Rationale-Early, accurate detection of degenerative neurological disorders such as Alzheimer's Disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a nonhuman model may therefore provide an improved tool for study of the etiology and treatment of dementia.Objective-The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs.Methods-Monkeys (7) were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 µg/kg, i.m.) and ketamine (0.3, 1.0, 1.78 mg/kg, i.m.).Results-Scopolamine produced a dose × difficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition.Conclusions-Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of ( Ϯ )3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.) Recreational use of the psychoactive drug ( Ϯ )3,4,-methylenedioxymethamphetamine (MDMA) has become increasingly popular over the past two decades (Peroutka 1987;Schuster et al. 1998). Although early studies focused on adverse physiological (e.g., hypertension, hyperthermia, hyponatraemia) or psychiatric (mood disorder, aggression) symptoms associated with acute and/or chronic MDMA exposure, recent evidence suggests that chronic MDMA use may also result in lasting disruption of cognitive function. A number of studies have shown that experienced, abstinent MDMA users are impaired on various tests of memory function (Bolla et al. 1998;Curran and Travill 1997;Krystal et al. 1992;Morgan 1999;, even when compared with users of other recreational drugs. The lasting functional effects of MDMA use may be relatively specific to mnemonic processing, since a number of studies have reported that MDMA users who are impaired on memory tasks exhibit normal performance on tests of reaction time, vigilance or selective attention (Krystal et al. 1992;Vollenweider et al. 1998). Additional evidence suggests that the degree of memory impairment in the MDMA user is positively correlated with the number of cumulative exposures to MDMA (Bolla et al. 1998;Parrott and Lasky 1998). Finally, recent studies have demonstrated that electroencephalographic and metabolic (PET) measures of brain function are altered in MDMA users (Dafters et al. 1999;

MDMA produces an acute hyperthermia in unrestrained rhesus monkeys, much as it does with rats, mice, pigs, rabbits and humans. Hyperthermia occurs despite no increase in locomotor activity thus the effect does not depend on motor activation. Each enantiomer appears to be equivalently active thus primates may differ from rodents in thermoregulatory sensitivity to the R(-) enantiomer. Significant differences in outcome between this and a prior study in monkeys indicate a need for additional study of the thermoregulatory impact of MDMA in nonhuman primates.

Available evidence suggests that recreational use and abuse of the dissociative anaesthetic ketamine is increasing. Characterization of the cognitive risks of ketamine exposure contributes substantially to understanding this growing public health threat. Although prior human studies demonstrate that ketamine impairs a range of cognitive skills, investigation in nonhuman models permits more precise exploration of neurochemical mechanisms which may underlie detrimental behavioral effects. Adult male rhesus monkeys (N=7) were trained on a neuropsychological battery including tests of memory (delayed match-to-sample, DMS; self-ordered spatial search, SOSS), reaction time (RT), reinforcer efficacy and sustained attention (progressive ratio, PR) and fine motor coordination (bimanual motor skill, BMS). Battery performance was then serially challenged with acute doses of ketamine (0.3, 1.0, 1.78 mg/kg IM). Ketamine impaired DMS and SOSS in a dose x difficulty dependent manner with the most difficult task conditions disrupted at the 1.0 and 1.78 mg/kg doses. Thus, both visual recognition memory and working memory indices were affected. Ketamine also slowed RT and BMS performance and interfered with PR performance at the 1.78 mg/kg dose. Overall the present findings confirm that ketamine interferes with multiple aspects of cognition at subanesthetic doses in monkeys.

The ambient temperature (T A ) under which rodents are exposed to (7)3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in 'neurotoxicity' models. The thermoregulatory effects of MDMA have not been well described in nonhuman primates and it is unknown if T A has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on T A as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg (7)MDMA under each of three T A conditions (18, 24, and 301C) in a randomized order. The temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was B11C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA; however, a 50% increase over vehicle was observed after 0.56 MDMA under the 301C condition. It is concluded that MDMA produces a similar degree of hyperthermia in rhesus monkeys across a range of T A conditions that result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.