Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications

Phosphodiesterase 10A ( PDE10A) is highly expressed in striatal medium spiny neuronsof both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10Ainhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10Ainhibitors as a new treatment for schizophrenia. However, PDE10Ainhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classesmay have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10Ainhibitor MP-10 to those of the clinical standard D2 antagonist risperidonein rhesus monkeys using a standardized motor disabilityscale for parkinsonian primates and a newly designed“ DrugEffects on Nervous System” scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidonebroadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10Ainhibitors for the treatment of psychotic symptoms.