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Rhesus monkeys with IV catheters were allowed to self-administer cocaine for 1 h/day. When responding was stable, saline or the D1 dopamine agonist SKF 81297 (SKF; 0.001-0.3 mg/kg/inj) was substituted for cocaine. At least two doses of SKF maintained responding above saline levels in all monkeys. The D1 antagonist SCH 39166 (0.001-0.03 mg/kg, IM) was then administered 30 min before sessions of self-administration of the lowest dose of SKF that maintained behavior (0.01 mg/kg/inj). SKF-maintained responding decreased in a dose-related manner, suggesting antagonism of the reinforcing effect. These results suggest that stimulation of D1 receptors can initiate a reinforcing effect and further implicate D1 receptors in the reinforcing effects of drugs that increase dopamine neurotransmission.

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.

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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;

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The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

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