MOTOR EFFECTS OF PDE10A INHIBITORS IN PRIMATES

$54,827P51FY2010RRNIH

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in the striatum where it participates in signaling mechanisms related to cognitive and motor function. PDE10A is localized to the cell membrane of medium spiny neurons (MSNs) that are the projection neurons driving the striatal output, and hydrolyzes cyclic phosphodiester bonds of cAMP and cGMP, which results in modulation of signal transduction in striatal output pathways. Signaling mechanisms in these pathways is key to the control of posture and movement. In recent years, selective PDE10A inhibitors have been synthesized, and preclinical tests of these agents have shown significant therapeutic potential for schizophrenia. At this time, the effects of these drugs on other realms of behavior are less clear. As with other antipsychotic drugs, it will be particularly important to evaluate the motor effects of PDE10A inhibitors. In this project, we will therefore study the effects of TP-10, a selective PDE10A inhibitor on motor behavior and brain metabolic activity in normal macaque monkeys. Knowing such motor effects would not only help us predict potential side effects of the clinical use of these drugs in schizophrenia, but may also lead us to discover alternative applications for PDE10A inhibitors. For instance, PDE10A may be predominantly expressed in certain subpopulations of striatal neurons. Blocking these receptors may revert some of the abnormalities of striatal function in parkinsonism. It is, therefore, conceivable that PDE10A inhibitors may show antiparkinsonian efficacy.

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