Levodopa: Faster and better word learning in normal humans

Knecht, Stefan; Breitenstein, Caterina; Bushuven, Stefan; Wailke, S.; Kamping, Sandra; Flöel, Agnes; Zwitserlood, Pienie; Ringelstein, E. B.

doi:10.1002/ana.20125

Cited by 217 publications

(200 citation statements)

References 59 publications

(122 reference statements)

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“…This relates well with its positive effect on learning and memory formation (Knecht et al, 2004;Floel et al, 2005a;Shohamy et al, 2005). However, L-DOPA did not improve performance in all studies testing its effects on cognition (Gotham et al, 1988;Shohamy et al, 2006;Ghilardi et al, 2007).…”

Section: Introductionmentioning

confidence: 65%

“…In neuropsychiatric diseases such as Parkinson's disease, Lewy body dementia, and schizophrenia, dopamine is associated with cognitive impairment (Molloy et al, 2005;Iversen and Iversen, 2007;Poewe et al, 2010). In the cognitive domain, dopamine improves learning and memory formation (Knecht et al, 2004;Shohamy et al, 2005;Molina-Luna et al, 2009). The likely neurophysiological basis of these effects is its impact on neuroplasticity, namely long term-potentiation (LTP) and -depression (LTD), as shown by animal experimentation (Seamans and Yang, 2004;Calabresi et al, 2007;Kung et al, 2007) and in humans (Kuo et al, 2008;Lang et al, 2008a).…”

Section: Introductionmentioning

confidence: 99%

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Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

Thirugnanasambandam

Grundey²,

Paulus³

et al. 2011

J. Neurosci.

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Dopamine is one of the major neuromodulators in the CNS, which is involved in learning and memory processes. A nonlinear, inverted U-shaped dose-response curve of its effects on cognition has been observed in animal studies. The basis for this nonlinear effect might be a similar effect of dopamine on neuroplasticity. Whereas it has been shown that dopamine affects paired associative stimulation (PAS)-induced plasticity, which might reflect learning-related processes to a larger degree than other noninvasive plasticity induction protocols in the human motor cortex in principle, its dose-dependency has not been explored previously. We studied the effect of different dosages of the dopamine precursor L-DOPA on motor cortex plasticity induced by facilitatory and inhibitory PAS of the motor cortex in 12 healthy humans. They received 25, 100, or 200 mg of L-DOPA or placebo medication combined with either excitability-enhancing or -diminishing PAS. Cortical excitability level was monitored before and for up to 2 d after plasticity induction by assessment of transcranial magnetic stimulation-induced motor-evoked potentials. Low-dose L-DOPA abolished the aftereffects of PAS and medium-dose L-DOPA prolonged facilitatory plasticity. High-dose L-DOPA reversed the excitability enhancement accomplished by facilitatory PAS to diminution. Thus, the results show a clear nonlinear effect of L-DOPA dosage on associative plasticity, different from that on nonfocal plasticity. This might help to explain dopaminergic effect on cognition and could be relevant for understanding the pathophysiology and treatment of neuropsychiatric diseases accompanied by alterations of the dopaminergic system.

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Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

Thirugnanasambandam

Grundey²,

Paulus³

et al. 2011

J. Neurosci.

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“…In humans, pathological alterations in the dopaminergic system are often accompanied by memory deficits (van Oostrom et al, 2003). The dopamine precursor L-3,4-dihydroxyphenylalanine (L-dopa) enhances memory performance (Knecht et al, 2004), and striatal dopamine transporter availability correlates positively with learning performance (Mozley et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

et al. 2006

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Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.

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“…The memory impairing effect of apomorphine in this previous study (Montoya et al, 2008) is, however, most likely due to apomorphine acting as a dopamine antagonist, rather than agonist, at the dose used. Although repeated administration of the dopamine precursor L-dopa has been shown to enhance learning of new words over successive days (Knecht et al, 2004), a differential benefit of L-dopa for novel vs. non-novel stimuli has yet to be shown. This is in contrast to the current data, which demonstrate selective C alleledependent memory enhancement for perceptual oddballs, and no general effect of genotype on control noun memory.…”

Section: Discussionmentioning

confidence: 99%

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

et al. 2014

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Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -5210T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

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Levodopa: Faster and better word learning in normal humans

Cited by 217 publications

References 59 publications

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

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