Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.

Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates.

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.

Induction of cognitive impairment by scopolamine and noncholinergic agents in rhesus monkeys.

In primates, treatment with scopolamine impairs performance of a spatial delayed response task in a way which mimics deficits seen spontaneously in aged primates and demented patients. Despite their efficacy in reversing scopolamine induced disruption, the effects of cholinergic agonists on cognition in aged primates and dements are unimpressive, suggesting that other neurotransmitter systems are also involved in this type of deficit. We have induced a scopolamine-like impairment of spatial delayed response performance in rhesus monkeys using phencyclidine (0.1-0.2 mg/kg i.m.), lorazepam (0.4-0.6 mg/kg s.c.) or tetrahydrocannabinol (1-4 mg/kg p.o.), but not amphetamine (0.1-0.4 mg/kg i.m.), yohimbine (0.1-1.0 mg/kg i.m.) or morphine (2-4 mg/kg i.m.). Our findings suggest that disruption of specific neurotransmitter systems other than acetylcholine may contribute importantly to cognitive decline in aging and dementia.

Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models.

Cognitive facilitation by physostigmine and tetrahydroaminoacridine (THA) was compared in two primate models. Disruption of spatial delayed response performance by scopolamine (0.03 mg/kg) was fully reversed by coadministration of 5 doses of physostigmine in the range 0.03-0.08 mg/kg, but by only one dose (4.0 mg/kg) of THA; partial reversal of some effects of scopolamine was observed at 1 and 3 mg/kg of THA. Visual recognition memory was enhanced following treatment with 4 doses of physostigmine in the range 0.001-0.03 mg/kg. The effect of THA across the group of animals was not significant but performance tended to improve using a dose of 0.8 mg/kg. Our findings indicate that THA does not have a superior profile to physostigmine as a cognitive enhancer in primates.

Nigrostriatal damage is required for induction of dyskinesias by L-DOPA in squirrel monkeys.

We examined the ability of L-DOPA to induce dyskinesias in MPTP-treated and normal squirrel monkeys to establish whether the underlying neuropathology associated with parkinsonism is an absolute requirement or merely promotes the development of drug-induced dyskinesias. Administration of L-DOPA (5-40 mg/kg p.o., following a 60 min pretreatment with carbidopa 2.5-20 mg/kg p.o.) induced a range of dopamine-mediated behaviours including locomotor activity, stereotyped scratching, and climbing in both lesioned and nonlesioned animals. However, the dose-response curves showed a marked (three- to fourfold) shift to the left in lesioned animals, indicating behavioural supersensitivity. In contrast, L-DOPA-induced dyskinesias were only observed in MPTP-treated monkeys. Doses required for induction of dyskinesias were lower than those required to induce climbing. These findings provide further evidence that nigrostriatal damage is essential for the genesis of L-DOPA-induced dyskinesias.

Modulatory role for CCK-B antagonists in Parkinson's disease.

We examined the ability of selective CCK-A and CCK-B receptor antagonists to induce or modulate the locomotor stimulant effects of dopamine agonists in MPTP-treated squirrel monkeys. Administration of 1-100 micrograms/kg i.p. of either the selective CCK-A receptor antagonist devazepide (MK-329) or the CCK-B receptor antagonist L-365,260 alone failed to stimulate a locomotor response in parkinsonian monkeys. In contrast, treatment with L-365,260 caused a 50-60% potentiation of the locomotor stimulatory effects of L-DOPA or (+)-PHNO. No such modulatory effects were observed following pretreatment with devazepide. We suggest that CCK-B receptor antagonists may be useful adjuncts to existing dopamine replacement therapy for improved management of Parkinson's disease.

Differential effects of D1 and D2 agonists in MPTP-treated primates: functional implications for Parkinson's disease.

