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Results are inconsistent. In one study with repeated intake of 100 mg levodopa per day for 3 weeks, patients improved in their motor functions significantly stronger than the placebo group. This higher level of performance persisted even after termination of the drug intake period (Scheidtmann et al. 2001). However, a more recent

► placebo-controlled study with application of 100 mg levodopa per day for 2 weeks did not demonstrate a superiority of levodopa. Single doses of levodopa were effective in the encoding of a motor memory and in improving procedural motor learning (serial reaction time task) (Floel et al. 2005b) but did not modulate more clinical aspects of motor functions (dexterity and strength) (Liepert 2008).

Undoubtly, levodopa reduces motor symptoms in patients with ► Parkinson's disease (PD). Astonishingly, its effects on cognitive functions and learning abilities are questionable and have even been shown to be detrimental. For example, PD patients treated with levodopa deteriorated in visual memory functions and motor sequence learning. It was suggested that levodopa effects depend on task demands and basal dopamine levels in distinct parts of the striatum.

Methylphenidate produces an increase in dopamine signalling through multiple actions. A trial with 21 sub-acute stroke patients indicated that the combination of

► methylphenidate with physical therapy over a period of 3 weeks improved motor functions and decreased depression. In patients with traumatic brain injury, the drug improved the speed of mental processing and had some effect on tests of ► attention and motor performance.

Noradrenergic Drugs

Healthy Subjects The noradrenaline re-uptake inhibitor

► reboxetine improved motor skill acquisition in a velocity-depending motor task (Plewnia et al. 2004).

D-amphetamine modulates not only noradrenergic, but also dopaminergic and serotonergic neurotransmission. In a paradigm with training of voluntary thumb movements, ► D-amphetamine facilitated use-dependent plasticity. However, in another study, the administration of D-amphetamine did not improve sensory functions in a tactile frequency discrimination training. There is some evidence that D-amphetamine exerts its effects in cognitive rather than motor networks. For example, D-amphetamine improved performance of ► selective attention tasks.

Patient Groups In chronic stroke patients, a single dose of reboxetine improved tapping speed and grip strength in the paretic but not in the non-affected hand.

Studies with D-amphetamine in stroke patients are inconclusive. In two studies, drug effects on motor recovery were found. In subsequently performed studies (n = 6), these positive results could not be replicated. A Cochrane review summarized that it is currently impossible to draw any definite conclusions about the potential role of D-amphetamine in motor rehabilitation (Martinsson et al. 2007).

Serotonergic Substances

Healthy Subjects There are no studies with serotonergic drugs for enhancement of learning in healthy subjects available.

Patient Groups The serotonin re-uptake inhibitor ► fluoxetine improved walking and activities of daily living in a group of subacute stroke patients. In eight chronic stroke patients, a single dose of fluoxetine improved motor functions of the affected hand. In another study, the more selective serotonin re-uptake inhibitor ► citalopram was used in chronic stroke patients. A single dose of citalo-pram was able to improve dexterity but not strength in the paretic hand. The effect was pronounced after 1 h of physiotherapy aimed at improving hand function (Zittel et al. 2008; Fig. 3). Taking these three studies together, results seem promising but one has to consider that only a very limited number of subjects have been studied so far.

Cholinergic Substances

This group mainly includes drugs that act as inhibitors of the enzyme acetylcholinesterase. This increases the amount of ► acetylcholine. Such drugs have been successfully tested in ► dementia and are recommended for patients with mild to moderate Alzheimer's disease.

Healthy Subjects In elderly healthy subjects, ► rivastig-mine improved motor learning and visuospatial processes. In contrast the ► anticholinergic agent biperiden impaired these abilities. In another study ► donepezil was applied in elderly subjects and improved their memory performance. In addition, ► rapid eye movement (REM) sleep was enhanced, and the positive correlation between memory function and REM sleep duration suggested an interrelationship between these two factors.

Patient Groups There is only limited evidence regarding beneficial effects of ► acetylcholinesterase inhibitors in ► stroke patients. One case study and one ► open-label pilot study suggest that these drugs may enhance the recovery of motor functions, in particular in cognitively

Verbal and Non-Verbal Learning in Humans. Fig. 3. Nine Hole Peg test results, expressed in percentage of the values obtained prior to drug ingestion. CIT, citalopram;PL, placebo;PT, physiotherapy. Error bars indicate standard deviations. *p < 0.05. (From Zittel et al. 2008.)

impaired stroke patients. One study combining the application of donepezil with constraint-induced movement therapy only showed a trend towards stronger improvement in the drug-treated group.

Modafinil

This wake-promoting drug is approved for application in patients with abnormal sleepiness, e.g., ► narcolepsy and sleep disorders of shift workers. Some studies also suggest that it is helpful in patients with multiple sclerosis suffering from fatigue. A recent study demonstrated that ► modafinil blocks ► dopamine transporters and increases dopa-mine in the human brain.

Healthy Subjects Studies in healthy subjects are inconclusive. One study reported a drug-related improvement of several cognitive abilities including digit span, visual pattern recognition memory, spatial planning, and ► stop-signal reaction time. Another study suggested an effectiveness in monotonous ► working-memory tasks, in a third study modafinil was found to be equal to placebo regarding reaction time, dexterity and the d2 test.

Patient Groups In patients with ► Huntington's disease, modafinil increased alertness but did not improve cognitive functions. In contrast, deleterious effects on visual recognition and working memory were observed. In schizophrenic patients, improvements of ► executive functions and ► attention were found.

Verbal Learning Dopaminergic Substances

Healthy Subjects Single doses of 100 mg levodopa improved verbal learning in young healthy subjects. Learning occurred faster and more successful, and the long-term retention of novel word learning was better than in the placebo-treated control group (Knecht et al. 2004; Fig. 4). A comparison between application of levodopa, d-amphetamine and placebo indicated a similar efficacy of levodopa and d-amphetamine and the superiority of both drugs compared to placebo. In contrast to beneficial effects of levodopa, the dopamine-receptor agonist ► pergolide impaired novel word learning. The authors suggested that this finding can be explained by the tonic dopaminergic effects produced by pergolide. Due to a much shorter ► half-life, levodopa rather exerts a phasic dopaminergic stimulation. Phasic stimulations might be more effective for associative learning.

Patient Groups Avery recent ► placebo-controlled study in stroke patients indicated that levodopa induced a greater improvement of verbal fluency and repetition than ► placebo. This positive effect was particularly obvious in patients with frontal lesions.

► Bromocriptine, a dopamine-receptor agonist, has yielded inconclusive results. In one study, reading-comprehension, repetition, dictation and verbal latency

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