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

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 08/2008; 34(3):624-33. DOI: 10.1038/npp.2008.104
Source: PubMed


Accumulating evidence indicates that synchronization of cortical neuronal activity at gamma-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 [(11)C]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) [(11)C]flumazenil-binding potential (BP(ND)) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.2+/-20.2% (p=0.05), sensory cortex +13.5+/-15.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.4+/-20.2% (p=0.03). The increase in [(11)C]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 gamma 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 gamma-band power in humans.

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    • "Weber and colleagues found a trend level increase in [ 11 C]flumazenil binding after acute administration of the irreversible GABA transaminase inhibitor vigabatrin (Weber et al., 1999). More recently, Frankle and colleagues found that acute administration of 16 mg tiagabine increased cortical and limbic [ 11 C]flumazenil binding (Frankle et al., 2009) and that an acute tiagabine dose of 0.25mg/kg (17.5mg tiabagine for 70kg participants) was required to produce significant increases in [ 11 C]flumazenil binding in the association cortex, sensory cortex and limbic regions (Frankle et al., 2012). "
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    • "Two separate reference regions were used as each in itself has limitations in relation to the Logan method. The pons has commonly been used in [ 18 F]FMZ studies [Frankle et al., 2012; Klumpers et al., 2012; Odano et al., 2009; Pearl et al., 2009]; however, recent studies have suggested that it displays a significant degree of specific binding [Frankle et al., 2009, 2012; Klumpers et al., 2008; Millet et al., 2002]. The cerebral white matter has been proposed as an alternative reference region due to its lower degree of specific binding [Klumpers et al., 2008; la Fougere et al., 2011]. "
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    • "On each day, an initial 'pre' MEG recording was obtained then participants orally ingested a capsule containing either placebo or 15 mg of tiagabine (Gabitril). This oral dose is similar to the 16 mg used in a PET study by Frankle et al (2009) and identical to several ongoing imaging studies by our group. Participants were blinded to the contents of the capsule and placebo/control session order was counterbalanced across participants. "
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