L-DOPA Disrupts Activity in the Nucleus Accumbens during Reversal Learning in Parkinson's Disease

Abstract

Evidence indicates that dopaminergic medication in Parkinson's disease may impair certain aspects of cognitive function, such as reversal learning. We used functional magnetic resonance imaging in patients with mild Parkinson's disease to investigate the neural site at which L-DOPA acts during reversal learning. Patients were scanned both ON and OFF their normal dopamine-enhancing L-DOPA medication during the performance of a probabilistic reversal learning task. We demonstrate that L-DOPA modulated reversal-related activity in the nucleus accumbens, but not in the dorsal striatum or the prefrontal cortex. These data concur with evidence from studies with experimental animals and indicate an important role for the human nucleus accumbens in the dopaminergic modulation of reversal learning.

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

“…The present data suggest that dopaminergic modulation of neural activity in the putamen is especially important when subjects change their behavior on the basis of negative feedback. These findings support a model of executive control in which dopaminergic signals originating in the striatum facilitate the flexible updating of new goal-related representations (Frank et al, 2001;Cools et al, 2007b).…”

“…Interestingly, the putaminal region in which methylphenidate modulated BOLD signal in the present study is different from the ventral striatal region in which levodopa modulated BOLD signal in patients with Parkinson's disease during reversal learning (Cools et al, 2007b). One possible reason for this discrepancy is that the study by Cools et al (2007b) involved patients with presumably abnormal dorsal striatal dopamine levels.…”

“…One possible reason for this discrepancy is that the study by Cools et al (2007b) involved patients with presumably abnormal dorsal striatal dopamine levels. It is likely that any effects of dopaminergic drugs on dorsal striatal BOLD signal in healthy volunteers will be abnormal in such patients.…”

Dopamine Release in Dissociable Striatal Subregions Predicts the Different Effects of Oral Methylphenidate on Reversal Learning and Spatial Working Memory

“…For example, this region of the striatum has been found to be associated with reversal learning in monkeys bearing lesions of the caudate nucleus (Divac et al, 1967). Consistent with an effect at striatal dopamine receptors, raclopride administration in rhesus monkeys produced marked reversal learning impairments (Lee et al, 2007), and in humans, L-DOPA impaired probabilistic reversal learning in patients with Parkinson's disease (Swainson et al, 2000;Cools et al, 2001) and abolished the reversal-related blood oxygen level-dependent (BOLD) signal in the nucleus accumbens (Cools et al, 2007a).…”

“…Such effects can be explained by different hypothesized "inverted U"-shaped relationships between performance on different tasks and PFC dopamine, at the systems (Williams and Goldman-Rakic, 1995;Mattay et al, 2003;Roberts et al, 1994) or cellular (Vijayraghavan et al, 2007) levels. Such relationships have been postulated in humans (Cools et al, 2001(Cools et al, , 2007a but not demonstrated for the striatum.…”