Effects of modulators at different subtypes of GABAA receptors on LTD-like plasticity in human motor cortex

Aims: Human cortical plasticity is significantly controlled by GABAAergic neurotransmission. However, it is not clear which specific subtypes of GABAA receptors mediate this effect. Here, we tested the effects of modulators at different subtypes of GABAA receptors on long-term depression (LTD)-like plasticity in human motor cortex.

Methods: Ten healthy subjects participated in this pharmacological placebo-controlled double-blind randomized crossover study. Subjects were given either a single oral dose of the benzodiazepine alprazolam (ALP, 1mg), the non-benzodiazepine hypnotic zolpidem (ZOL, 10mg), two different dosages of ethanol (low/high EtOH), or placebo. Motor cortex excitability was assessed by input-output curves of motor-evoked potentials (IO-MEP) recorded from right abductor pollicis brevis muscle. Paired associative stimulation (PAS) was used to induce LTD-like plasticity in primary motor cortex 90min after drug intake (Müller-Dahlhaus et al. [2010] Front Synaptic Neurosci 2: 34). IO-MEP was recorded at baseline before drug intake as well as before and after PAS. Drug-induced sedation was assessed by visually guided saccade velocity (SV).

Results: IO-MEP was significantly decreased after ALP and showed a strong trend towards a decrease for ZOL, whereas low EtOH, high EtOH and placebo had no effect on IO-MEP. Additionally, both ALP and ZOL significantly decreased SV, which was not changed by low EtOH, high EtOH or placebo. PAS induced LTD-like plasticity at higher stimulation intensities in the placebo condition. This LTD-like effect was completely suppressed by prior application of ZOL, but not by any of the other GABAAergic drugs.

Conclusion: Our data provide evidence that LTD-like plasticity may be differentially modulated by different GABAAergic drugs in human M1 and thus suggests specific control of this form of human cortical plasticity at the level of GABAA receptor subtypes.