Comparative Effects of LY3020371, a Potent and Selective mGlu2/3 Receptor Antagonist, and Ketamine, a Non-Competitive NMDA Receptor Antagonist, in Rodents: Evidence Supporting Use for the Treatment of Depression

The ability of the NMDA receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment resistant depression (TRD) is well documented. In this report, we directly compare in vivo biological responses in rodents elicited by a recently discovered mGlu2/3 receptor antagonist (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active DA cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in SSRI-sensitive and -insensitive rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebral spinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 (LY3027788) was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biological responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical test of this hypothesis.