Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs

Abstract

Transcranial magnetic stimulation was used to probe the acute effect of a single oral dose of various dopaminergic (levodopa, selegiline, bromocriptine) and antidopaminergic drugs (sulpiride, haloperidol) on motor cortex excitability in healthy volunteers. Motor threshold, intracortical inhibition and intracortical facilitation were tested in the abductor digiti minimi muscle. The latter two parameters were studied in a conditioning-test paired stimulus paradigm. The principal findings were an increase in intracortical inhibition by bromocriptine, and, conversely, a decrease in intracortical inhibition and an increase in intracortical facilitation by haloperidol. Effects peaked at delays consistent with the pharmacokinetics of the two drugs and were fully reversible. In conclusion, dopamine receptor agonists and antagonists can be considered inverse modulators of motor cortex excitability: the former enhance inhibition while the latter reduce it. The relation of the present findings to current models of motor excitability abnormalities in movement disorders will be discussed.

Introduction

Since its introduction (Barker et al., 1985), transcranial magnetic stimulation (TMS) has been widely used as a non-invasive technique to explore the integrity and excitability of the motor system in health and disease (for review, see Rothwell et al., 1991; Murray, 1992; Rossini et al., 1994). More recently, in addition to motor threshold and motor evoked potential (MEP) size, intracortical (or cortico-cortical) inhibition and facilitation (together referred to as intracortical excitability) were introduced as other parameters of motor excitability. They are obtained in a conditioning-test paired stimulus paradigm at short (~2–5 ms) and longer (~7–20 ms) interstimulus intervals, respectively. Very likely, they test the excitability of separate inhibitory and excitatory interneuronal circuits at the level of the motor cortex (Kujirai et al., 1993; Ziemann et al., 1996f; Rothwell, 1996(review); Nakamura et al., 1997). With this variety of parameters of motor excitability at hand, several authors have started to look at changes in motor excitability produced by CNS active drugs or neurological disorders. A single oral dose of an antiepileptic drug, depending on whether its main mode of action is a blockade of ion channels or a modulation of neurotransmitter action (support of the action of γ-aminobutyric acid), elevates motor threshold or suppresses intracortical excitability, respectively (Mavroudakis et al., 1994; Ziemann et al., 1995; Ziemann et al., 1996d; Ziemann et al., 1996e; Chen et al., 1997; Mavroudakis et al., 1997).

We undertook the present study in order to investigate systematically the effect of various dopaminergic and anti-dopaminergic drugs on motor excitability. This may be of interest, since it was demonstrated that basal ganglia disorders with major involvement of the dopaminergic system show certain abnormalities in motor excitability: intracortical inhibition seems to be deficient in Parkinson's disease (Ridding et al., 1995a; Hanajima et al., 1996; Ziemann et al., 1996b), progressive supranuclear palsy (Ziemann et al., 1996b), corticobasal degeneration (Hanajima et al., 1996), cerebrovascular lesions of the putamen, globus pallidus or supplementary motor area (Terao et al., 1995; Hanajima et al., 1996), task-specific dystonia (Ridding et al., 1995b), and Tourette's syndrome (Ziemann et al., 1997), but normal in Huntington's disease (Hanajima et al., 1996). Consistent with these clinical data, it was shown that the dopamine receptor agonist pergolide which is now widely used in the treatment of Parkinson's disease enhances intracortical inhibition even in normal subjects (Ziemann et al., 1996a).

Upon this framework, we hypothesised that dopaminergic and anti-dopaminergic drugs should exert opposite effects on motor cortex excitability.