The behavioral consequences of phosphodiesterase 10A (PDE10A) inhibition combined with the associated biochemical indicators of striatal activation suggest that chronic suppression of PDE10A activity might be expected to drive significant changes in striatal gene expression. Kleiman et al. investigated the changes in gene expression with chronic PDE10A inhibition with a selective PDE10A inhibitor in PDE10A knockout mice to determine the pathways regulated by PDE10A and their potential role in the therapeutic activity of PDE10A inhibition. Regulation of specific genes first suggests that long-term suppression of PDE10A is consistent with altered striatal excitability with potential utility as an antipsychotic therapy. Regulation of histone 3 and histone deacetylase 4, along with the specific biochemical and transcriptional pattern of activity produced by PDE10A inhibition, also points to the potential application of such agents in neurodegenerative conditions such as Huntington's disease. The microarray analysis highlights the power of evaluating therapeutic targets from both genetic and pharmacological perspectives to gain a broader insight into the biological system affected and to more fully evaluate the therapeutic potential of novel biological targets.
See article at J Pharmacol Exp Ther 2011, 336:64–76.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics