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 (PD10A) is highly expressed in the striatum where it participates in signaling mechanisms related to cognitive and motor function. 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. These effects are not fully characterized, and we will study them in non-human primates. 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. As indicated by recent physiology data, PDE10A may be expressed predominantly in certain subpopulations of striatal neurons that could then be selectively targeted by PDE10A inhibitors. Imbalances between the activities of neuronal subpopulations in the striatum are at the core of the pathophysiology of movement disorders such as Parkinson's disease. It is therefore conceivable that PDE10A inhibitors may show efficacy against parkinsonian symptoms. In this project, we will characterize the motor effects of TP-10, a selective PDE10A inhibitor, in primates. This is a newly activated project.
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