Relevance Of The Chroniclowdose Mptp Monkey Model To Other Disorders

While the deficits in chronic-low-dose MPTP-treated monkeys described earlier in this chapter are strikingly similar in nature to those described in early Parkinson's disease patients, the frontal/attentional/executive function deficits observed in these animals have significant overlap with, and clinical relevance for, other disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia in which frontostriatal dysfunction has been implicated.

A number of similarities between the cognitive deficits of chronic-low-dose (CLD) MPTP-treated monkeys and children with attention deficit disorder have been noted and attributed to frontostriatal dysfunction secondary to deficits in dopamin-ergic and noradrenergic neurotransmission [40]. Recent studies of children and adolescents with attention deficit hyperactivity disorder (ADHD) indicate that, in addition to inattention and distractibility, a number of executive functioning deficits have also been documented [41-43]. Additionally, the sense of time is reportedly impaired in children with ADHD and is not improved with administration of stimulant medication [44]. Thus, we suggest that the CLD MPTP model in nonhuman primates may also be a valid large-animal model for studying cognitive deficits associated with attention deficit disorder. The CLD MPTP-treated monkey appears to encompass a number of the criteria suggested by Solanto [45] that should be present in a valid model of ADHD, including deficits in measures of attention and impulsivity and amelioration of deficits by clinically effective treatments [46-48].

Schizophrenia is characterized by dysregulation of attention [49]. Four important domains of cognitive functioning have been described as impaired in schizophrenia: attention, verbal fluency, working memory, and executive functioning [50]. Sustained attention appears to be a particular problem in schizophrenia that contributes to problems in other aspects of higher cognitive functioning [51]. Because of the apparent specificity of sustained attention to schizophrenia and its relationship to other important cognitive abilities, this aspect of cognition (which can be modeled in chronic-low-dose MPTP-treated monkeys) may be an important future target of intervention.

Executive functions encompass a number of abilities, including but not limited to the ability to initiate, plan, and sequence behaviors, the ability to abstract a principle or problem-solving strategy, and the ability to be cognitively flexible (i.e., switch cognitive sets). Whereas executive functions are largely subserved by the frontal cortex, they are also related to other parts of the brain that have strong connections to the frontal cortex, such as the striatum and temporal-limbic complex [51]. A recent meta-analysis from 71 studies [52] demonstrated an overall effect size of -1.45 for schizophrenia patients relative to controls on measures of executive functioning. This is a large effect size, suggesting that patients with schizophrenia have significant difficulty on these measures compared with other psychiatric patients (effect size of -0.40). In addition, functional imaging studies have provided support for dysfunction in frontal-basal ganglia circuitry [53] as a neural substrate for attention/executive cognitive dysfunction in schizophrenia. Considering the cognitive deficits known to affect schizophrenics and the attention/executive deficits described in chronic-low-dose MPTP-treated monkeys, these animals may serve as a useful model for the cognitive deficits of schizophrenia and as a good model system for evaluating new treatment modalities.

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