Dosage-dependent effect of dopamine D2 receptor activation on motor cortex plasticity in humans

Abstract

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose-response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.

Keywords: dopamine; dopamine receptors; neuroplasticity; paired associative stimulation; transcranial direct current stimulation; transcranial magnetic stimulation.

Figure 1.

Course of the experiments. MEPs elicited by single-pulse TMS over the motor hotspot of the right ADM were recorded at 1 mV intensity before drug intake (baseline 1). Two hours after drug intake, baseline 2 was recorded to look for an effect of the drug on cortical excitability. In case of any MEP alterations from baseline 1, baseline 3 was recorded by adjusting the stimulator output to obtain a mean MEP amplitude of 1 mV. Then tDCS (anodal or cathodal) or PAS (excitatory or inhibitory) was administered, immediately followed by MEP after-measurements that covered 120 min. Additional after-measurements were performed at the same evening (SE) and the morning (NM), afternoon (NA), and evening (NE) of the second day after plasticity induction. ISI, Interstimulus interval.

Figure 2.

Dose-dependent effect of D₂ receptor activation on nonfocal plasticity induced by anodal and cathodal tDCS (Experiment 1). The x-axis displays the time points (in minutes) of after-measurements during the experiment. MEP amplitudes standardized to the corresponding baseline values (mean ± SEM) are plotted on the y-axis. The graphs show that, under placebo medication, anodal tDCS induces an excitability enhancement lasting for ∼30 min, whereas cathodal tDCS diminishes excitability for 25 min after stimulation. A, Low-dose (2.5 mg), medium-dose (10 mg), and high-dose (20 mg) bromocriptine prevented the anodal tDCS-generated aftereffects. B, Low-dose and high-dose bromocriptine prevented the cathodal tDCS-generated aftereffects, whereas under medium dose, the aftereffects were preserved. Filled symbols indicate statistically significant deviations of the post-tDCS MEP values compared with baseline. #, *, and × symbols indicate significant differences of the real medication compared with the placebo medication conditions at the same time points after plasticity induction (Fisher's LSD post hoc test, paired, two-tailed, p ≤ 0.05). SE, Same evening; NM, next morning; NA, next afternoon; NE, next evening. Error bars show SEM. ^#2.5 mg of bromocriptine, *10 mg of bromocriptine, and ^×20 mg of bromocriptine.

Figure 3.

Dose-dependent effects of D₂ receptor activation on focal neuroplasticity induced by PAS25 and PAS10 (Experiment 2). The x-axis displays the time points (in minutes) of after-measurements during the experiment. MEP amplitudes standardized to the corresponding baseline values (mean ± SEM) are plotted on the y-axis. The graphs show that, under placebo medication, excitatory PAS (PAS25) induces an excitability enhancement lasting for ∼30 min, whereas inhibitory PAS (PAS10) diminishes excitability for 60 min after stimulation. A, Low-dose (2.5 mg) and high-dose (20 mg) bromocriptine suppress the aftereffects of PAS25, whereas the medium dose (10 mg) reduced but did not abolish them. B, Low-dose (2.5 mg) and high-dose (20 mg) bromocriptine prevented the PAS10 aftereffects. Filled symbols indicate statistically significant deviations of the post-tDCS MEP values compared with baseline. #, *, and × symbols indicate significant differences of the real medication compared with the placebo medication conditions at the same time points after plasticity induction (Fisher's LSD post hoc test, paired, two-tailed, p ≤ 0.05). SE, Same evening; NM, next morning; NA, next afternoon; NE, next evening. Error bars show SEM. ^#2.5 mg of bromocriptine, *10 mg of bromocriptine, and ^×20 mg of bromocriptine.

Figure 4.

Dose-dependent effects of D₂ receptor activation on nonfocal and focal plasticity induced by tDCS and PAS. The horizontal line represents the baseline value of 1 mV before the start of the each stimulation condition, whereas the vertical line (y-axis) represent the MEP amplitudes standardized to the corresponding baseline values. A, D₂ receptor activation by bromocriptine has a nonlinear dosage-dependent effect on neuroplasticity induced by cathodal tDCS and inhibitory PAS. Low and high dosages impaired or prevented excitability alterations, whereas the medium dosage preserved these. In contrast, the effects of anodal tDCS and excitatory PAS were either impaired or prevented in all dosages. Each column represents the baseline-standardized MEP amplitudes pooled for 60 min after anodal/cathodal tDCS and PAS25/PAS10 from 24 participants. Error bars represent the SEM of the measurement immediately after until 60 min after stimulation. The # symbol indicates significant differences of the real medication compared with placebo medication (post hoc t test, paired, two-tailed, p ≤ 0.05). B, Each point represents the mean of the MEP amplitude (calculated for the first 60 min after intervention) from each subject for each drug/stimulation condition combination. The results show considerable interindividual variability, especially under bromocriptine.