Elucidation of the neural circuits activated by a GABA receptor positive modulator: Relevance to anxiety.

Although there is much evidence for a role of GABA receptors in the pathophysiology of anxiety, the underlying neuronal mechanisms are largely unclear. The GABA receptor allosteric positive modulator, GS39783, exerts anxiolytic effects without interfering with GABA-mediated modulation of body temperature, cognitive performance and locomotor activity thus offering advantages over GABA receptor agonists. However, the precise neural circuits underlying the anxiolytic effects of GS39783 are unknown. The aim of the present study was to identify brain structures and associated neuronal circuits that are modulated by GS39783 under either basal or mild stress conditions. To this end, the expression pattern of c-Fos, a marker of neuronal activation, was examined in mice acutely treated with GS39783 under basal conditions or following a mild anxiogenic challenge induced by exposure to the Open Arm (OA) of an Elevated Plus Maze. OA exposure enhanced c-Fos expression in vehicle-treated animals in several brain regions, including the medial prefrontal cortex, lateral septum, amygdala, hippocampus, paraventricular nucleus of the hypothalamus and the periaqueductal gray (PAG). Under basal conditions, GS39783 increased c-Fos in a restricted panel of areas notably amygdala nuclei, cortical areas and PAG subregions, while it inhibited c-Fos expression in the dorsal raphe nucleus (DRN). Under stress conditions, GS39783 reversed OA-induced c-Fos expression in the granular cell layer of the dentate gyrus, no longer increased c-Fos expression in the amygdala nor reduced c-Fos expression in the DRN. These specific patterns of neural activation by GS39783 might explain the neurobiological correlates implicated in GABA-mediated anti-anxiety effects. This article is part of the "Special Issue Dedicated to Norman G. Bowery".