Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.
Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.
Division of Brain Sciences, Centre for Neuropsychopharmacology, Imperial College London, London, W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Bristol, BS8 2BN, United Kingdom.
James F M
JF
Myers
C John
CJ
Evans
Nicola J
NJ
Kalk
Richard A E
RA
Edden
Anne R
AR
Lingford-Hughes
D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000009:adverse effects; D009557:Nipecotic Acids / Q000009:adverse effects; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D000078308:Tiagabine; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D050485:GABA Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; C493413:SLC6A1 protein, human; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine
GAT1; MEGA-PRESS; magnetic resonance spectroscopy