A2AR/MGLUR5 ANTAGONIST COMBINATION ANTIPARKINSONIAN THERAPY IN MPTP MONKEYS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Current pharmacological treatments for Parkinson's Disease (PD) act on the dopamine neurotransmitter system and cause debilitating motor side effects. This project seeks to study new potential antiparkinsonian drugs (and their mechanisms of action) that act on other neurotransmitter systems and are therefore not likely to cause motor side effects. Antagonists of metabotropic glutamate receptor 5 (mGluR5) and adenosine A2A receptor (A2AR) are the focus of this study. These drugs will be injected systemically or locally into various nuclei of the basal ganglia of MPTP-treated parkinsonian monkeys (the gold-standard model of PD), and their motor behavior will be monitored. These drugs will be administered both alone and together. We have found that when injected systemically, the mGluR5 antagonist MTEP provides a modest anti-akinetic benefit to MPTP-treated monkeys. After trying several different A2AR antagonists, we have been unable to measure any behavioral antiparkinsonian effect in our monkeys, whether the drugs were administered systemically or locally in the basal ganglia, either given alone or in combination with mGluR5 antagonist. We were unable to obtain the only A2AR drug published to have antiparkinsonian effects in monkeys at the time (KW-6002), due to the proprietary nature of the drug. Since then, one more A2AR drug (preladenant) has been published to have antiparkinsonian effects in monkeys. We have made arrangements to get some of this new compound, with better affinity/selectivity/bioavailability, for testing in our monkeys.