Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents

Background: Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D-1 receptor-expressing medium spiny neurons (D-1-MSNs) may be higher than that in D-2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D-2-MSNs but partially activated D-1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates. Methods: Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D-1- and D-2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D-1- and D-2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice. Results: Compared with T-609, T-773 comparably activated D-2-MSNs but partially activated D-1-MSNs. Haloperidol (a D-2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D-2-MSNs by all drugs and those in D-1-MSNs by T-773 and T-609 were qualitatively similar. Conclusions: Differential pharmacological profiles among those drugs could be attributable to activation balance of D-1- and D-2-MSNs. The balanced activation of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.