In vivo imaging of designer receptor that enables to modify reward-related behavior in monkeys

DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are pharmacogenetic agents that, when expressed on neuronal cell membranes and activated through systemic delivery of the targeting drug, will inhibit (or excite) activity of all neurons expressing the DREADD. Using the hM4Di receptor, an inhibitory DREADD that can be activated by clozapine-n-oxide (CNO), we have been able to (1) monitor the location and intensity of receptor expression by in vivo PET-imaging, and (2) modify monkey\u27s behavior reversibly. In our experiments, a lentiviral vector expressing the hM4Di receptor was injected into the putamen of two macaque monkeys. PET imaging using a ligand targeting the receptor showed a focal patch of high uptake at the injection site. The location matched the site of neuronal hM4Di expression identified histochemically post-mortem. Measuring uptake of the PET ligand following different CNO doses yielded to estimate the dose-occupancy relationship for binding of CNO to the hM4Di receptor. To assess the behavioral effect, an AAV vector expressing the hM4Di receptor was injected bilaterally into the ventral striatum of two monkeys that had been trained to perform a reward-size task. PET imaging verified the expression of the hM4Di receptor. The monkey\u27s performance was altered by CNO treatment in a manner similar to that seen after bilateral inactivation of the ventral striatum with muscimol in two other monkeys. Given that PET-imaging is capable of monitoring in vivo DREADD expression, the DREADD provides a novel tool to study the neural mechanism of higher brain functions in nonhuman primates and, also, contributes to the development of human therapeutic settings.2014年度 包括脳ネットワーク冬のシンポジウ