Antagonism of the D2 dopamine receptor enhances tremor but reduces voluntary muscle activation in humans

Neural circuits that comprise the indirect pathway in the basal ganglia have been implicated in tremor genesis, and possibly play a role in the voluntary activation of muscles. However, an absence of in vivo human studies that target striatal D2 dopamine receptors of the indirect pathway have prevented causal links being made between the D2 receptor and motor control. Healthy individuals ingested 3 mg of the competitive D2 antagonist haloperidol in a double-blinded, placebo-controlled, two-way, cross-over study. Two experiments were performed to examine involuntary and voluntary movement. The first experiment (n = 10) assessed time- and frequency-domain measures of force tremor during isometric elbow flexions, and the second experiment (n = 8) examined voluntary activation of the elbow flexors during unfatigued and fatigued maximum contractions. Blockade of the D2 receptor had no effect on tremor frequency, but increased the amplitude of force variability and 8-12 Hz power during moderate intensity isometric elbow flexions. These findings provide direct evidence that D2 receptors relate to physiological tremor generation during muscle contractions, whereby the gain of tremor is increased after D2 antagonism. The ability to voluntarily activate the elbow flexors was compromised under both non-fatigued and fatigued conditions. Consequently, the duration that maximum contractions could be sustained was reduced with D2 antagonism. These results provide further support that the D2 receptor has a critical role in skeletal muscle activation, where central fatigue is exacerbated by enhancing activity of the indirect basal ganglia pathway during maximum muscle contractions.