Phosphodiesterase 10A (PDE10A) inhibitors have recently been proposed as a new therapy for schizophrenia. The aim of this study was to enhance our understanding of the role of PDE10A inhibitors on and to potentially identify a clinically useful mechanistic/functional biomarker using 2-deoxyglucose (2-DG) autoradiography. PDE10A inhibitors papaverine (10 and 40 mg/kg), PQ-10 (0.16-10 mg/kg) and MP-10 (0.16-40 mg/kg) induced region specific hypermetabolism in the globus pallidus and lateral habenula of C57BL/6 mice. Studies with MP-10 revealed a dose-dependent relative increase in globus pallidus activation, while a bell-shape curve was observed for the lateral habenula. While the relative increase in 2-DG uptake in lateral habenula was also characteristic of D2 antagonist haloperidol (0.01-0.63 mg/kg), relative 2-DG changes were absent in the globus pallidus. This observation is likely explained by interaction of PDE10A inhibitors with the D1 direct pathway as suggested by experiments in combination with D1 agonist SKF-82958 (0.16 mg/kg). The absence of an effect of MP-10 (2.5 mg/kg) on relative glucose metabolism in globus pallidus and lateral habenula of PDE10A knockout mice confirmed the specificity of the signal induced by PDE10A inhibitors. These studies substantiate the regulatory role of PDE10A in the basal ganglia circuit, and as such support the potential of PDE10A inhibitors for treating psychiatric disorders. Moreover, we could differentiate PDE10A inhibitors from haloperidol based on specific patterns of hypermetabolism likely due to its combined action at both direct and indirect dopaminergic pathways. Finally, these specific changes in brain glucose metabolism may act as a translational biomarker for target engagement in future clinical studies.
- Received April 12, 2011.
- Revision received July 7, 2011.
- Accepted July 7, 2011.
- The American Society for Pharmacology and Experimental Therapeutics