Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine

• Published in: Synapse (New York, N.Y.) N.Y.), 2014-08, Vol.68 (8), p.355-362
• Main Authors: Myers, James F.M., Evans, C. John, Kalk, Nicola J., Edden, Richard A.E., Lingford-Hughes, Anne R.
• Format: Article
• Language: English
• Subjects: Adult; Brain - drug effects; Brain - metabolism; Extracellular Space - drug effects; Extracellular Space - metabolism; GABA Plasma Membrane Transport Proteins - metabolism; gamma-Aminobutyric Acid - metabolism; GAT1; Humans; magnetic resonance spectroscopy; Male; MEGA-PRESS; Middle Aged; Neurotransmitter Uptake Inhibitors - adverse effects; Nipecotic Acids - adverse effects; Proton Magnetic Resonance Spectroscopy - methods; Synapses - drug effects; Synapses - metabolism; Tiagabine; Young Adult
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.21747

ABSTRACT 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 1H‐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 1H‐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. Synapse 68:355–362, 2014. © 2014 Wiley Periodicals, Inc. Synaptic GABA uptake can be blocked using the GAT1 inhibitor tiagabine, to increase GABA concentrations in the synaptic cleft. J‐difference edited MRS is useful for measuring brain GABA concentrations, but is shown here to be insensitive to these acute and transient changes in inhibitory signalling.