Acute in vivo effect of valproic acid on the GABAergic system in rat brain: A [C]Ro15-4513 microPET study.

γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system acting mainly through GABA receptors. In the presence of high levels of GABA, an allosteric shift in the GABA receptors can change the affinity of benzodiazepine (BZD) ligands. Valproic acid (VPA) is an anticonvulsant that enhances the level of endogenous GABA in the brain. The BZD ligand, Ro15-4513 has a high affinity for GABA receptors containing the α subunit and can be used to investigate the GABA shift in the brains of living rats after VPA exposure. Seven Wistar rats were scanned using a Mediso NanoScan PET/MRI. A baseline 90-min dynamic [C]Ro15-4513 PET scan was acquired prior to an intravenous injection of 50 mg/kg VPA, and was followed by a second [C]Ro15-4513 PET scan. Standardized uptake values were obtained for regions of high GABA binding, including the hippocampus and amygdala, and low GABA binding such as the cerebellum. We showed a significant increase in [C]Ro15-4513 uptake in hippocampus and amygdala, but no significant differences in cerebellar uptake, after acute VPA exposure. In contrast to several in vitro studies, we demonstrated a positive allosteric change in the GABA receptors after pharmacologically enhanced GABA levels resulting in enhanced Ro15-4513 uptake. Knowledge of how subtypes of the GABA receptors react will provide us with information useful to fine-tune pharmacological interventions and design receptor subtype specific drugs.