Further Evaluation of Mechanisms Associated with the Antidepressantlike Signature of Scopolamine in Mice

Title:Further Evaluation of Mechanisms Associated with the Antidepressantlike Signature of Scopolamine in Mice

Volume: 16 Issue: 4

Author(s): Anna E. Martin, Douglas A. Schober, Alexander Nikolayev, Vladimir V. Tolstikov, Wesley H. Anderson, Richard E. Higgs, Ming-Shang Kuo, Anastasia Laksmanan, John T. Catlow, Xia Li, Christian C. Felder*Jeffrey M. Witkin*

Affiliation:

• Neuroscience Discovery Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285-0510,United States

• Neuroscience Discovery Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285-0510,United States

Keywords: Antidepressant, ketamine, metabolomics, mice, scopolamine, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Abstract: Background: Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action.

Method: Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test.

Results: The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action.

Conclusion: Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.

Cite this article as:

Martin E. Anna, Schober A. Douglas, Nikolayev Alexander, Tolstikov V. Vladimir, Anderson H. Wesley, Higgs E. Richard, Kuo Ming-Shang, Laksmanan Anastasia, Catlow T. John, Li Xia, Felder C. Christian*, Witkin M. Jeffrey*, Further Evaluation of Mechanisms Associated with the Antidepressantlike Signature of Scopolamine in Mice, CNS & Neurological Disorders - Drug Targets 2017; 16 (4) . https://dx.doi.org/10.2174/1871527316666170309142646

DOI https://dx.doi.org/10.2174/1871527316666170309142646	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181