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Combined treatment with a selective PDE10A inhibitor TAK-063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic-like effects

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.

 

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