Administration of the indirect agonist L-dopa, the nonselective direct agonist apomorphine, or the selective D2 agonist (+)-PHNO, reversed parkinsonism and induced locomotor activation in MPTP-treated squirrel monkeys. In contrast, administration of the selective partial D1 agonist SKF38393 did not induce locomotor activity, but rather decreased activity. Choreiform movements were observed only following treatment with L-dopa. Coadministration of the D1 antagonist SCH23390 prevented L-dopa-induced chorea at the time of peak effect. However, a rebound exaggeration of chorea was observed following SCH 23390 at the time when chorea induced by L-dopa alone would normally be subsiding. Unlike chorea, dystonia could be induced by treatment with either L-dopa or (+)-PHNO. Administration of apomorphine failed to significantly induce dystonia, although a small increase was observed with the highest dose. Treatment with SKF38393 actually decreased dystonia. Our findings clearly indicate that D2 receptor stimulation appears essential for antiparkinsonian activity, and also implicate D2 receptors in the genesis of dystonia, but not chorea. D1 receptor stimulation appears to be involved in the genesis of chorea and possibly also dystonia.

Characterisation of dyskinesias induced by L-dopa in MPTP-treated squirrel monkeys.

Intermittent treatment with L-dopa over a 2-year period induced abnormal involuntary movements in MPTP-treated squirrel monkeys. Dyskinesias included a choreic and dystonic component. Dose-response curves for chorea and dystonia revealed that the same dose of L-dopa (30 mg/kg) induced the highest score for both dyskinesias: however, the severity was much greater for chorea. Choreic movements were always most prevalent at the time of peak effect, whereas dystonia was apparent at the time of peak effect and at "end-of-dose", and was occasionally observed spontaneously. Our findings indicate that squirrel monkeys treated with MPTP develop L-dopa-induced dyskinesias which closely resemble those observed in Parkinson's disease. This species provides a valuable animal model to develop improved therapeutic agents.

Spontaneous orofacial dyskinesias in a captive cynomolgus monkey: implications for tardive dyskinesia.

We describe a syndrome of spontaneous orofacial dyskinesias and cage stereotypies in a singly housed adult cynomolgus monkey never previously exposed to neuroleptic drugs. Abnormal movements were readily suppressed by acute treatment with haloperidol (0.03-0.24 mg/kg i.m.) or SCH23390 (0.05-0.2 mg/kg i.m.) but not by physostigmine (0.005-0.04 mg/kg i.m.) or scopolamine (0.0025-0.04 mg/kg i.m.). The symptomatology and response to pharmacological manipulations was indistinguishable from that previously attributed to chronic neuroleptic treatment in primates. Our findings indicate that neuroleptic-induced tardive dyskinesias in most primate studies have not been clearly demonstrated.

Comparison of the effects of four cholinomimetic agents on cognition in primates following disruption by scopolamine or by lists of objects.

The ability of four central cholinomimetics to reverse a scopolamine-induced spatial memory impairment or to improve visual recognition memory in primates was examined. Physostigmine (0.04-0.08 mg/kg IM) fully reversed the effects of scopolamine (0.03 mg/kg). Coadministration of pilocarpine (3.0-5.0 mg/kg) caused partial reversal of the scopolamine impairment after intermediate or long retention intervals (10 or 20 s). Treatment with arecoline (0.1-1.8 mg/kg) or nicotine (1.0-2.0 mg/kg) generally did not reverse the effects of scopolamine. A task in which memory could be taxed by increasing the number of visual stimuli presented appeared more sensitive to the effects of cholinomimetics on cognition than the scopolamine reversal model. In this paradigm treatment with physostigmine (0.001, 0.01 or 0.03 mg/kg) increased choice accuracy from about 55 to 70% correct. Arecoline improved performance at one dose only (0.1 mg/kg) which also induced marked adverse side-effects (salivation and tremor). Pilocarpine improved performance in the dose range 0.125-0.35 mg/kg, but not at higher doses which also induced marked salivation. Treatment with nicotine (0.001-2.0 mg/kg tended to improve performance but this did not reach statistical significance. The relevance of these findings for studies in man and for animal models of dementia is discussed.