Inhibitory Effect of Apomorphine on Focal and Nonfocal Plasticity in the Human Motor Cortex

Abstract

Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.

Keywords: apomorphine: transcranial direct current stimulation; dopamine; motor cortex; motor evoked potential; paired associative stimulation; plasticity; transcranial magnetic stimulation.

Figure 1

Time course of the experiments. Single-pulse TMS-evoked MEPs over the right ADM motor hotspot were recorded at intensities that evoked 1mV MEP amplitudes before drug injection (Baseline 1). Baseline 2 was recorded ten minutes after drug injection to look for drug-induced changes of 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) in Experiment 1 or PAS (PAS25 or PAS10) in Experiment 2 was administered, immediately followed by MEP after-measurements covering 120 min. Additional after-measurements were performed at the same evening (SE) and the morning at approximately 9:00 AM (NM), noon, at approximately 12:00 PM (NN), and evening, at approximately 6:00 PM (NE) of the second day after plasticity induction. Motor evoked potential (MEP). Transcranial direct current stimulation (tDCS). Paired associative stimulation (PAS).

Figure 2

Effects of apomorphine on nonfocal plasticity induced by anodal and cathodal tDCS (Experiment 1). The x-axis displays the time points (in minutes) of post-stimulation measurements. The y-axis displays the mean MEP amplitudes after stimulation (MEPs were standardized to the corresponding baseline values for each participant). The graphs show that under placebo medication anodal tDCS enhanced excitability, and cathodal tDCS diminished excitability for ∼30 min after stimulation. (A) Low-dose (0.1 mg) abolished, medium-dose (0.2 mg) and high-dose (0.3 mg) transiently reversed the after-effect of anodal tDCS. (B) All dosages of apomorphine abolished the after-effect of cathodal tDCS. 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 (Bonferroni corrected, two-tailed, paired t-test, p ≤ 0.05). Error bars show standard error of mean (SEM). * 0.1 mg of apomorphine, # 0.2 mg of apomorphine, and ‡ 0.3 mg of apomorphine.

Figure 3

Effects of apomorphine on focal neuroplasticity induced by PAS25 and PAS10 (Experiment 2). The x-axis displays the time points (in minutes) of post-stimulation measurements. The y-axis shows the mean MEP amplitudes after stimulation (MEPs were standardized to the corresponding baseline values for each participant). The graphs show that, under placebo, excitatory (PAS25) and inhibitory PAS (PAS10) induce excitability enhancements and reductions lasting for ∼30 min after stimulation, respectively. (A) Low-dose (0.1 mg), medium-dose (0.2 mg), and high-dose (0.3 mg) apomorphine abolished, or diminished the after-effects of PAS25. (B) All dosages of apomorphine abolished the after-effect of PAS10. Filled symbols indicate statistically significant deviations of the post-PAS 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 (Bonferroni corrected, two-tailed, paired t-test, p ≤ 0.05). Error bars show standard error of mean (SEM). * 0.1 mg of apomorphine, # 0.2 mg of apomorphine, and ‡ 0.3 mg of apomorphine.