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

doi:10.1016/0166-4328(94)90138-4

Behavioural Brain Research

Volume 60, Issue 2, 28 February 1994, Pages 115-124

https://doi.org/10.1016/0166-4328(94)90138-4 Get rights and content

Abstract

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 Parkinson's disease and attention deficit hyperactivity disorder is discussed. Cognitive and behavioral similarities between chronic low dose MPTP-treated monkeys, early Parksinson's disease patients and people with attention deficit hyperactivity disorder may suggest the existence of related pathophysiological mechanisms in these disorders.

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The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the cognitive and motor functions in rodents: A systematic review and meta-analysis
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Our meta-analysis confirmed significant dysfunction in motor coordination and balance, locomotor activity, anxiety-like behaviors, and depression-like behaviors on the rotarod (beam walking test), open field, elevated plus-maze (and hole-board test), and forced swimming and tail suspension tests (Liu et al., 2018a; Yang et al., 2017a; Kim et al., 2014a; Ho et al., 2011) in rodents. Notably, in addition to rodents and primates (Decamp and Schneider, 2004, 2006; Decamp et al., 2004; Schneider et al., 2002; Roeltgen and Schneider, 1994), MPTP injection models of PD have been successfully created in zebrafish (Bashirzade et al., 2022; Anichtchik et al., 2004), C. Elegans and Drosophila (Fatima et al., 2018; Johnson et al., 2018). In these species MPTP also lead to decrease on locomotor activity (distance moved and velocity) 16 and to spatial working memory deficits as measured by reduced spontaneous alternation behavior in the Y-maze test (Mattila et al., 2001).
Memory and motor deficits are commonly identified in Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is transformed to MPP+ via monoamine oxidase B (MAOB), which causes oxidative stress and destroys dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) and is widely used to create animal models of PD. However, to-date, a comprehensive analysis of the MPTP effects on various aspects of PD does not exist. Here, we provide a systematic review and meta-analysis on the MPTP effects on memory and motor functions by analyzing 51 studies on more than one thousand animals mainly including rats and mice. The results showed that in addition to motor functions such as coordination, balance and locomotor activity, MPTP significantly affects various mnemonic processes including spatial memory, working memory, recognition memory, and associative memory compared with the control group with some differences between systemic and intra-nigral injections on spatial memory, familiar object recognition, and anxiety-like behaviors. Nevertheless, our analysis failed to find systematic relationship between MPTP injection protocol parameters reported and the extent of the induced PD symptoms that can be a cause of concern for replicability of MPTP studies.
Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease
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NHP models are advantageous in that their long life spans allow for chronic administration of low-doses of MPTP, which better reflects the chronic pathogenesis of PD in humans (Hantraye et al., 1993; Smith et al., 1992; Bezard et al., 1997; Meissner et al., 2003). Similar to humans suffering from PD, NHP MPTP models demonstrate cognitive deficits (Schneider and Pope-Coleman, 1995; Schneider and Kovelowski, 1990; Schneider and Roeltgen, 1993; Roeltgen and Schneider, 1994) and loss of dopamine neuron innervation in extrastriatal targets such as the globus pallidus (Jan et al., 2000) and the prefrontal cortex (Brozoski et al., 1979; Aron Badin et al., 2015) – symptoms that are not observed in rodent models (see above Sections 2.1 and 2.2) (Table 1). Specifically in baboons, chronic administration of MPTP induces a selective destruction of dopaminergic neurons in the caudal and ventrolateral regions of the SNc (Varastet et al., 1994), a pattern that has otherwise only been noted in cases of human PD (Kish et al., 1988).
The derivation of dopaminergic neurons from induced pluripotent stem cells brings new hope for a patient-specific, stem cell-based replacement therapy to treat Parkinson's disease (PD) and related neurodegenerative diseases; and this novel cell-based approach has already proven effective in animal models. However, there are several aspects of this procedure that have yet to be optimized to the extent required for translation to an optimal cell-based transplantation protocol in humans. These challenges include pinpointing the optimal graft location, appropriately scaling up the graft volume, and minimizing the risk of chronic immune rejection, among others. To advance this procedure to the clinic, it is imperative that a model that accurately and fully recapitulates characteristics most pertinent to a cell-based transplantation to the human brain is used to optimize key technical aspects of the procedure. Nonhuman primates mimic humans in multiple ways including similarities in genomics, neuroanatomy, neurophysiology, immunogenetics, and age-related changes in immune function. These characteristics are critical to the establishment of a relevant model in which to conduct preclinical studies to optimize the efficacy and safety of cell-based therapeutic approaches to the treatment of PD. Here we review previous studies in rodent models, and emphasize additional advantages afforded by nonhuman primate models in general, and the baboon model in particular, for preclinical optimization of cell-based therapeutic approaches to the treatment of PD and other neurodegenerative diseases. We outline current unresolved challenges to the successful application of stem cell therapies in humans and propose that the baboon model in particular affords a number of traits that render it most useful for preclinical studies designed to overcome these challenges.
Pathophysiology of the basal ganglia and movement disorders: From animal models to human clinical applications
2008, Neuroscience and Biobehavioral Reviews
Electrophysiological studies in control and MPTP treated primates have played a major role in our understanding of the physiology of the basal ganglia and the pathophysiology of Parkinson's disease (PD). Early models emphasized discharge rate and viewed the basal ganglia as a network of boxes (nuclei) connected by excitatory or inhibitory connections. More recent studies view the basal ganglia as neural networks with weak and non-linear interactions in and between the different nuclei.
Microelectrode electrophysiological recording enables the high resolution—both in the temporal domain (spike) and the spatial domain (neuron)—required for the in vivo investigation of neuronal networks of the basal ganglia. MPTP treated primates exhibit the full pathological and clinical spectrum of human Parkinsonism and therefore their electrophysiological study has promoted better understanding of the normal state, the dopamine-depleted state, and finally the testing of potential therapeutic interventions for PD. Here, we review the main insights learned from microelectrode physiological studies of MPTP monkeys over the last 20 years since the introduction of this animal model.
Performance- and task-dependent effects of the dopamine D<inf>1</inf>/D<inf>5</inf> receptor agonist SKF 38393 on learning and memory in the rat
2007, European Journal of Pharmacology
Dopamine D₁/D₅ receptor agonists may enhance cognition by mimicking dopamine's neurophysiological actions on the processes underlying learning and memory. The present study examined the task- and performance- dependence of the cognitive effects of a partial agonist at dopamine D₁/D₅ receptors, SKF 38393 [(±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], in rats. Spatial working memory was assessed in a T-maze, spatial reference memory in a water maze and habituation learning in a novel environment, a hole board. The muscarinic acetylcholine receptor antagonist scopolamine (1.5 mg/kg, i.p.) was used to cause an impairment of performance of these learning tasks. Administration of SKF 38393 (6 mg/kg, i.p.) alone had no significant effect on spontaneous alternation in the T-maze, latency to escape to a hidden platform in the water maze or the habituation of spontaneous behaviour in the hole board. In contrast, in scopolamine-treated rats, whereas SKF 38393 prevented the scopolamine-induced deficit in the T-maze, it exacerbated the impairment in the water maze and did not significantly alter the disruption of habituation. These results suggest that dopamine D₁/D₅ receptor activation has performance- and task-dependent effects on cognitive function.
Reprint of "Neurobiology of animal models of attention-deficit hyperactivity disorder"
2007, Journal of Neuroscience Methods
Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous, highly heritable, disorder resulting from complex gene–gene and gene–environment interactions. The defining symptoms of hyperactivity, impulsivity and impaired sustained attention are not unique to ADHD. It is therefore not surprising that animals with distinctly different neural defects model the behavioural characteristics of the disorder. Consistent with ADHD being a developmental disorder, animal models are either genetic (spontaneously hypertensive rats (SHR), dopamine transporter (DAT) knock-out mice, SNAP-25 mutant mice, mice expressing a mutant thyroid receptor) or have suffered an insult to the central nervous system during the early stages of development (anoxia, 6-hydroxydopamine). It appears that neural transmission is impaired by either direct disruption of dopaminergic transmission or a more general impairment of neurotransmission that gives rise to compensatory changes in monoaminergic systems that are not sufficient to completely normalize neural function. In general, results obtained with animal studies suggest that dopamine neurons are functionally impaired. However, evidence obtained from some animal models suggests that the noradrenergic and serotonergic neurotransmitter systems may be the target of drugs that ameliorate ADHD symptoms.
Neurobiology of animal models of attention-deficit hyperactivity disorder
2007, Journal of Neuroscience Methods
Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous, highly heritable, disorder resulting from complex gene–gene and gene–environment interactions. The defining symptoms of hyperactivity, impulsivity and impaired sustained attention are not unique to ADHD. It is therefore not surprising that animals with distinctly different neural defects model the behavioural characteristics of the disorder. Consistent with ADHD being a developmental disorder, animal models are either genetic (spontaneously hypertensive rats (SHR), dopamine transporter (DAT) knock-out mice, SNAP-25 mutant mice, mice expressing a mutant thyroid receptor) or have suffered an insult to the central nervous system during the early stages of development (anoxia, 6-hydroxydopamine). It appears that neural transmission is impaired by either direct disruption of dopaminergic transmission or a more general impairment of neurotransmission that gives rise to compensatory changes in monoaminergic systems that are not sufficient to completely normalize neural function. In general, results obtained with animal studies suggest that dopamine neurons are functionally impaired. However, evidence obtained from some animal models suggests that the noradrenergic and serotonergic neurotransmitter systems may be the target of drugs that ameliorate ADHD symptoms.

