Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test

• Published in: Behavioural brain research Vol. 409; p. 113323
• Main Authors: Fitzgerald, Paul J., Hale, Pho J., Ghimire, Anjesh, Watson, Brendon O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 09.07.2021
• Subjects: Acetylcholine; Animals; Antidepressive Agents - pharmacology; Association Learning - drug effects; Associative learning; Behavior, Animal - drug effects; Cholinesterase inhibitor; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - pharmacology; Donepezil - pharmacology; Dose-Response Relationship, Drug; Drug Repositioning; Drug repurposing; Forced swim test; Galantamine - pharmacology; Major depression; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Physostigmine - pharmacology; Rivastigmine - pharmacology; Swimming; Drug repurposing; Associative learning; Acetylcholine; Forced swim test; Major depression; Cholinesterase inhibitor
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2021.113323

•We recently studied the acetylcholinesterase inhibitor (AChEI) donepezil in mice.•We showed that it has antidepressant-like properties in the forced swim test.•Here we study three other AChEIs: galantamine, physostigmine, rivastigmine.•Like donepezil, they show antidepressant-like effects and u-shaped properties.•These four drugs are candidates for repurposing as antidepressants in humans. There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.