M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

Abstract

Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forcedswim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M 1 and M 2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and 2/2 mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M 1 and M 2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

Ventral tegmental area muscarinic receptors modulate depression and anxiety-related behaviors in rats

“…These results have important clinical implications, especially in light of the evidence demonstrating rapid antidepressant effects following systemic administration of the mAChR antagonist, scopolamine [10, 24, 40]. Based on our findings, we suggest that additional VTA mAChR examination may provide important, new understanding of the neurobiological mechanisms that underlie stress and anxiety-related disorders.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…These antidepressant effects in animal models were shown to be mediated by the effects of scopolamine to block the M1 subtype of mAChRs [81, 85], however, some evidence for M2 mAChR blockade as the mediator of these effects of scopolamine in animal models also exists [86]. …”

Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity

“…Furthermore, repeated administration of scopolamine and VU0255035 reduced anhedonia in CUS-exposed rats [91]. A separate study using higher doses of scopolamine indicated that mutant mice lacking M1- or M2-ACh receptor do not show antidepressant responses to scopolamine [92]. In this context it is relevant to note that prior studies with other partially selective M1-AChR compounds (i.e., biperiden) report antidepressant effects in severely depressed, but not moderately depressed patients [89, 93].…”