Role of dopamine in learning and memory: implications for the treatment of cognitive dysfunction in patients with Parkinson's disease.

Along with dementia, Parkinson's disease (PD) is associated with subtle but widespread cognitive impairment even in the absence of clinically apparent cognitive decline. Many of the deficits are reminiscent of those observed in patients with lesions of the prefrontal cortex, that is, failure in executive function that involves skills required for anticipation, planning, initiation and monitoring of goal-directed behaviours. This paper reviews the dopaminergic brain circuitry, and preclinical and clinical evidence supporting the regulation of prefrontal cortex activity by dopamine, and the role of dopamine in cognitive impairment in patients with PD. It addresses the need to integrate these facts and the findings of positive, neutral or detrimental frontal cognitive response to dopaminergic drugs in PD which should be viewed mainly in the context of methodological differences for subject selection. The cognitive effect of levodopa does not much depend on a neuropsychological specificity of the drug, the years of evolution of the disease or the severity of the motor signs. Instead, it may be a function of the level of dopamine depletion in different parts of the basal ganglia and prefrontal cortex. Consequently, dopaminergic agents may enhance cognitive functions in some patients and impair them in others. De novo patients tend to improve during the first year of treatment; stable responders to oral levodopa tend to show no changes; and wearing-off responders tend to deteriorate with acute levodopa challenge. Enhancement and impairment of cognitive function with dopaminergic treatment is incomplete and task-specific, suggesting the need to integrate the above dopamine facts with other neurotransmitter systems findings in PD. Meanwhile, such cognitive dissociation can be useful in refining the definition of the cognitive deficit in PD patients without dementia and emphasising the need to develop new and specific strategies for treatment.