Age-related Variability in GABA-A Receptor Sensitivity and the Pharmacodynamics of Midazolam

Research Objectives: To evaluate the efficacy of pharmacological modulation of GABA-A receptors in improving response to neurorehabilitation therapies, particularly in patients with diminished cortical excitability.

Design: The study employed a multi-session pharmaco-manipulation to investigate the effects of midazolam and its reversal by flumazenil on cortical excitability and inhibition using short-interval intracortical inhibition (SICI) and motor evoked potential (MEP) amplitude across two age groups: young and older adults. Data presented here are from the first manipulation involving administration of midazolam prior to the administration flumazenil.

Basic Study Design
Pre-Intervention

Assessment: All participants underwent a baseline assessment using Transcranial Magnetic Stimulation (TMS) to measure initial levels of SICI and MEP amplitude.
Midazolam Administration: Following baseline assessment, participants received an intravenous dose of midazolam. Post-administration, TMS measurements were taken to assess the drug’s effects on cortical excitability and inhibition.
Flumazenil Administration: Shortly after the midazolam assessment, flumazenil was administered intravenously to reverse the effects of midazolam. Subsequent TMS measurements were recorded to evaluate the restoration of SICI and MEP to baseline levels.

Setting: The study was conducted in a laboratory within an institutional research facility.

Participants: Age Groups: Participants were divided into two age groups:

Young Adults: Aged 18-35 years. Older Adults: Aged 60 and above. All participants were required to be healthy with no neurological or psychiatric conditions.

Specific exclusions included: History of epileptic seizures or other conditions contraindicated with TMS; Use of medications known to affect GABAergic systems, such as other benzodiazepines.

Interventions: The study involved two main pharmacological interventions, Midazolam and Flumazenil, which were administered to assess their impact on cortical excitability and inhibition as measured by SICI (short-interval intracortical inhibition) and MEP (motor evoked potential) amplitude.

Main Outcome Measures: MEP Ratio of short intracortical inhibition (SICI) protocol

Results: At baseline, SICI was absent in older adults, whereas it was present in younger counterparts. After midazolam administration, SICI was abolished in younger adults, suggesting heightened pharmacological sensitivity. In contrast, older adults showed no change, possibly indicating age-related loss of receptor sensitivity or altered pharmacokinetics.

Conclusions: The findings suggest significant age-related differences in GABA-A receptor function and benzodiazepine sensitivity, with potential implications for the clinical use of benzodiazepines in different age groups. Further research is warranted to explore the underlying mechanisms of these differences and to evaluate the impact of methodological variations in SICI measurement protocols.

Author(s) Disclosures: The findings and opinions expressed in this study are those of the authors and do not necessarily reflect the views of the United States government.