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Rationale: The ameliorative effects of levodopa (l-3,4-dihydroxy-phenylalanine) on the motor impairment in Parkinson’s disease patients is well established, but characterization of its effects on the associated cognitive deficits is still incomplete. Objective: The present study determined the effect of different doses of levodopa on performance on a test of working memory in MPTP-treated rhesus monkeys, an animal model of Parkinson’s disease. Methods: Four MPTP-treated monkeys and their age-matched controls with the same experimental history as the MPTP-treated monkeys were tested on a spatial delay response task. Each daily session consisted of five trials at each of seven randomly presented delays (0, 10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five different conditions. In the first condition, control and MPTP-treated animals performed the task without levodopa. In the second condition, both groups were tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in which the doses of levodopa were increased to 250 and 500 mg, respectively, only the MPTP-treated animals were tested. In the final condition, the MPTP-treated animals where retested without levodopa. Results: Significant improvement was observed at all doses tested (range 100–500 mg). Conclusions: Levodopa can ameliorate memory impairments in this parkinsonian model.

Administration of either a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), or a muscarinic antagonist, scopolamine, produces dose-related impairments in performance of a visual recognition memory task, delayed non-matching to sample (DNMS) with lists of 20 symbols, in rhesus monkeys. In the present study, low doses of these two drugs, which were ineffective when given alone, significantly impaired performance when given in combination. Moreover, the effect was greater than additive, indicating a synergistic interaction. These results suggest that interactions between cholinergic and glutamatergic systems play an important role in regulation of visual recognition memory.

In vivo biochemical microdialysis in primate brain would greatly expand our understanding of functional neuronal systems. This work describes our efforts to establish a microdialysis system in primate brain. Seven anesthetized rhesus monkeys underwent magnetic resonance imaging (MRI) with the head fixed in a compatible stereotaxic frame. This allowed stereotaxic localization of the caudate nucleus and putamen. Guide cannulae were implanted and fixed to the skull. Microdialysis probes made from polyethylene and fused silica were inserted into the caudate and putamen through the guide cannulae and perfused at the rate of 1.3 microliters/min. The putamens were approached horizontally, while the caudate nuclei were reached via a 30 degrees-45 degrees angle from the vertical. Postdialysis MRI and histologic evaluation proved that all probes accurately arrived at the predetermined region. Our data show that MRI guided stereotaxis allows accurate placement of dialysis probes and that implantation of guide cannulae is a reliable and convenient way to perform repeated brain microdialysis procedures.

Isoflurane is a chiral volatile anaesthetic, routinely administered as racemate. It has a low metabolic rate and is mostly eliminated via respiration. In blood samples, S(+) enantiomers are found in greater proportion in the days immediately after administration of isoflurane racemate whereas the ratio in breath samples is unknown.Breath and blood samples were drawn immediately after recovery and daily up to 19 days after operation from patients undergoing anaesthesia with isoflurane racemate. The percentage of isoflurane enantiomer was determined by gas chromatography mass spectrometry in blood and thermodesorption gas chromatography mass spectrometry in breath samples.In breath samples, there were significant differences in S(+) enantiomers at all time points compared to the racemate. During the early postoperative phase, the percentage of S(+) enantiomers were significantly enhanced whereas 5 days after surgery predominantly R(-) enantiomers (50.41%) were detected in the breath samples. Also in blood samples a statistical significant accumulation of the S(+) enantiomer was noted between days 1 and 5 compared to isoflurane racemate blood control. S(+) enantiomers were significantly higher in blood compared to breath samples and was most evident on the third day after surgery (51.43%).During the first days after application of isoflurane racemate, the percentage of S(+) enantiomers are higher in breath and blood samples of patients. We suggest that resorption and/or redistribution of enantiomers are responsible for the different kinetics of isoflurane enantiomers.

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored.

Extracellular levels of acetylcholine in inferior temporal cortex (IT), perirhinal cortex (PR), and dentate gyrus (DG) of the hippocampus were monitored using in vivo microdialysis in rhesus monkeys performing two behavioral tasks. Performance on a visual recognition task was associated with 26%, 41% and 24% increases in acetylcholine overflow in IT, PR and DG, respectively, compared with pre-test baseline levels. Performance on a memory-independent task was associated with increases in acetylcholine release of 24%, 34% and 7% above baseline in IT, PR and DG, respectively. The PR-DG differences were significant, but the others were not. The results provide biochemical evidence for cerebral cholinergic system activation during visually mediated behavior in non-human primates, and are consistent with the view that such activation is a prerequisite for visual recognition memory.

