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Abstract #1034

A GABA-A receptor α5 subtype specific fMRI Signature in the Rat Brain: Negative versus Positive Allosteric Modulation effects

Thomas Mueggler1, Basil Künnecke1, Henner Knust1, Andreas Bruns1, Rodolfo Gasser1, Andrew Thomas1, Maria-Clemencia Hernandez1, and Markus von Kienlin1

1Pharma Research and Early Development, Roche Innovation Center Basel, Hoffmann-La Roche, Basel, Switzerland

The GABA-A α5 subunit-containing receptors are prominently expressed in the hippocampus. There is genetic and pharmacological evidence for a modulatory role in learning and memory positioning the GABA-A α5 subunit-containing receptor as potential target for treatment of cognitive dysfunction. In order to investigate the circuitry engaged by modulation of the GABA-A α5 subtype-containing receptors we performed pharmacological MRI (phMRI) studies in the sedated rat using a selective GABA-A α5 negative (NAM) and a positive allosteric modulator (PAM) and demonstrated a differential neurofunctional response which contrasted to that of the non-selective benzodiazepine agonist diazepam.

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