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Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans

Konrad J. Werhahn *, Erwin Kunesch, Soheyl Noachtar *, Reiner Benecke and Joseph Classen

Blockade of uptake carriers of -aminobutyric acid (GABA) has been shown to modulate inhibition in cortical slices of experimental animals, although little is known about this mechanism in vivo and, in particular, in humans.

The effects of blockade of GABA uptake were studied using transcranial magnetic stimulation (TMS) in humans. In eight healthy volunteers several measures of cortical excitation and inhibition were obtained before and ~2 h after ingestion of 5-15 mg of tiagabine (TGB).

After TGB ingestion, the duration of the TMS-induced silent period observable in the electromyogram of the voluntarily contracted target muscle was prolonged. Similarly, paired-pulse inhibition of the motor-evoked potential (MEP), as tested by delivering two magnetic shocks of equal suprathreshold intensities at 160 ms interstimulus interval (ISI), was more pronounced. In apparent contradistinction, paired-pulse inhibition of the MEPs produced by a subthreshold conditioning stimulus delivered 3 ms prior to a suprathreshold stimulus was reduced. Paired-pulse facilitation elicited by the same double-shock protocol at an ISI of 10 ms was increased.

The prolongation of the GABA_B receptor-mediated component of the inhibitory postsynaptic potential observed with TGB in in vitro studies probably underlies the increase in cortical silent period duration. The reduction of the paired-pulse inhibition at 3 ms, in turn, probably reflects inhibition of GABA_A receptor-mediated inhibition via presynaptic GABA_B receptors.

These data provide in vivo evidence of differential modulation of cortical inhibition by blockade of GABA uptake. Presynaptic GABA autoreceptors may be involved in modulating cortical inhibition in the human motor cortex.

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