Dopaminergic Impact on External Brain Stimulation-induced Neuroplasticity in Human Motor Cortex

Dopamine (DA) is involved in learning and memory formation, which are thought to depend on synaptic modifications like long-term potentiation (LTP) and long-term depression (LTD). Despite huge efforts to unravel the dopaminergic impact on these functions, the respective knowledge is still far from being complete. This might especially be due to the neuromodulatory impact of DA on cortical function, i.e. DA might affect cortical excitability and plasticity differently, dependent on DA dosage, DA sub-receptors, and the focality of plasticity induced, amongst others. The aim of the present thesis, which contains three studies, was to explore the impact of DA on cortical plasticity in healthy humans into larger detail. Specifically, we sought to determine if the multiple modes of action of DA on neuroplasticity depend on sub-receptor specificity, concentration level and type of plasticity. In all experiments the primary motor cortex served as a model system, and plasticity was monitored by motor evoked potential (MEP) amplitudes via transcranial magnetic stimulation (TMS). Focal plasticity was induced non-invasively by paired associative stimulation (PAS), while non-focal plasticity was generated by transcranial direct current stimulation (tDCS). In the first study we explored the impact of D1 receptor activity on plasticity. Here, shifting the balance of DA activation in direction of D1 by D2 block abolished non-focal plasticity and focal inhibition. Further enhancing D1 activity by adding L-dopa under D2 block reestablished all kinds of plasticity. In concordance with animal experiments, the results favor an important impact of D1 receptor activity on neuroplasticity in humans. In the second study, in order to reveal if DA receptor activation exerts a non-linear dosedependent effect on cortical plasticity, we explored the impact of different dosages of Ldopa on tDCS-induced plasticity. In accordance, the results show a nonlinear dosageeffect relation of dopamine receptor activation on plasticity, resulting in a ‘U’-shaped dose-response curve for anodal tDCS and in an inverted ‘U’-shaped dose-response curve for cathodal tDCS. The results are pinpointing to the importance of a specific dosage of dopamine optimally suited to improve plasticity. In the third study, we combined different doses of the D2/D3 dopamine agonist ropinirole (RP) with focal and non-focal plasticity induction in order to determine if the nonlinear effect of DA on plasticity depends on sub-receptor specificity and the kind of plasticity induced. D2-like receptor activation produced an inverted ‘U’-shaped dose response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. However, no dose-dependent response effect of D2-like receptor activation was evident for iPAS. The results of this study support the assumption that modulation of D2-like receptors exerts a dosedependent non-linear effect on neuroplasticity in the human motor cortex, which differs for the type of plasticity induced. In summary, our results demonstrate that the dopaminergic influence on cortical plasticity (a) is specific for DA sub-receptors, and (b) is dosage-dependent. They furthermore demonstrate that (c) the effect differs for the specific kind of plasticity induced, and (d) suggest that the focusing effect and the stabilizing effect of DA on plasticity depends on the interaction of dopaminergic subreceptors. These results might be important for the therapeutic application of dopaminergic agents, especially for rehabilitative purposes, and explain some opposing results of former studies.