Tiagabine Increases [11C]flumazenil Binding in Cortical Brain Regions in Healthy Control Subjects

Accumulating evidence indicates that synchronization of cortical neuronal activity at γ-band frequencies is important for various types of perceptual and cognitive processes and that GABA-A receptor-mediated transmission is required for the induction of these network oscillations. In turn, the abnormalities in GABA transmission postulated to play a role in psychiatric conditions such as schizophrenia might contribute to the cognitive deficits seen in this illness. We measured the ability to increase GABA in eight healthy subjects by comparing the binding of [11C]flumazenil, a positron emission tomography (PET) radiotracer specific for the benzodiazepine (BDZ) site, at baseline and in the presence of an acute elevation in GABA levels through the blockade of the GABA membrane transporter (GAT1). Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands (termed ‘GABA shift’). Theoretically, such an increase in the affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. GAT1 blockade resulted in significant increases in mean ( ± SD) [11C]flumazenil-binding potential (BPND) over baseline in brain regions representing the major functional domains of the cerebral cortex: association corte