EXPERIMENTALNEUROLOGY 102,307-313 (1988) Cerebral Metabolism of Parkinsonian Primates 21 Days after MPTP ROBERTJ.SCHWARTZMAN, *slG~~~~~~~~M.A~~~~~~~~,*T~~~~~N.F~~~~~~,* JOHN R. GROTHUSEN,* AND STEPHEN M. STAHL? *Department of Neurology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, and tNeuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Essex, England This study evaluates the changes in the local cerebral metabolic rate for glucose (LCMRg) in primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropy- ridine (MPTP). The LCMRg was evaluated 2 1 days fol- lowing the last dose of MPTP. At this time, all MPTP- injected animals demonstrated parkinsonism and stria- tal dopamine was reduced to less than 3% of control values. The structures whose LCMRg was most affected were the motor cortex, the intermediate zone of the pu- tamen, the external segment of the globus pallidus, the medial part of the ventrolateral nucleus of the thalamus (VL,), visual cortex, locus ceruleus, and the dorsolat- era1 segment of the substantia nigra pars compacta. The structure whose increase in LCMRg correlated most closely to the clinical severity of parkinsonism was the external segment of the globus pallidus. o 1989 Academic Press, Inc. INTRODUCTION The clinical and neuropathological model of Parkin- son’s Disease produced by the intravenous administra- tion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is now well established in humans and pri- mates (6, 8). The changes in glucose metabolism in the striatonigral, mesolimbic-cortical, and thalamospinal systems 3 days following the last MPTP dose were re- cently described (14-16). These metabolic changes pri- marily reflect the damage caused by MPTP to monoami- nergic cells and terminals. However, a component of these early changes may be attributable to the residual MPTP and 1-methyl-4-phenylpyridine (MPP+) that re- main in the primate brain. In a recent study the LCMRg of primates was evaluated 3 or more months following injection of MPTP, changes were seen in the external segment of the globus pallidus, subthalamic nucelus, frontal eye fields, and medial dorsal nucleus of the thala- mus (11). The present study was undertaken 21 days fol- ’ The authors express their gratitude to Mrs. D. L. Brainard and S. Lehman for their technical assistance. This study was supported in part by a grant from Merck Sharp & Dohme Research Laboratories. lowing the last dose of MPTP. At this time the animal is in an intermediate stage, and most of the MPTP has been cleared from the central nervous system (CNS) (9). There is evidence in rodents that at this time some regeneration of monoaminergic terminals has oc- curred (13). METHODS Fourteen adult male monkeys (A4acaca fascicularis), weighing between 4 and 6 kg, were used in this study. Six animals that received no MPTP were used as controls. Three monkeys received MPTP (0.5 mgjkg) daily for 4 days and one animal was injected once a week for 4 weeks. These animals were sacrificed 3 days after the last injection (MPTP Acute). Four animals received MPTP (0.35-0.5 mg/kg) daily for 4 consecutive days and were sacrificed 21 to 25 days after the last MPTP injec- tion (MPTP Intermediate). Neurological examinations were performed on all ani- mals prior to MPTP injections and once a week after MPTP injections. The neurologic examination evalu- ated cranial nerve function, muscle tone, deep tendon reflexes, sensorimotor integration, tremor, fine move- ment, and free movement. The cranial nerve examina- tion evaluated eye movements, vocalization, swallowing, facial movements, and brain stem reflexes. The deep tendon reflexes tested were the brachial radialis, knee jerk, and ankle jerk. Sensorimotor integration was tested by examining touch-placing, grasp avoidance, and threat response. Tremor was rated on severity and the number of extremities involved. Each animal was video- taped in his cage for a 5-h period (10:00 AM to 3:00 PM) once a week. Fine movement of the extremities was eval- uated by observing avoidance responses and manipula- tion of the fingers while eating and grooming. Free movement was evaluated by counting the number of movements the animal made across the four base quad- rants of his cage, as well as in the vertical plane (between floor and perch). Measurement of LCMRg was performed in the same manner for both control and MPTP-treated animals. All animals were anesthetized with ketamine (15 mg/kg) 307 0014-4886/88 $3.00 Copyright 0 1988 by Academic Press, Inc. All rights of reproduction in BIIY form reserved.