Assessment of ketamine in the developing nonhuman primate. Ketamine is a priority drug for study under Best Pharaceuticals for Children Act, BPCA. Determine whether ketamine, a frequently used anesthetic in children, is able to induce immature primate abnormal neuronal apoptosis as has been demonstrated in immature rodents.FDA will seek to determine the reversibility of the ketamine-induced insult at the most sensitive developmental stage using the maximally effective dose. The developmental stage at which ketamine produces maximal neuronal apoptosis will be used to determine the reversibility of the apoptosis induced by ketamine. Three groups of animals will be studied - a saline control group and two ketamine dose groups (doses to be determined based on the outcome of the Phase 2, dose-response experiment). Control and treated animals will be exposed as in the Phase 1 and 2 experiments and allowed to mature for up to 2 years of age. Beginning at 6 months of age, the animals will be trained to perform the NCTR Operant Test Battery (OTB, see section below) and assessed 5 days per week. At approximately 2 years of age the animals will be sacrificed and brain tissue collected as in the Phase 1 and 2 experiments. Six monkeys will be used for each of the three experimental groups_ Because the PET imaging may be done either at the NCTR location or at the University of Arkansas for Medical Sciences depending on the availability of equipment, this portion of the protocol will be Completed updated at a later date. Noninvasive MicroPET imaging of the developing animals will be conducted to determine the timecourse of the neuronal apoptosis. Animals of Phase 3 will be longitudinally assessed with the use of MicroPET in collaboration with Ron Walker. University of Arkansas for Medical Sciences. These noninvasive imaging studies will focus on the time-course of apoptosis occurrence in the central nervous system following ketamine exposure and determine if this clinically relevant, noninvasive tool can be used to visualize this important loss of neurons in the developing animal. The apoptosis identifying ligand, Annexin V, tagged to a PET agent will provide the resolution and quantitation necessary. The PET agents that will be useful includ1-124, Gal!ium-68, or a positron-emitting form of Technetium (Tc-94m) The Phase 3 experiment will not be conducted if ketamine induced apoptosis is not observed in the Phase 1 experiment.
