Journal Article

Acute increases in synaptic GABA detectable in the living human brain: A 11CRo15-4513 PET study

Myers, Jim F., Hammers, Alexander, Lingford-Hughes, Anne R., Kalk, Nicola J., Barros, Daniela Riano, Watson, Ben J., Erritzoe, David, Wilson, Sue J., Turkheimer, Federico E., Nutt, David J., Cunningham, Vincent J., Stokes, Paul R.A.

2014

Overview

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [11C]Ro15-4513. We examined the effect of 15mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [11C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [11C]Ro15-4513 binding. We also examined the test–retest reliability of α1 and a5-specific [11C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [11C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test–retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [11C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system. •Increases in synaptic GABA investigated using [11C]Ro15-4513 PET.•Synaptic α1 [11C]Ro15-4513 binding reduced by increased GABA.•α1 [11C]Ro15-4513 binding reductions were greater than test–retest reliability.•Suggests [11C]Ro15-4513 PET can measure increased synaptic GABA in the human brain.•Findings have important implications for examining the human in vivo GABA system.

• Publisher: Elsevier Inc,Elsevier,Elsevier Limited
• Subject: [11C]Ro15-4513 / Adult / Anxiety / Azides / Benzodiazepines / Biological and medical sciences / Brain - diagnostic imaging / Brain Chemistry - drug effects / Dose-Response Relationship, Drug / Double-Blind Method / Fundamental and applied biological sciences. Psychology / GABA / GABA Agonists - pharmacology / gamma-Aminobutyric Acid - metabolism / Humans / Male / Medical research / Memory - drug effects / Middle Aged / Nipecotic Acids - pharmacology / PET / Positron-Emission Tomography / Psychomotor Performance - drug effects / Radiopharmaceuticals / Receptors, GABA-A - metabolism / Rodents / Studies / Synapses - metabolism / Synaptic / Tiagabine / Vertebrates: nervous system and sense organs