J.S. Schneider

Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys

Cognitive deficits which may occur following chronic low-dose exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in monkeys who remained motor asymptomatic for parkinsonism throughout the study. The tasks used to assess cognitive functioning are those which have proved in the past to be sensitive to disruption of frontal cortical and or striatal integrity (delayed response and delayed alternation) or sensitive to inferior temporal lobe dysfunction (visual pattern discrimination). Since Parkinsons disease patients have been described as exhibiting frontal signs, we were interested to examine whether MPTP-treated monkeys might exhibit deficits on frontally-mediated tasks, without the confound of motor disturbances. We found that macaque nemistrina monkeys exposed to cumulative doses of 14.94-75.42 mg of MPTP over periods ranging from 5 to 13 months never developed parkinsonian motor signs. However, all 4 animals examined showed significant post-MPTP deficits in delayed response and delayed alternation performance, while visual pattern discrimination performance remained intact. These animals also developed other behavioral problems including irritability and decreased attentiveness. These results show that MPTP can cause specific cognitive deficits independent of the motor deficits which can be produced by this toxin.

Cognitive deficits precede motor deficits in a slowly progressing model of parkinsonism in the monkey

Five adult Macaca fascicularis monkeys were trained to perform tests of cognitive and motor functioning that included a complex visual pattern discrimination task, an object retrieval task, a test of task persistence, and a timed motor task. Once stable baseline performance was achieved, monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at doses of 0.05 to 0.075 mg/kg, 2 to 3 times per week for a total of 24 weeks. Animals were assessed weekly for performance on the previously learned tasks. All monkeys developed performance deficits in a predictable pattern with behavioural and cognitive deficits (i.e. deficits in task persistence and the cognitive component of object retrieval) appearing in advance of measurable motor deficits. Deficits in visual pattern discrimination never appeared. These results show that specific cognitive dysfunction pre-dates motor dysfunction in a chronic, slowly progressing parkinson model in monkeys and support the contention that cognitive deficits in Parkinsons disease may precede the motor signs of the disorder and may not be caused by them.

Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys

Chronic low-dose MPTP exposure was previously found to impair cognitive performance in monkeys. These monkeys developed deficits in performance of delayed response and delayed alternation tasks but maintained performance on visual pattern discrimination. This, along with other subtle behavioral changes, occurred in the absence of gross parkinsonian motor symptoms. The present study reports the results of neurochemical and neuropathological examination of the brains of these animals. Chronic low-dose MPTP exposure resulted in profound decreases in caudate dopamine (DA) levels and slightly less severe depletions in the putamen. Increases in striatal HVA/DA ratios suggest an increase in DA turnover in these areas. In contrast to striatal DA depletions, we found significant increases in striatal serotonin levels without an associated increase in serotonin turnover. At the cortical level, we found inconsistent changes in frontal cortical DA levels and variable decreases in norepinephrine levels. Since the most profound and consistent deficits were in the nigrostriatal dopamine system, we suggest that most of the behavioral consequences of chronic low-dose MPTP exposure stem from the striatal dopamine depletion. We also suggest that the maintenance of motor function in the presence of massive striatal DA depletions may be due to less impairment of putamen DA vs. caudate DA, by an increase in striatal DA turnover, a compensatory increase in serotonin availability, or a combination of these and possibly other as yet undetermined compensatory mechanisms. Furthermore, we propose the present model utilizing chronic low-dose exposure to MPTP as a model for the early, compensated form of Parkinsons disease.

Delayed matching-to-sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP-treated monkeys

Cognitive deficits following chronic exposure to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in monkeys asymptomatic for a gross parkinsonian motor disorder. Monkeys developed deficits in performance of delayed matching-to-sample, visual pattern discrimination reversal, and object retrieval tasks, all tasks that rely upon the integrity of the frontal-striatal axis. Performance on a visual pattern discrimination task, that relies primarily on inferotemporal cortex function, remained intact. These results extend previous findings of frontal-like cognitive deficits in MPTP-treated monkeys and further support the use of this model for studying the pathophysiology of the cognitive deficits associated with parkinsonism.

Volume transmission of dopamine over large distances may contribute to recovery from experimental parkinsonism

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome that spontaneously recovers by 6 weeks after induction. Striatal dopamine depletions in these animals are heterogenous with more extensive damage dorsolaterally than ventromedially. Measures of extracellular dopamine levels by in vivo microdialysis showed that dopamine released from a relatively preserved ventral striatal innervation can diffuse over a distance of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribute to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reuptake inhibition, but not in normal animals without reuptake inhibition. In cats recovered from MPTP-induced parkinsonism, a greater amount of dopamine was recovered from the extracellular fluid in the dorsolateral caudate following stimulated release of dopamine from the ventromedial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmission of dopamine over large distances is possible and perhaps an important contributor to functional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to significant functional improvement.

Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys.

Monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over long periods of time develop cognitive deficits without severe parkinsonian motor signs. In the present study we assessed the effects of the selective and full dopamine D-1 receptor agonist dihydrexidine on delayed response deficits in chronic low dose (CLD) MPTP-treated monkeys. Dihydrexidine caused a dose-dependent improvement in task performance, that could be blocked by the D-1 receptor antagonist SCH-23390. In addition to reducing the number of mistakes made during delayed response performance, dihydrexidine also improved task persistence. These data suggest that dihydrexidine may be useful in treating cognitive as well as motor deficits of parkinsonism.

Effects of dopamine agonists on delayed response performance in chronic low-dose MPTP-treated monkeys.

Monkeys exposed to low doses of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop difficulty in performing a previously learned delayed response (DR) task. In the present group of animals, performance deficits were manifested as a combination of mistakes or incorrect responses and no response errors, trials on which the animals failed to respond. Methylphenidate and the dopamine D2 receptor agonist LY-171555, at low doses, decreased the number of no-response errors but not mistakes. The partial D1 agonist SKF-38393 had no effects on no-response errors or mistakes. Thus, behavioral deficits associated with decreased task persistence may be amenable to treatment with dopamine agonists, and particularly D2 agonists, while cognitive performance per se may not be improved by such drugs. The similarities between this primate model and the cognitive/behavioral deficits associated with early Parkinsons disease and attention deficit hyperactivity disorder suggest that this may be a useful model for testing hypotheses concerning the pharmacological treatment of these disorders.

Task persistence and learning ability in normal and chronic low dose MPTP-treated monkeys

Monkeys exposed to low doses of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop cognitive deficits in the absence of gross motor dysfunction. Attentional deficits and task impersistence are now also described in these animals. The task impersistence correlated with no-response errors (i.e. errors of omission) on a delayed response task and improved with dopamine agonist therapy. In parallel studies, it was observed that there were significant differences in the ability of normal monkeys to learn to perform cognitive tasks. We found that monkeys classified as poor learners had similar deficits in task persistence as did MPTP-exposed monkeys, suggesting a relationship between poor cognitive performance and task impersistence in untreated as well as MPTP-treated monkeys. The possible significance of these results for two clinical disorders, early Parkinsons disease and attention deficit hyperactivity disorder is discussed. Cognitive and behavioral similarities between chronic low dose MPTP-treated monkeys, early Parkinsons disease patients and people with attention deficit hyperactivity disorder may suggest the existence of related pathophysiological mechanisms in these disorders.

Relative sparing of the dopaminergic innervation of the globus pallidus in monkeys made hemi-parkinsonian by intracarotid MPTP infusion.

Tyrosine hydroxylase immunohistochemical analysis was performed on tissue sections through the pallidal complex from Nemistrina monkeys which had been made hemi-parkinsonian by intracarotid MPTP infusion 8-12 months earlier. The side contralateral to the MPTP infusion showed a dense dopaminergic innervation of the pallidum (both internal and external segments), but particularly the internal pallidum. The side of the brain ipsilateral to the MPTP infusion showed a remarkable sparing of the pallidal dopaminergic innervation, despite almost total loss of the dopaminergic innervation of the caudate and putamen. These results support the view that in the primate, the nigropallidal projection is mostly distinct from the nigrostriatal projection. It is also suggested that perhaps the sparing of pallidal dopamine at least in part may contribute to some of the recovery of function observed in some monkeys following exposure to MPTP.

Met-enkephalin immunoreactivity in the basal ganglia in symptomatic and asymptomatic MPTP-exposed monkeys: correlation with degree of parkinsonian symptoms.

The immunohistochemical localization of Met-enkephalin (Enk) was examined in the brains of normal monkeys (Macaca nemistrina), monkeys made parkinsonian by systemic MPTP administration and sacrificed while symptomatic, and monkeys exposed to low doses of MPTP over several months and sacrificed while asymptomatic for a gross parkinsonian motor disorder. The animals that had severe parkinsonian features had a large number of intensely Enk-immunoreactive perikarya in the putamen. Normal control animals had no Enk-immunoreactive perikarya while asymptomatic animals had small numbers of lightly to moderately stained perikarya in the putamen. Symptomatic animals also showed the most intense Enk immunoreactivity in the lateral globus pallidus (LGP) while the asymptomatic animals showed LGP Enk immunoreactivity intermediate between that seen in symptomatic and normal animals. These results suggest an increase in putamen Enk synthesis and LGP Enk content in animals with massive striatal dopamine depletions (greater than or equal to 97%) and which actively show parkinsonian features. Animals with slightly less striatal dopamine depletion and with no parkinsonian symptoms, had increased activity in this system but not to the extent seen in symptomatic animals.