Tolerance to a paradoxical increase in motor activity induced by PDE10A
inhibition under hypodopaminergic conditions
Abstract
Background and Purpose: Phosphodiesterases (PDEs) are a family of
enzymes, which hydrolyze cAMP and cGMP. PDE10A is expressed mainly in
the medium spiny neurons of the striatum that provides an opportunity to
modulate the movement control pathways of the basal ganglia: “direct”
(D1 receptor-dependent) and “indirect” (D2 receptor-dependent). Thus,
inhibition of PDE10A can functionally mimic the action of both D1
receptor agonists and D2 receptor antagonists, although much less
attention has been paid to the assessment of D1 receptor agonist-like
effects. The purpose of the present study was (1) to confirm the motor
stimulatory effects of PDE10A inhibitors and (2) to test whether these
effects are subject to the development of tolerance. Experimental
Approach: The ability of single or repeated (5 or 10 days)
administration of selective PDE10A inhibitors, MP-10 (0,3-5 mg/kg) and
RO5545965 (0.1-0.9 mg/kg), to stimulate locomotor activity was assessed
in rats after single tetrabenazine challenge (3 mg/kg). The study was
pre-registered on PreclinicalTrials.eu. Key Results: PDE-10A inhibition
exerted paradoxical motor stimulatory properties in a dose-dependent
manner. However, repeated administration of PDE10A inhibitors led to a
reduction of their effects. Conclusion and Implications: PDE-10A
inhibition produces a paradoxical increase in motor activity in animals
with low dopamine tone. After repeated administration of PDE-10A
inhibitors, these effects disappeared. The development of tolerance
similar to that previously observed for D1-receptor agonists may limit
the potential clinical use of the stimulatory effects of PDE10A
inhibitors. Further studies aimed at analyzing the molecular mechanisms
of this tolerance are warrant