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl-D-asparate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1-10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficity following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2-32 micrograms/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 micrograms/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 micrograms/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

Strychnine-insensitive glycine binding sites have recently been shown to positively modulate N-methyl-D-aspartate (NMDA) receptors. In the present study, the effects on recognition memory of D-cycloserine, a partial agonist at the glycine modulatory site on the NMDA receptor, were evaluated in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trail-unique graphic symbols. Single administration of D-cycloserine (100-1000 micrograms/kg i.m.) facilitated DNMS performance significantly with an inverted U-shaped dose-response curve when given 30 min before testing. To assess further the possible neural mechanisms, D-cycloserine was evaluated for its effects on the memory impairments after blockade of the glycine sites by HA-966, N-methyl-D-aspartate receptors by MK-801, or cholinergic receptors by scopolamine. D-Cycloserine completely reversed the visual recognition memory deficits produced by HA-966 (3.2 mg/kg i.m.). D-Cycloserine also dose-dependently and significantly restored the memory deficits produced by MK-801 (32 micrograms/kg i.m.). In addition, D-cycloserine produced a partial, though significant, improvement on the recognition memory deficits after cholinergic blockade with scopolamine (10 micrograms/kg i.m.). From these results, we propose that D-cycloserine has a cognition-enhancing property in non-human primates and that it may have a potential value in treating dementias. Furthermore, the present results provide new evidence for the important role for the glycine sites in the regulation of recognition memory.

1. The results of neuropsychological, neuropharmacological, and neurophysiological experiments have implicated the ventral striatum in reward-related processes. We designed a task to allow us to separate the effects of sensory, motor, and internal signals so that we could study the correlation between the activity of neurons in the ventral striatum and different motivational states. In this task, a visual stimulus was used to cue the monkeys as to their progress toward earning a reward. The monkeys performed more quickly and with fewer mistakes in the rewarded trials. After analyzing the behavioral results from three monkeys, we recorded from 143 neurons from two of the monkeys while they performed the task with either juice or cocaine reward. 2. In this task the monkey was required to release its grip on a bar when a small visual response cue changed colors from red (the wait signal) to green (the go signal). The duration of the wait signal was varied randomly. The cue became blue whenever the monkey successfully responded to the go signal within 1 s of its appearance. A reward was delivered after the monkey successfully completed one, two, or three trials. The schedules were randomly interleaved. A second visual stimulus that progressively brightened or dimmed signaled to the monkeys their progress toward earning a reward. This discriminative cue allowed the monkeys to judge the proportion of work remaining in the current ratio schedule of reinforcement. Data were collected from three monkeys while they performed this task. 3. The average reaction times became faster and error rates declined as the monkeys progressed toward completing the current schedule of reinforcement and thereby earning a reward, whereas the modal reaction time did not change. As the duration of the wait period before the go signal increased, the monkeys reacted more quickly but their error rates scarcely changed. From these results we infer that the effects of motivation and motor readiness in this task are generated by separate mechanisms rather than by a single mechanism subserving generalized arousal. 4. The activity of 138 ventral striatal neurons was sampled in two monkeys while they performed the task to earn juice reward. We saw tonic changes in activity throughout the trials, and we saw phasic activity following the reward. The activity of these neurons was markedly different during juice-rewarded trials than during correctly performed trials when no reward was forthcoming (or expected). The responses also were weakly, but significantly, related to the proximity of the reward in the schedules requiring more than one trial. 5. The monkeys worked to obtain intravenous cocaine while we recorded 62 neurons. For 57 of the neurons, we recorded activity while the monkeys worked in blocks of trials during which they self-administered cocaine after blocks during which they worked for juice. Although fewer neurons responded to cocaine than to juice reward (19 vs. 33%), this difference was not significant. The neuronal response properties to cocaine and juice rewards were independent; that is, the responses when one was the reward one failed to predict the response when the other was the reward. In addition, the neuronal activity lost most of its selectivity for rewarded trials, i.e, the activity did not distinguish nearly as well between cocaine and sham rewards as between juice and sham rewards. 6. Our results show that mechanisms by which cocaine acts do not appear to be the same as the ones activated when the monkeys were presented with an oral juice reward. This finding raises the intriguing possibility that the effects of cocaine could be reduced selectively without blocking the effects of many natural rewards.

