Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1 M2 and M4 receptor knockout mice

摘要

Muscarinic M1/M4 stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S^D) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M1, M2, or M4 receptors (M1^-/-, M2^-/-, M4^-/-), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10 mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M1, M2, or M4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M1/M4 receptors partially substituted for cocaine and increased the S^D effect of cocaine, while M2-preferring antagonists did not substitute, and reduced the S^D effect of cocaine. The cocaine-like effects of scopolamine were absent in M1^-/- mice. The cocaine S^D attenuating effects of methoctramine were absent in M2^-/- mice and almost absent in M₁^-/- mice. The findings indicate that the cocaine-like S^D effects of muscarinic antagonists are primarily mediated through M₁ receptors, with a minor contribution of M₄ receptors. The data also support our previous findings that stimulation of M₁ receptors and M₄ receptors can each attenuate the S^D effect of cocaine, and show that this can also be achieved by blocking M₂ autoreceptors, likely via increased acetylcholine release.