Novel phosphodiesterase 10A inhibitor drugs, through a distinct mechanism on striatal dopamine receptors, could raise the possibility of producing an augmented pharmacological antipsychotic effects by a combination therapy with the standard antipsychotic drug.
TAK-063 is a novel phosphodiesterase 10A inhibitor which has been evaluated for this hypothesis. Results show that the use of TAK-063 can produce augmented antipsychotic-like activities in combination with antipsychotics without alteration of plasma prolactin levels and catalepsy
In this collaborative paper with Takeda, we demonstrate that:
- Combined treatment with TAK-063 and either haloperidol or olanzapine leads to a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum.
- TAK-063 enhances N-methyl-D-aspartic acid receptor mediated synaptic responses in rat cortical striatal slices in both direct and indirect pathway MSNs to a similar extent.
- Co-administration of TAK-063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway.
- Combined treatment with TAK-063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine- or MK-801-induced hyperactivity in rats and MK-801-induced deficits in prepulse inhibition in mice.
- TAK-063 did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats.