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

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.