Ketamine impairs multiple cognitive domains in rhesus monkeys
Introduction
Recreational use and abuse of the dissociative anaesthetic ketamine (Ketalar®, Ketaset®) is not new (Jansen, 2001), however, the available evidence suggests that such use of ketamine has increased substantially in recent years (Colfax et al., 2001, Dalgarno and Shewan, 1996, Garfield et al., 2001, Mansergh et al., 2001, Mattison et al., 2001, Riley et al., 2001, Weir, 2000). Ketamine functions as a non competitive antagonist of N-methyl-D-aspartate (NMDA) glutamatergic receptors which play a crucial role in long-term potentiation, a putative cellular mechanism subserving memory (for review see Huang and Stevens, 1998, Nicoll and Malenka, 1999). This mechanism is intuitively a general one, thus interference with NMDA function would be predicted to produce widespread impairment of memory. Studies have shown that noncompetitive NMDA antagonists interfere with performance of memory tasks in a number of species (e.g. Buffalo et al., 1994, Ghoneim et al., 1985, Morris et al., 1986) and, furthermore, the chronic abuse of ketamine may be associated with persisting impairment of memory and other cognitive functions in humans (Curran and Monaghan, 2001, Jansen, 1990). Therefore, the exploration of the cognitive impact of ketamine exposure is of interest to further delineate the possible health risks of ketamine abuse and the role that NMDA receptors may play in various aspects of behavior.
Subanaesthetic doses of ketamine have been administered in a number of human neuropsychological studies as a putative model of psychosis (Curran and Monaghan, 2001, Curran and Morgan, 2000, Ghoneim et al., 1985, Grunwald et al., 1999, Hetem et al., 2000, Krystal et al., 2000, Krystal et al., 1994, Malhotra et al., 1996, Newcomer et al., 1999) and in such studies ketamine has been shown to interfere with recall and recognition memory for words and nonverbal stimuli (Adler et al., 1998, Ghoneim et al., 1985, Grunwald et al., 1999, Hetem et al., 2000, Malhotra et al., 1996) as well as working memory (Adler et al., 1998) and executive function (Krystal et al., 2000). There is some evidence that ketamine does not affect attentional processes (Adler et al., 1998, Newcomer et al., 1999, Oranje et al., 2000), digit span (Ghoneim et al., 1985, Grunwald et al., 1999) or spatial memory (Newcomer et al., 1999), thus ketamine may interfere only selectively with cognition.
Such acute drug-challenge investigations in human subjects are necessarily limited, however, in terms of the breadth of pharmacological investigations that may be performed in the same subjects. Investigations utilizing nonhumans more readily permit the evaluation of extensive dose-response functions, direct within-subjects comparison of the effects of multiple alternate drug challenges, and the use of combined drug challenges to further delineate the behavioral effects of psychoactive drugs. As the macaque monkey may be readily trained to perform a wide range of behavioral tasks concurrently (Paule et al., 1990, Voytko, 1993, Weed et al., 1999), it is an ideal model for comprehensive characterization of cognitive status following a variety of CNS challenges. Investigation of the effects of ketamine on a range of behavioral procedures in monkeys might, therefore, contribute substantially to understanding of the risks posed by ketamine to cognitive function in a more mechanistic manner than is possible with human studies.
The behavioral effects of phencyclidine (PCP), dizocilpine (MK-801) and ketamine have been characterized in a number of studies in monkeys (Buffalo et al., 1994, Byrd et al., 1987, Frederick et al., 1995, Harder et al., 1998, Ogura and Aigner, 1993, Rupniak et al., 1992, Thompson et al., 1987). While all three compounds share noncompetitive NMDA antagonist properties, ketamine has substantially lower affinity for the NMDA receptor (Parsons et al., 1996, Sihver et al., 1998) and the available direct comparison studies suggest that ketamine is approximately one-tenth as potent as PCP in monkeys performing operant tasks (Brady et al., 1980, Byrd et al., 1987, Thompson et al., 1987). Prior monkey studies have generally focused on one or two behavioral or operant measures rather than an array of measures as is common in human studies, and the multi-task studies evaluated PCP and MK-801 but not ketamine (Buffalo et al., 1994, Frederick et al., 1995). In sum, there is relatively little evidence regarding the effects of ketamine on behavioral function in nonhuman primates available for comparison with profiles in human volunteers or ketamine abusers.
