Rewarding effects of M4 but not M3 muscarinic cholinergic receptor antagonism in the rostromedial tegmental nucleus

Abstract

The rostromedial tegmental nucleus (RMTg) receives inputs from the laterodorsal tegmental and pedunculopontine tegmental nuclei, the two principle brainstem cholinergic nuclei. We tested the effects of RMTg M3 and M4 muscarinic cholinergic receptor antagonism in a conditioned place preference (CPP) paradigm in mice. RMTg infusions of the M3 muscarinic cholinergic receptor antagonist 1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) do not result in the acquisition of CPP but increase locomotor activation. By contrast, RMTg infusions of the M4 muscarinic cholinergic receptor antagonist Tropicamide result in the acquisition of CPP but do not increase locomotor activation. The rewarding effects of RMTg Tropicamide infusions are dopamine-dependent as systemic pre-treatment with the broad-spectrum dopamine receptor antagonist flupenthixol prevents the acquisition of CPP induced by RMTg Tropicamide infusions. Under conditions of systemic dopamine receptor blockade, RMTg Tropicamide infusions significantly increase locomotor activation. These data provide further support for an important role of endogenous cholinergic input to the RMTg in reward function and suggest that the contributions of RMTg cholinergic input to rewarding and locomotor-activating effects involve differential contributions of RMTg M4 and M3 muscarinic receptors, respectively.

Exploring the underlying mechanisms of drug‐induced impulse control disorders: a pharmacovigilance‐pharmacodynamic study

“…Coherently, even if tropicamide, an M4‐receptor antagonist, was observed to induce reward‐driven behaviors in mice, 67 muscarinic receptor antagonism has shown fewer risk‐taking behaviors in rats, 68 and mice lacking M4 in cholinergic receptors were unable to learn positive reinforcement 69 . Nonetheless, contrary to the literature, it should be noted that no sensitivity analysis supported the role of M4.…”

“…The laterodorsal and pedunculopontine neurons, in particular, contribute with cholinergic input that, through the post‐synaptic muscarinic G q ‐protein coupled receptor M3, activates the GABAergic neurons and inhibits behaviors. Acetylcholine also starts negative feedback mediated by the pre‐synaptic muscarinic G i ‐protein coupled receptor M4, which reduces acetylcholine release, and therefore contrasts the acetylcholine‐mediated activation of GABAergic neurons 67 . Therefore, it is biologically plausible that M4 receptor antagonism, impairing this negative feedback, may reduce ventrotegmental neurons activity and protect against ICDs.…”

“…Acetylcholine also starts negative feedback mediated by the pre-synaptic muscarinic G i -protein coupled receptor M4, which reduces acetylcholine release, and therefore contrasts the acetylcholine-mediated activation of GABAergic neurons. 67 Therefore, it is biologically plausible that M4 receptor antagonism, impairing this negative feedback, may reduce ventrotegmental neurons activity and protect against ICDs. The protective role of M3-receptor antagonism is instead more difficult to explain since, in theory, it should result in lower GABAergic activity and facilitated behaviors.…”