Pergamon Pharmacology Biochemistry and Behavior,Vol. 48, No. 4, pp. 935-940, 1994 Copyright© 1994 Elsevier Science Ltd Printedin the USA.All rightsreserved 0091-3057/94 $6.00 + .00 0091-3057(94)E0057-O Acute Behavioral Effects of MK-801 in Rhesus Monkeys: Assessment Using an Operant Test Battery ELIZABETH A. BUFFALO,* MICHAEL P. GILLAM,* RICHARD R. ALLENI" AND MERLE G. PAULE*~: 1 *Division of Neurotoxicology, and ~fComputer Based Systems, Inc., National Center for Toxicological Research, Jefferson, AR 72079-9502 YjDepartments of Pharmacology and Toxicology, and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 Received 30 July 1993 BUFFALO, E. A., M. P. GILLAM, R. R. ALLEN AND M. G. PAULE. Acute behavioraleffects of MK-801 inrhe- sus monkeys: Assessment using an operant test battery. PHARMACOL BIOCHEM BEHAV 48(4) 935-940, 1994.-The acute effects of MK-801, a selective, noncompetitive NMDA receptor antagonist, were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). MK-801 (0.003-0.075 mg/kg, IV), given 15 rain pretesting, produced significant dose-dependent decreases in measures of IRA and TRD performance at doses :,-0.03 mg/kg. In both tasks, MK-801 produced significant decreases in accuracy at doses lower than those required to affect response rate. MK-801 also produced statistically significant decreases in PR, CPR, and DMTS measures, but only at higher doses (_>0.056 mg/kg) that caused significant decreases in both response rates and accuracies. These results indicate that, in monkeys, performance of operant tasks designed to model learning and time estimation is more sensitive to the disruptive effects of MK-801 than performance of tasks that model motivation, color, and position discrimination, and short-term memory and attention. MK-801 Macaca mulatta Operant behavior Learning Color and position discrimination Short-term memory Motivation Attention Time estimation Incremental repeated acquisition Temporal response differentiation Delayed matching-to-sample Food reinforcement ( + )-5-METHYL- 10,11-dihydro-5H-dibenzo-[a,d]cyclo-hep- ten-5,10-imine maleate (MK-801) is a selective, noncompeti- tive N-methyl-d-aspartate (NMDA) receptor antagonist that blocks NMDA-induced excitation by interacting with open ion channels linked to the NMDA receptor (3,7,17). The NMDA receptor has been shown to play a critical role in the induction of the phenomenon known as long-term potentiation (LTP) (2). This receptor mediates calcium influx across the postsyn- aptic membrane and it is this calcium influx that is believed to lead to the development of LTP. LTP has been described as a substantial increase in synaptic efficacy that can be induced by tetanic stimulation (3,26) and it is believed that the mecha- nisms involved in the induction and maintenance of LTP are fundamental to learning and memory processes (1). There- fore, we predicted that MK-801 (an LTP antagonist) would selectively impair performance in tasks that model learning and memory. Some of the behavioral effects of MK-801 are qualitatively similar to those of PCP, ketamine, and other PCP-like com- pounds, with the most striking difference being the longer duration of action of MK-801 (25). In nonhuman primates, PCP and MK-801 induce similar effects such as calming, ataxia, salivation, and slight respiratory depression (27). Also, certain similarities in effects on conical EEG have been ob- i To whom requests for reprints should be addressed. 935