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

Abstract

Synaptic inhibition in the brain is mainly mediated by ã_aminobutyric acid (GABA) (Biggio, 1992). The effects of GABA are modulated by a powerful uptake system (Dingledine & Korn, 1985) that limits spatial diffusion of GABA and the duration of inhibitory postsynaptic potentials (IPSPs) (Isaacson et al. 1993). If GABA uptake is blocked pharmacologically, profound changes in the shape and duration of stimulus-induced IPSPs can be observed in cortical slices of experimental animals (Dingledine & Korn, 1985;Thompson & G ahwiler, 1992). Tiagabine (TGB), a lipophilic derivative of nipecotic acid, is a novel antiepileptic drug effective in controlling partial seizures (Ben-Menachem, 1995). In in vitro experiments, TGB has been shown to inhibit the uptake of GABA from the synaptic cleft into glial cells and neurons (Suzdak & Jansen, 1995). Because so much is known concerning the mechanism of action of TGB as elucidated in experiments in animals and cortical slice preparations, it may serve as a suitable substance for enabling us to learn more about the organizational principles of cortical inhibition in humans. We used transcranial magnetic stimulation (TMS) to study non-invasively the effects of blocking GABA uptake in the human motor cortex. Although the exact neuronal mechanisms leading to inhibitory or facilitatory phenomena are not known, TMS techniques are now widely used to assess intracortical excitability in certain neurological disorders and under experimental conditions (Rothwell, 1997) including neuropharmacological manipulation (Ziemann et al. 1996b). Our

Investigating TMS–EEG Indices of Long-Interval Intracortical Inhibition at Different Interstimulus Intervals

“…This is supported by studies showing reductions in the amplitude of the late indirect (I) waves following LICI [36,37]. Furthermore, several studies using pharmacological interventions to modulate GABAergic tone suggest that LICI is mediated by activation of the metabotropic GABA B receptor [10,11,38].…”

“…When applied over the primary motor cortex (M1), suprathreshold ppTMS at long (100-200 ms) interstimulus intervals (ISIs) produce a motor evoked potential (MEP) in peripheral muscles that is reduced in amplitude relative to the MEP produced by a single magnetic stimulus. This effect, referred to as long-interval intracortical inhibition [LICI; 9] is thought to be mediated by interactions between GABA type B (GABA B ) receptors activated by the first (conditioning) stimulus and corticospinal neurons activated by the second (test) stimulus [10][11][12].…”

Intracortical Inhibition Assessed with Paired-Pulse Transcranial Magnetic Stimulation is Modulated during Shortening and Lengthening Contractions in Young and Old Adults

“…However, this has been more clearly defined for LICI [43][44][45], with some evidence suggesting that the SP may reflect composite activity of both GABAA and GABAB receptors [46], as well as have contributions from brain areas 'upstream' from M1 [47]. Our assessment of LICI therefore provides a more precise measure of changes in GABAB mediated inhibition within M1 during shortening and lengthening contractions.…”

Age-related Differences in Pre- and Post-synaptic Motor Cortex Inhibition are Task Dependent

“…This process is known as short-interval intracortical inhibition (SICI; [8]). However, when both stimuli are suprathreshold and separated by a long inter-stimulus interval (100 -150 ms; ISI), inhibition of the test MEP is thought to involve post-synaptic GABAB receptors [9] and is known as long-interval intracortical inhibition (LICI; [10]). During triple-pulse TMS, the interaction between LICI and SICI is assessed by preceding the conditioning and test stimuli for SICI by the conditioning stimulus for LICI [11].…”