The present study was designed to evaluate the cognitive effects of acute ketamine exposure in rhesus monkeys, trained to concurrently perform a number of behavioral tasks comprising a nonhuman primate neuropsychological test battery (Weed et al., 1999). Rhesus monkeys’ performance on tests from this battery have been previously demonstrated to be sensitive to the effects of pharmacological manipulation (Taffe et al., 2002a, Taffe et al., 1999, Taffe et al., 2002b, Weed and Gold, 1998). Use of this battery serves a number of specific purposes for the present investigation. First, this study will investigate the effects of ketamine, concurrently, on a range of behaviors much as has been done previously for PCP and MK-801 but not ketamine. Second, this test battery has been derived from one used in various human studies, thus behavioral profiles may be compared with prior results from human populations with traumatic, developmental or other known brain insults (see Weed et al. (1999) for review). Since the behavioral assays used here may be more directly related to specific brain regions or mechanisms (unlike the tests used in the Buffalo et al., 1994, Frederick et al., 1995 studies) additional information regarding the behavioral effect of noncompetitive NMDA antagonists will result. Here, it is predicted that ketamine will interfere specifically (i.e. in a dose×difficulty dependent manner) with pattern recognition memory and spatial working memory as assessed with the delayed match-to-sample (DMS) and self-ordered spatial search (SOSS) procedures, respectively, since humans challenged with ketamine are impaired on tasks associated with similar cognitive constructs (Adler et al., 1998, Ghoneim et al., 1985, Grunwald et al., 1999, Hetem et al., 2000, Malhotra et al., 1996).
Evaluation of the behavioral effects of ketamine in monkeys trained on the test battery serves a number of additional goals. It will provide an important extension of our previous study of the effect of muscarinic blockade on these battery tasks (Taffe et al., 1999), and a complement to our contrast of scopolamine and ketamine effects (Taffe et al., 2002b) on a new memory test with proposed sensitivity and specificity for Alzheimer's Disease (Fowler et al., 2002, Swainson et al., 2001). Together these efforts explore the possible unique or overlapping contributions of muscarinic and NMDA mechanisms to the regulation of cognition with a particular emphasis on learning and memory. Thus, this work serves a continuing goal of determining the role various neurotransmitter systems and subsystems play in cognitive function across a range of performance domains in a single preclinical model. Furthering this understanding will also assist in the interpretation of behavioral outcome in continuing studies of the effects of neurotropic virus infection (e.g. Gold et al., 1998, Weed and Gold, 2001), exposure to putative neurotoxicants (e.g. Taffe et al., 2002a, Taffe et al., 2001) and chronic exposure to drugs of abuse by generating neuropharmacological profiles of performance analogous to the profiles generated by evaluating various human populations on similar tasks. Finally, this study is a necessary preliminary for the development of a chronic-exposure, nonhuman model of the cognitive risks associated with long-term use and abuse of ketamine.
Section snippets
Subjects
Eight adult male rhesus monkeys (Macacca mulatta) served as subjects. The monkeys were approximately 5 years of age and weighed 6.5–8.0 kg at the beginning of the study. Animals were individually housed and fed in the home cage after completion of the daily testing session. The animals’ normal diet (Lab Diet 5045, PMI Nutrition International) was supplemented with fruit or vegetables 4 days/week and water was available ad libitum in the home cage. Principles of laboratory animal care (Clark et
DMS
Choice accuracy in the DMS task was significantly decreased by increasing the retention interval and by the administration of ketamine as is illustrated in Fig. 1. Performance remained substantially above chance responding (i.e. 25%), however, for all conditions and trial types. The ANOVA confirmed a significant main effect of retention interval [F2,10=9.744; P<0.05], drug treatment condition [F4,20=13.051; P<0.05] and the interaction [F8,40=2.650; P<0.05]. Post hoc analysis of these effects
Discussion
The present findings show that subanaesthetic doses of ketamine interfere with multiple aspects of behavioral performance in rhesus monkeys, much as has been reported with humans (Curran and Monaghan, 2001, Curran and Morgan, 2000, Ghoneim et al., 1985, Grunwald et al., 1999, Hetem et al., 2000, Krystal et al., 2000, Krystal et al., 1994, Malhotra et al., 1996, Newcomer et al., 1999). Dose related decrements in performance were observed in all of the behavioral tests, thus ketamine interfered
Acknowledgements
We are grateful to Dr Simon N. Katner and Dr Michael R. Weed for comments on an earlier version of the manuscript and to Dr William J. Taffe for assistance with the SOSS strategy algorithm. This research was supported by funds from the Universitywide AIDS Research Program, University of California, Grant No. F99-SRI-051 (MAT) and by USPHS grants DA13390 (MAT) and MH47680 (LHG). This is publication #14686-NP from The Scripps Research Institute.
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- 1
Present address: Department of Psychology, The University of Georgia, Athens, GA 30602-3013, USA.
- 2
Present address: Pharmacia Corporation, Mail code 7251-209-405, 301 Henrietta Street, Kalamazoo, MI 49007, USA.