Dose-dependent inverted U-shaped effect of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans

Abstract

The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D(2)-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D(2)/D(3) dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D(2)-like receptor activation produced an inverted "U"-shaped dose-response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of ropinirole impaired plasticity. However, no dose-dependent response effect of D(2)-like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D(2)-like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.

Figures

Figure 1.

Experimental course of the present study. TMS was applied over the left motor cortical representational area of the right ADM with an intensity to elicit MEPs with a peak-to-peak amplitude of on average 1 mV (baseline—BL 1). One hour after intake of RP, but not after placebo (PLC) medication, a second baseline (baseline 2—BL 2) was determined to control for a possible influence of the drug on cortical excitability and adjusted if necessary (baseline 3—BL 3). Two methods of plasticity induction were used, tDCS (experiment 1) and PAS (experiment 2). In the tDCS experiment, a current strength of 1 mA for 13 (anodal tDCS) or 9 min (cathodal tDCS) was applied. In the PAS experiment, ePAS (ISI of 25 ms) and iPAS (ISI of 10 ms) were used (for more details, see Materials and Methods). Immediately after tDCS and PAS, MEPs were recorded. For the drug conditions, TMS recordings were performed up to next evening after intervention. Under PLC, the aftereffects of tDCS and PAS were evaluated until 120 min after the stimulation.

Figure 2.

Effect of D2-like activation under highest RP dosage (1 mg) on cortical excitability (control experiment). The control experiment with sham tDCS was performed for the highest RP dosage (1 mg) to observe whether RP alone influences cortical excitability. Shown are baseline-standardized MEP amplitudes after plasticity induction by cathodal and anodal tDCS under placebo medication condition and after 1.0 mg of RP intake without tDCS (Sham stimulation condition). Filled symbols indicate significant deviations of the MEP amplitudes from baseline values (Student's t test, two-tailed, paired samples, p < 0.05).

Figure 3.

Dose-dependent effect of D2-like activation on nonfocal plasticity induced by anodal and cathodal tDCS (experiment 1). The time course plots show the effect of different doses of RP on tDCS-induced nonfocal neuroplasticity. Shown are baseline-standardized MEP amplitudes after plasticity induction by cathodal and anodal tDCS under 0.125, 0.25, 0.5, and 1.0 mg of RP or PLC up to the evening of the poststimulation day. As shown by TMS-elicited MEP amplitudes, RP produced a biphasic response, where low (0.125 and 0.25 mg) and high (1.0 mg) dosages impaired both cathodal and anodal tDCS-induced neuroplasticity, compared with the placebo (PLC) condition. Under medium dosage (0.5 mg), RP does not influence the anodal tDCS-elicited aftereffects. In contrast, a prolonged inhibition was observed in the cathodal tDCS condition. Shown are the mean ± SEM amplitudes vs baseline across time following anodal or cathodal tDCS for 0.125 (A), 0.25 mg (B), 0.5 (C), and 1.0 mg (D) of RP and PLC conditions. Filled symbols indicate significant deviations of the post-tDCS MEP amplitudes from baseline values, and “#” symbols mark significant deviations of drug versus PLC conditions with regard to identical time points and tDCS polarities (Student's t test, two-tailed, paired samples, p < 0.05). ne, Next evening; nm, next morning; na, next afternoon; se, same evening.

Figure 4.

Dose-dependent effect of D2-like receptor activation on focal plasticity induced by PAS25 and PAS10 (experiment 2). The time course plots showing the effect of different doses of RP on PAS-induced focal neuroplasticity. Shown are baseline-standardized MEP amplitudes after plasticity induction by ePAS (ISI of 25 ms) and iPAS (ISI of 10 ms) under 0.125 (A), 0.5 (B), and 1.0 mg (C) of ropinirole up to the evening of the poststimulation day. Under placebo medication, ePAS enhances while iPAS diminishes excitability significantly for up to 30 min after stimulation. Under the medium ropinirole dosage, the PAS-generated excitability enhancement remains largely unaffected, whereas the high and low doses abolish this excitatory effect. For iPAS-induced excitability reduction, no significant dose-dependent effect was observed. A prolonged inhibition was observed until 60 min after stimulation in the iPAS condition under 0.125 mg. Filled symbols indicate significant deviations of the poststimulation MEP amplitudes from baseline with regard to each drug dose. The “#” symbols indicate significant differences of the drug versus PLC conditions with regard to identical time points (Student's t test, two-tailed, paired samples, p < 0.05). Error bars indicate SEM. ne, Next evening; nm, next morning; na, next afternoon; se, same evening.

Figure 5.

Dose-dependent effect of D2-like receptor activation on nonfocal and focal plasticity induced by tDCS and PAS. D2-like receptor activation by ropinirole has an inverted U-shaped effect on neuroplasticity induced by tDCS and ePAS. High or low D2-like agonist dosage impaired plasticity. No dose-dependent alterations on iPAS-induced aftereffects were observed. Each column represents the mean of baseline-standardized MEP amplitudes ± SEM until 30 min after stimulation.