neurons of the striatum. Functionally, PDE10A inhibition imitates the effect of D1-like agonists and D2-like dopamine receptor antagonists, and simultaneously modulating “direct” and “indirect” striato-thalamo-cortical brain pathway. To date, the effects of PDE10A inhibition have been characterized mainly, reproducing the inhibitory motor activity of D2-like dopamine receptor antagonists.The objective was to evaluate the stimulating motor activity of the effect of PDE10A inhibitors, as well as the possible development of tolerance to these effects when they are re-administered.Methods and materials. The hypodopaminergic state in male Wistar stock rats was modeled by administration of the VMAT2 inhibitor tetrabenazine (3 mg/kg). The effects of selective inhibitors PDE10A, MP-10 (0.3–5 mg/kg) and RO5545965 (0.1–0.9 mg/kg), on the motor activity of rats were evaluated with single and repeated administration (5 and 10 days).Results. Switching off PDE10A dose-dependently stimulated the motor activity of rats after administration of tetrabenazine. However, repeated administration of PDE10A inhibitors was accompanied by the development of tolerance to their paradoxical stimulating effect.Conclusion. The development of tolerance may limit the potential clinical use of PDE10A inhibitors to correct hypodopaminergic symptoms in patients with Parkinson’s disease. It is necessary to study the molecular mechanism of this phenomenon.