NON-INVASIVE METHOD TO MEASURE NEURAL PHARMACOKINETICS AND PHARMACODYNAMICS

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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. A critical part of therapeutic drug development is determining the efficacy of a drug (pharmacodynamics) and its lifetime within the body (pharmacokinetics). We hypothesize that the electroretinogram (ERG), an in vivo recording of retinal function, can provide a unique non-invasive method for deriving the neural pharmacodynamics/pharmacokinetics of novel compounds that are candidate therapies for neurological disorders. Glutamate is the main excitatory neurotransmitter in both the brain and retina. Because of their role in regulating synaptic transmission, the G protein-coupled metabotropic glutamate receptors (mGluRs) are being studied as potential sites for new drugs aimed at the treatment of neurological disorders. My collaborator, Dr Robert Duvoisin and I are studying the distribution and function of group-III mGluRs in the retina. We recently found in mice that ERG oscillatory potentials (OPs), are altered by systemic administration of three new classes of drugs that act as selective agonists or modulators of mGluR4, -R7 or -R8. The retina is embryologically part of the CNS, and synapses within the inner retina share similar structure and function with cortical synapses. The blood-retina barrier and blood-brain barrier are also comparable in structure and mode of action. Thus, measurable effects within the retina could serve as a proxy for effects on brain function. We propose that the ERG oscillatory potentials, generated by neural activity within the inner retina, could serve as an accessible, non-invasive functional assay for measuring the neural effects of drugs. A non-human primate model is essential as old-world monkeys, such as the rhesus, are the only animals with a retina almost identical to the human. The goal of this pilot project is to adapt our method developed in mice for use in non-human primates, which in turn will serve as a foundation for extending our technique to pre-clinical trials in humans.