Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans

Rationale. LY354740, a structural analogue of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models. Objective. This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodology. Methods. Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examined startle potentiation to shock anticipation and to darkness. Results. Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and negative affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740. Conclusions. These results suggest that LY354740 has an anxiolytic profile in humans without being sedative.