Sertraline and Escitalopram But Not Other Antidepressants Increase Acetylcholinesterase Activity Ex Vivo in the Rat Frontal Cortex

Background Depression is a pervasive mental health disorder that has been extensively studied, but effective treatment remains elusive. This is due to the lack of understanding regarding the underlying molecular mechanisms. Antidepressants usually target the monoaminergic system, but studies show that other neurotransmitters, such as acetylcholine (ACh), may be involved. Many clinical and preclinical studies show that increased ACh levels are associated with depression. Particularly, acetylcholinesterase (AChE) activity is shown to decrease in depression and antidepressants are known to increase it. However, it is not known whether this effect is direct or downstream. Purpose To check whether antidepressants can directly modulate AChE activity, we evaluated the effect of various classes of antidepressants on ex vivo AChE activity in the frontal cortex, hippocampus and striatum of male and female rats. Methods Briefly, sertraline (SER), escitalopram (ESC), amitriptyline (AT), duloxetine (DUL), bupropion (BUP) and ketamine (KET) were incubated with the brain tissue homogenates in a 96-well plate for 30 min, following which AChE activity was evaluated by modified Ellman’s method. Results SER and ESC increased AChE activity in the frontal cortex, while AT, DUL, BUP and KET did not affect it. Conclusion This points to a novel mechanism of action of selective serotonin reuptake inhibitors (SSRIs) and a potential target for developing new therapeutics with better efficacy and lower side effect profiles.