Abstract
Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention. Furthermore, the classically engaged monoaminergic neurotransmitter systems in depression treatment—serotonin, norepinephrine, and dopamine—interact directly at times with cholinergic signaling. Here we investigate in greater detail how the cholinergic system may impact depression-related behavior, by administering widely ranging doses of the cholinesterase inhibitor drug, donepezil, to C57BL/6J mice in the forced swim test. First, we confirm prior findings that this drug, which is thought to boost synaptic acetylcholine, promotes depression-like behavior at a high dose (2.0 mg/kg, i.p.). But we also find paradoxically that it has an antidepressant-like effect at lower doses (0.02 and 0.2 mg/kg). Further this antidepressant-like effect is not due to generalized hyperactivity, since we did not observe increased locomotor activity in the open field test. These data support a novel antidepressant-like role for donepezil at lower doses as part of an overall u-shaped dose-response curve. This raises the possibility that donepezil could have antidepressant properties in humans suffering from MDD.
Highlights
Major depressive disorder (MDD) is a debilitating neuropsychiatric disorder that is a significant public health problem throughout the world[1,2]
We carried out multiple forced swim test (FST) in each cohort of mice to determine if antidepressant-like effects would emerge after the first swim session
Here we have shown that acute administration of low doses of the acetylcholinesterase inhibitor, donepezil, has antidepressant-like effects in the C57BL/6J mouse FST in some circumstances
Summary
Major depressive disorder (MDD) is a debilitating neuropsychiatric disorder that is a significant public health problem throughout the world[1,2]. Most of the drugs used by clinicians to treat depression (selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, norepinephrine–dopamine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors) are thought to act primarily via the monoaminergic neurotransmitters: serotonin, norepinephrine, and dopamine. While these classes of drugs are effective antidepressants for many cases of MDD, other cases show only a partial response or no response to them, possibly due to different underlying mechanisms of the depressive state in these cases. Most antidepressant medications require weeks to begin taking effect[4], creating a clinical demand for new types or classes of antidepressants, especially those with rapid effects
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