Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Psychopharmacology
Jodi E GresackVictoria B Risbrough

Abstract

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32-10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disrupti...Continue Reading

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Citations

Apr 3, 2016·The International Journal of Neuropsychopharmacology·Pim R A HeckmanJos Prickaerts
Jun 2, 2017·Journal of Chemical Information and Modeling·Luca CoduttiTeresa Carlomagno
Nov 7, 2019·Journal of Clinical Psychopharmacology·David P WallingNicholas DeMartinis
Feb 9, 2021·Frontiers in Neuroscience·Frank S MennitiChristopher J Schmidt

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