1. ¹Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
2. ²Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: Dr WG Frankle, Departments of Psychiatry and Radiology, University of Pittsburgh, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. Tel: +412 246 5829; Fax: +412 586 9040; E-mail: franklewg@upmc.edu

Received 16 April 2008; Revised 23 May 2008; Accepted 27 May 2008; Published online 9 July 2008.

Abstract

Accumulating evidence indicates that synchronization of cortical neuronal activity at -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 (BP_ND) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.220.2% (p=0.05), sensory cortex +13.515.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.420.2% (p=0.03). The increase in [¹¹C]flumazenil-BP_ND was not accounted for by differences in the plasma-free fraction (f_P; paired t-test p=0.24) or changes in the nonspecific binding (pons V_T, p=0.73). Moreover, the ability to increase GABA strongly predicted (r=0.85, p=0.015) the ability to entrain cortical networks, measured through EEG synchrony during a cognitive control task in these same subjects. Although additional studies are necessary to further validate this technique, these data provide preliminary evidence of the ability to measure in vivo, with PET, acute fluctuations in extracellular GABA levels and provide the first in vivo documentation of a relationship between GABA neurotransmission and EEG -band power in humans.