Research reportScopolamine alters rhesus monkey performance on a novel neuropsychological test battery
Introduction
Acting on the basis of information once present but no longer available is necessary for the survival of numerous organisms. The ability to store and recall information (memory) aids in foraging, reproduction and escaping predation amongst other less crucial behavior. In humans, the failure of memory processes can have a dramatic and detrimental effect on daily life as is observed in individuals who suffer from dementia of the Alzheimer's type (DAT). Although DAT is associated with dysfunction or loss of a number of neural systems, the cholinergic impairment is particularly pronounced, which has focused attention on the relationship between brain cholinergic circuits and cognitive performance with particular regard for memory function (Refs. 3, 31, for review). The study of memory in animals in which lesions of central cholinergic systems were produced has supported the hypothesis that cholinergic systems are required for normal memory (Ref. [45], for review). These observations have engendered the creation of a number of animal models of cholinergic dysfunction which have provided a wealth of information regarding the specific relationship between memory and cholinergic mechanisms (Refs. 21, 29, for review). One major category of such models utilizes the administration of an anticholinergic drug to produce cognitive deficits in normal animals.
The drug scopolamine has been shown to produce poor performance on a wide range of memory tasks in numerous species including rats 10, 22, pigeons [39], nonhuman primates 1, 4, 30, 33, 34and humans 6, 11, 15, 17, 32, 36. This effect is thought to be mediated through antagonism of the muscarinic subtype of cholinergic receptor. Similar observations have been made after administration of atropine, another muscarinic antagonist, in rats 13, 18, nonhuman primates 16, 26, 40and humans 19, 20. Less well established is the relationship between cholinergic mechanisms and specific aspects of memory task performance. There has been some disagreement as to whether the effect of muscarinic antagonism is specific to memory retention (e.g., Ref. [4]), memory storage (e.g., Ref. [2]) or whether it primarily affects other cognitive functions which contribute to successful memory task performance such as selective attention (e.g., Ref. [42]), sustained attention (e.g., Ref. [7]) or visual perception (e.g., Ref. [14]). The utility of scopolamine as a specific model of memory dysfunction would be greatly enhanced by the resolution of these questions.
A number of investigators have examined the effect of scopolamine on memory retention in nonhuman primates by using a forgetting task in which the subject is briefly shown a sample stimulus. After a variable interval of time (retention interval) the subject is allowed to choose between the sample and one or more alternatives, gaining a reinforcer for a correct choice. In delayed-response tasks (DR) the crucial distinguishing feature is the spatial location of the sample. In delayed (non)matching to sample tasks (DMS/DNMS) the crucial features are the visual characteristics of the sample item (e.g., color, form). These tasks are “forgetting” tasks in the sense that choice accuracy tends to decrease as the retention interval is increased. Research has shown that muscarinic blockade can result in increasingly larger performance decrements as the retention interval is lengthened 4, 26, 34. Bartus and Johnson [4]argue that this increase in the rate of forgetting implies that the detrimental effect of muscarinic blockade is specific to memory retention mechanisms and cannot be entirely due to alterations in visual perception or attention. This effect may, however, be specific to memory for spatial information, as other investigators have reported that scopolamine reduces choice accuracy in stimulus-recognition memory forgetting tasks (e.g., DNMS) but that it does so to approximately the same degree regardless of retention interval, indicating no change in the rate of forgetting 1, 33. These latter results have also been interpreted to mean that muscarinic blockade impedes the entrance of information into memory while not affecting the retention of information once it has been stored.
Additional experiments conducted in rat 41, 46, human 12, 17and nonhuman primate [2]have provided direct evidence that scopolamine interferes with storage but does not impair the retention or retrieval of information. For example, Aigner et al. [2]used a modified version of the DNMS task in which scopolamine was administered either before the presentation of sample stimuli or during the retention interval between the sample and choice (recognition) phases of the task. When scopolamine was administered before the presentation of the sample, performance was impaired but when scopolamine was administered after the sample presentation, performance was unchanged. This finding supports the hypothesis that scopolamine affects memory processes up to and including storage but not memory maintenance or retrieval processes.
Although a number of similarities exist in reports of the effects of muscarinic antagonism in human and nonhuman primates, direct comparisons are difficult. Studies of cognitive function in humans often rely on language-based tasks which cannot be used in the nonhuman primate 6, 15. In addition, most studies of the effects of scopolamine in humans have used multiple tests designed to measure several aspects of memory and often a range of cognitive behavior 6, 15, 32. In contrast, investigators studying non-human species have typically utilized only a single behavioral task (e.g., DMS/DNMS or DR). This makes it difficult to analyze the relative effect of scopolamine on memory processing vs. either general effects on behavior (e.g., sedation, motoric slowing) or specific effects on other cognitive processing (e.g., perception, attention). It is possible that either of the latter alternatives might produce secondary detrimental effects on the performance of memory tests. Therefore, direct, within-subjects comparisons of the effects of scopolamine on a range of behaviors would contribute substantially to the understanding of the dependence of memory on intact cholinergic functioning.
The present study utilizes a battery of several behavioral tasks [44]to determine the effects of scopolamine on the cognitive performance of Rhesus monkeys. The battery includes tests of short-term recognition memory (delayed non-matching to sample; DNMS) and short-term spatial memory (self-ordered spatial search; SOSS). A third test of the battery is designed to test alterations of vigilance and reaction time (RT). Finally, tests of fine motor coordination (bimanual motor) and reinforcer efficacy (progressive ratio; PR) are included. Monkeys are trained to perform all tasks concurrently at a stable level of performance which provides at least two significant advantages. First, the use of multiple tests in the same animals make it possible to conduct within-subjects comparisons of the simultaneous effects of scopolamine on several behaviors. Second, these memory tasks have been used in a similar form to study cognitive dysfunction in human subjects associated with a number of conditions including DAT 23, 37, 38and the administration of scopolamine [32].
The purpose of the following investigation is twofold. The first purpose is to confirm that Rhesus monkeys' performance on a novel neuropsychological test battery is sensitive to drug manipulation. Scopolamine is of particular use for this purpose because it has been demonstrated to produce impairment of cognitive performance in a variety of contexts. The second purpose is to use the advantages of the battery approach to cognitive evaluation to provide a comprehensive assessment of the acute effects of scopolamine administration.
Section snippets
Subjects
Six male Rhesus monkeys (Macacca mulatta) served as subjects. The subjects were approximately 4 years of age and weighed between 3.5 and 6.1 kg. Animals were individually housed and fed in the home cage after completion of the daily testing session. Normal diet (Lab Diet 5045, PMI Nutrition International) was supplemented with fruit and/or vegetables 4 days/week and water was available ad libitum in the home cage at all times. Principles of laboratory animal care (Guide for the Care and Use of
Results
The monkeys' performance on each task was not altered from baseline by the intramuscular injection protocol as shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5. Post-hoc comparison following each ANOVA confirmed that performance on all tasks after vehicle injections was not significantly different from performance on days in which no injection was given.
Discussion
In the present results, systemic administration of scopolamine impaired monkeys' performance on putative memory tasks, including those thought to test short-term recognition memory (DNMS) and short-term spatial memory (SOSS), in a manner consistent with previous observations. While scopolamine decreased choice accuracy in the DNMS task, the impairment was not dependent on retention interval, thus implying no effect of the drug on memory retention or retrieval mechanisms. This pattern of results
Acknowledgements
We are grateful to Ilham Polis and Amanda Ormsby for expert technical assistance. Supported by USPHS grants: MH 19185 and DA 09111. This is publication #12047-NP from The Scripps Research Institute.
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