Characterization of Selective M₅Acetylcholine Muscarinic Receptor Modulators on Dopamine Signaling in the Striatum

Abstract

The type-5 muscarinic acetylcholine receptor (mAChR, M 5 ) is almost exclusively expressed in dopamine (DA) neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc); therefore, ideally located to modulate DA signaling and underlying behaviors. However, the role of M 5 in shaping DA release is still poorly characterized. In this study, we first quantitatively mapped the expression of M 5 in different neurons of the mouse midbrain, then used voltammetry in mouse striatum to evaluate the effect of M 5 -selective modulators on DA release. The M 5 negative allosteric modulator, ML375, significantly decreased electrically-evoked DA release and blocked the effect of Oxotremorine-M (Oxo-M, non-selective mAChR agonist) on DA release in presence of an acetylcholine nicotinic receptor blocker. Conversely, the M 5 positive allosteric modulator, VU0365114, significantly increased electrically-evoked DA release and the Oxo-M effect on DA release. We then assessed M 5 impact on mesolimbic circuit function in vivo. Although psychostimulant-induced locomotor activity models in knockout mice have previously been used to characterize the role of M 5 in DA transmission, the results of these studies conflict, leading us to select a different in vivo model, namely a cocaine self-administration paradigm. In contrast to a previous study which also used this model, however, in the current study administration of ML375 did not decrease cocaine selfadministration in rats (using fixed and progressive ratio). These conflicting results illustrate the complexity of M 5 modulation and the need to further characterize its involvement in the regulation of dopamine signaling, central to multiple neuropsychiatric diseases.

Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M5 Muscarinic Acetylcholine Receptor

“…Compound 15 was synthesized according to exemplary synthetic procedure (7.3 mg). 1 6-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)- [1,2,4]triazolo [1,5-a]pyridine (17). Compound 17 was synthesized according to exemplary synthetic procedure (9.5 mg).…”

“…8−15 However, recent studies highlighted the complex nature of M 5 biology and underscored the importance of further investigation into its role. 16,17 In short, the physiological role of M 5 remains unclear even decades after its initial identification and in-depth studies from multiple angles using a variety of tools are still required.…”