Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.
J M Witkin, S N Mitchell, K A Wafford, G Carter, G Gilmour, J Li, B J Eastwood, C Overshiner, X Li, L Rorick-Kehn, K Rasmussen, W H Anderson, A Nikolayev, V V Tolstikov, M-S Kuo, J T Catlow, R Li, S C Smith, C H Mitch, P L Ornstein, S Swanson, J A Monn
Journal of Pharmacology and Experimental Therapeutics April 2017 DOI: 10.1124/jpet.116.238121 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats (anesthetized and behaving rodents) |
| Interventions | LY3020371 Ketamine LY3027788 Fluoxetine Citalopram |
| Topics | Depression Esketamine Ketamine |
| Key points | The mGlu2/3 receptor antagonist LY3020371 and ketamine produced overlapping biological responses in rodents, including increased dopamine cell activity, cortical oxygen, wakefulness, biogenic amine efflux, and antidepressant-like behavior; the oral prodrug LY3027788 reproduced these effects and augmented fluoxetine or citalopram. The authors argue this overlap supports mGlu2/3 receptor blockade as a possible novel therapeutic approach for treatment-resistant depression. |
Abstract
The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine 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 rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal 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 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (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 biologic 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 tests of this hypothesis.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 15
- ( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions Proceedings of the National Academy of Sciences March 13, 2019
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
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- A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats. ACS Chemical Neuroscience June 3, 2020
- Rapid-Acting Antidepressants Current Pharmaceutical Design October 19, 2018
and 10 more in the library
Cites 13
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and 8 more in the library