[11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [11C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [11C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [11C]flumazenil VT in Group II in association cortices (6.8±0.8 mL g−1 vs. 7.3±0.4 mL g−1;p = 0.03), sensory cortices (6.7±0.8 mL g−1 vs. 7.3±0.5 mL g−1;p = 0.02) and limbic regions (5.2±0.6 mL g−1 vs. 5.7±0.3 mL g−1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [11C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA

Cortical dopamine transmission as measured with the [¹¹C]FLB 457 - Amphetamine PET imaging paradigm is not influenced by COMT genotype

Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND

The Synaptic Hypothesis of Schizophrenia

12 páginas, 5 figuras.-- The following is a report of the meeting “Synaptic Dysfunction and Schizophrenia” held at the Juan March Center for International Meetings on Biology Workshop in Madrid, Spain, 10–12 February 2003.Peer reviewe

Gender differences in systolic blood pressure.

<p>Systolic blood pressure readings from males (black bars) and females (white bars) across three separate measurements. The analysis includes both healthy controls and patients. *, <i>P</i> < 0.0001 by a repeated measures ANOVA followed by the Bonferronni post <i>t</i>-test (α = 0.05).</p

Vital signs on day of PET scan.

<p>(A) Systolic blood pressure, (B) diastolic blood pressure, (C) and heart rate at baseline, peak, and discharge time points for all subjects. (D) Mean arterial pressure during the amphetamine administration for all subjects. Abbreviations: ADHD, attention deficit hyperactivity disorder; ALC, alcoholism; COC, cocaine addiction; EAT, eating disorders; MAJ, marijuana addiction; SCH, schizophrenia; bpm, beats per minute. *, <i>P</i> < 0.05 by a one-way ANOVA followed by the Bonferronni post <i>t</i>-test (α = 0.05).</p