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.