The metabotropic glutamate 2/3 receptor agonist LY379268 induces anxiety-like behavior at the highest dose tested in two rat models of anxiety

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The activation of Group II metabotropic glutamate 2/3 (mGlu2/3) receptors reduces the excessive glutamate release that is hypothesized to be associated with neurodegenerative and psychiatric disorders. LY379268 is a highly potent mGlu2/3 receptor agonist that has shown efficacy in several animal models of stroke, epilepsy, drug abuse, schizophrenia, and pain. The present study investigated the effects of LY379268 on anxiety-like behavior in rats assessed in the light/dark and open field tests. The effects of LY379268 on motility in a locomotor activity chamber were also investigated in rats. Administration of the two lower doses of LY379268 used (0.3 and 1 mg/kg) did not influence rats' performance either in the light/dark or in the open field test. Importantly, the administration of a higher LY379268 dose (3 mg/kg) induced decrease in the number of transitions between the light and dark chambers and time spent in the light chamber compared to the vehicle-treated animals in the light/dark test. In the open field test, rats that received 3 mg/kg LY379268 made fewer entries and spent less time in the central zone of the apparatus, exhibited a decrease of rearing episodes, but displayed higher grooming activity compared to controls. Nevertheless, the 3 mg/kg dose did not alter locomotor activity compared with vehicle-treated rats in a motility test. The present results indicate that the highest LY379268 dose used in this study induced an anxiety-like effect in the light/dark and open field tests that cannot be attributed to changes in locomotor activity, while lower doses had no effect.

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