Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.
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, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]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 [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]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 [(11)C]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 [(11)C]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.
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK; Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, UK. Electronic address: paul.stokes@imperial.ac.uk.
Paul R A
PR
Stokes
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK; Psychopharmacology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, BS8 2BN, UK.
Jim F
JF
Myers
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK.
Nicola J
NJ
Kalk
Psychopharmacology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, BS8 2BN, UK.
Ben J
BJ
Watson
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK.
David
D
Erritzoe
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK; Psychopharmacology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, BS8 2BN, UK.
Sue J
SJ
Wilson
School of Medical Sciences, University of Aberdeen, IMS Building, Foresterhill, Aberdeen AB25 2ZD, UK.
Vincent J
VJ
Cunningham
MRC Clinical Sciences Centre and Division of Medicine, Imperial College London, Hammersmith Hospital, UK.
Daniela
D
Riano Barros
MRC Clinical Sciences Centre and Division of Medicine, Imperial College London, Hammersmith Hospital, UK; The Neurodis Foundation, CERMEP Imagerie du Vivant, Lyon, France.
Alexander
A
Hammers
Centre for Neuroimaging Sciences, Institute of Psychiatry, PO89, De Crespigny Park, London SE5 8AF, UK.
Federico E
FE
Turkheimer
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK.
David J
DJ
Nutt
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK.
Anne R
AR
Lingford-Hughes
D000328:Adult; D001386:Azides; D001569:Benzodiazepines; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018755:GABA Agonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D009557:Nipecotic Acids / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011597:Psychomotor Performance / Q000187:drug effects; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001386:Azides; D018755:GABA Agonists; C546240:GABRA1 protein, human; C527986:GABRA5 protein, human; D009557:Nipecotic Acids; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C042957:Ro 15-4513; D000078308:Tiagabine
GABA; PET; Synaptic; Tiagabine; [(11)C]Ro15-4513