Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M, M, and M receptor knockout mice.

Muscarinic M/M receptor 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) 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 M, M, or M receptors (M, M, M), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M, M, or M subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M/M receptors partially substituted for cocaine and increased the S effect of cocaine, while M-preferring antagonists did not substitute, and reduced the S effect of cocaine. The cocaine-like effects of scopolamine were absent in M mice. The cocaine S attenuating effects of methoctramine were absent in M mice and almost absent in M mice. The findings indicate that the cocaine-like S effects of muscarinic antagonists are primarily mediated through M receptors, with a minor contribution of M receptors. The data also support our previous findings that stimulation of M receptors and M receptors can each attenuate the S effect of cocaine, and show that this can also be achieved by blocking M autoreceptors, likely via increased acetylcholine release.