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

Abstract

Brain Res.

Brain Res.

Cortex

J. Pediatr.

J. Am. Acad. Child Adolesc. Psychiatry.

Incidental learning, distraction and sustained attention in hyperactive and control subjects

J. Abn. Child Psychol.

Production deficiencies in free recall: a comparison of hyperactive, learning disabled, and normal children

J. Abn. Child Psychol.

Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate

Pediatrics.

Comparison of the effects of frontal and caudate lesions in delayed response and alternation in monkeys

J. Comp. Psychol

Automatic and efforfful processing in attention deficit hyperactivity disorder

J. Abn. Child Psychol.

A primate model of Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,

Effects of methylphenidate on hyperactive children's ability to sustain attention

Pediatrics

Frontal lobe disinhibition in attention deficit disorder

Child Psychiat. Hum. Dev.

Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson's disease

Brain

Attentional and cognitive problems

Neuropsychiatric sequelae of acute epidemic encephalitis in children

Am. J. Dis. Child.

Cognitive performance in early Parkinson's disease

Acta Neurol. Scand.

Attention deficit hyperactivity disorder (ADHD) and asymmetry of the caudate nucleus

J. Clin. Exp. Neuropsychol.

The neuropsychological evaluation of attention deficit disorder

Psychiat. Ann.

The prognosis of sequelae of epidemic encephalitis in children

Am. J. Dis. Child.

Attention Deficit Disorder

Pharmacological manipulation of cognitive performance and impersistence in motor asymptomatic monkeys chronically exposed to MPTP

Soc. Neurosci. Abstr.

The epidemiology of neurological disease

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