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinson's patients, the MPTP-treated primates display spatial deficits.

Both N-methyl-D-aspartate (NMDA) and cholinergic receptors are thought to participate in processes of learning and memory. The effects of the noncompetitive NMDA antagonist ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) MK-801 on recognition memory in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample DNMS were compared to those of the cholinergic compounds physostigmine and scopolamine. In the sample phase of the test, 20 symbols were presented sequentially every 30 sec on a color monitor fitted with a touch-sensitive screen. These symbols were then presented again in the same order as before, but each symbol was now paired with a different novel symbol. A monkey was rewarded with a food pellet if it touched the symbol in the sample phase and the previously unseen symbol in the choice phase. Physostigmine (3.2, 10 and 32 micrograms/kg), scopolamine (3.2, 10, 17.8 and 32 micrograms/kg) or MK-801 (3.2, 10 and 32 micrograms/kg) was injected i.m. 20, 20 and 30 min before testing, respectively. The highest doses of both MK-801 and scopolamine significantly impaired performance. In addition, scopolamine, but not MK-801, prolonged response latency, whereas MK-801, but not scopolamine, increased response bias. Physostigmine produced a small but significant increase in correct responses at the intermediate dose, but not at the highest dose. These results suggest that both the glutamatergic and the cholinergic systems participate in visual recognition memory in monkeys, though probably by different mechanisms.

Performance of three rhesus monkeys on a test of one-trial stimulus-reward association, in which recall intervals ranged from 0.5 to 6.5 min, was evaluated during nondrug-control conditions and following administration of the muscarinic-receptor blocker scopolamine. During control sessions, performance averaged 78% correct responses. Following administration of 10.0 and 17.8 μg/kg of scopolamine, performance fell significantly, to 69% and 63% correct responses, respectively. This dose-dependent impairment in recall was similar to the impairment we reported previously in recognition. Although the results thus failed to support a suggestion derived from behavioral electrophysiological findings that stimulus-reward association might be more vulnerable to scopolamine than stimulus recognition, they provide additional evidence for a cholinergic contribution to cognitive memory.

The sensitivity of 18F-DOPA positron emission tomography for imaging presynaptic dopamine systems is limited by the amount of specific-to-nonspecific accumulation of radioactivity in brain. In rhesus monkeys, we have been able to increase this ratio by taking advantage of the lag time between 18F-DOPA injection and the formation of its main metabolite, the amino acid 18F-fluoromethoxydopa, the entrance of which into brain is responsible for most of the brain's nonspecific radioactivity. By infusing an unlabeled amino acid, L-phenylalanine, starting 15 min after 18F-DOPA administration, we preferentially blocked the accumulation of 18F-fluoromethoxydopa by preventing its entrance into brain through competition at the large neutral amino acid transport system of the blood-brain barrier. This method appears as reliable as the original and more sensitive, as demonstrated by the comparison of normal and MPTP-treated animals under both conditions.

Previous studies have shown that a variety of local anesthetics including procaine are self-administered at high rates by rhesus monkeys. In the present study two rhesus monkeys were given a mutually exclusive choice between various doses of intravenous cocaine and procaine. In almost all comparisons cocaine was preferred even when the procaine dose was 16 times that of cocaine. Other measures of performance such as rate of responding did not vary systematically with preference. These data provide further support for the idea that rate of responding under simple schedules of drug delivery is an unreliable measure of relative reinforcing efficacy. In addition, the consistent preference for cocaine over procaine in monkeys suggests that the infrequent abuse of procaine by humans may be related to its low reinforcing efficacy relative to drugs such as cocaine.

d-Glaucine is an alkaloid derived from Glaucium flavum, which is as effective as codeine as an antitussive. d, l-Glaucine. 1.5 phosphate is a synthetic compound related to d-glaucine. The ability of d, l-glaucine.1.5 phosphate to maintain responding in rhesus monkeys was assessed in 2 procedures. In the first responding was maintained under a fixed-ratio 10 schedule of codeine delivery during daily 3-hr sessions. When d, l-glaucine.1.5 phosphate (0.05-0.4 mg/kg) was substituted for codeine, responding was not maintained. In the second procedure, monkeys given 23-hr/day access to 0.5-1.0 mg/kg under a fixed-ratio schedule did not self-administer d,l-glaucine.1.5 phosphate above saline levels even after a 21-day period of programmed injections. Following the period of programmed injections, there were not signs of opiate withdrawal following the administration of naloxone. These results indicate that the abuse potential of d,l-glaucine.1.5 phosphate is low relative to codeine.

