Muscarinic receptor M₄ positive allosteric modulators attenuate central effects of cocaine

Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M₄ receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking.

We tested the M₄-selective positive allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M₁ or M₄ receptors (M₁^-/-, M₄^-/-). We also replicated previous findings in cocaine-induced locomotor hyperactivity and striatal dopamine microdialysis assays.

VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M₁^-/- mice, but not in M₄^-/- mice, without affecting rates of responding. As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference.

These findings further support the notion that M₄ receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M₄ positive allosteric modulators can also attenuate subjective and conditioned effects relevant to relapse.