The behavioral effects of acute IP administration of 1-alpha-acetylmethadol, its metabolites, 1-alpha-noracetylmethadol and 1-alpha-dinoracetylmethadol, and morphine were studied in the rat using behavior controlled by a fixed-interval schedule of food reinforcement. Administraiton of all compounds produced a dose-related decrease in response rate. The metabolites were approximately three to four times the potency of the parent compound which was approximately five times the potency of morphine. Data obtained from cumulative response records suggested that the onset of effects for the metabolites was more rapid than for the parent compound.

Rhesus monkeys were allowed to choose between intravenous injections of cocaine and food reinforcement for lever pressing. A choice trial was available every 15 minutes continuously for 8 days. The animals chose cocaine almost exclusively, which resulted in high cocaine intake, decreased food intake, weight loss, and marked behavioral toxicity. The study provides evidence of the reinforcing efficacy of cocaine.

The effects of orally administered delta-9-tetrahydrocannabinol (THC) were evaluated on two different learning abilities in monkeys. Visual recognition memory, known to depend on limbic system integrity, was tested by means of delayed nonmatching-to-sample and found to be significantly impaired by acute administration of 2 and 4 mg/kg THC given 1 or 2 h prior to testing. Performance was significantly impaired throughout a 21-day period of repeated administration of 4 mg/kg THC and also during a 3-5 day period that began 7-10 days after the last dose of THC. By contrast, 24-h concurrent discrimination learning, a task that monkeys with limbic lesions can perform normally, was not impaired by THC, even following doses as high as 16 mg/kg. These results suggest that THC interferes with recognition memory more than discrimination learning, possibly reflecting a selective action of THC on limbic mechanisms.

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.

Six rhesus monkeys were trained to extend their arms through a tube to press a lever between 25 and 40 g of force for 3 or 5 sec. Responding was maintained by the delivery of 1.5 cc of water. Stimulus lights indicated whether the exerted force was below 25 g, between 25 and 40 g (i.e., correct) or above 40 g. Sessions were terminated after 50 water deliveries or 30 min had elapsed. Performance was well-maintained in all monkeys. Allowing the animals access to water prior to the session had no effect on performance. Discontinuing sessions for two weeks disrupted some aspects of performance but responding improved within 5 sessions. Single injections of methamphetamine (0.06–0.5 ,mg/kg) were given IM 20 min prior to the session. The highest dose of 0.5 mg/kg totally eliminated responding. Lower doses decreased rate of responding somewhat and increased phasic activity (i.e., tremors) in a dose-dependent manner. The procedure seems ideally suited for investigating the effects of psychotropic drugs on fine motor control in rhesus monkeys.

Rhesus monkeys were trained to press a lever one hundred times (FR 100) to obtain either a food pellet or an intravenous drug injection. Two daily experimental sessions, one in the morning and one in the afternoon, were divided into three 15 minute periods each. In Periods 1 and 3 lever pressing behavior was maintained by the delivery of food. Period 2 lever pressing was maintained by the intravenous injection of a drug solution. The drug available each day followed a four day sequence of cocaine (30 microgram/kg/injection), saline (1.0 ml/injection), cocaine, and test compound. This four day sequence was repeated to test a series of 16 psychoactive compounds at two doses each. These drugs were compared to saline for their ability to maintain Period 2 responding during the afternoon session. Morphine, oxymorphone, codeine, pentazocine, d-amphetamine and methylphenidate all maintained responding at rates significantly greater than for saline. Cyclazocine, naloxone, levallorphan, scopolamine, chlorpromazine, fenfluramine, and (+/-)-9-nor-9-alpha-hydroxy-hexahydrocannabinol (alpha-HHC) did not maintain responding during Period 2. The results with procaine, beta-HHC and nalorphine were considered equivocal. The authors suggest the use of a rapid substitution procedure as a method of initial screening of drugs with potential reinforcement efficacy.