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Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine’s abuse-related effects. Here we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine’s discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine’s discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M1 and/or M4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The non-selective muscarinic antagonists scopolamine and methylscopolamine, the non-selective muscarinic agonists oxotremorine and pilocarpine, the M1/M4-preferring agonist xanomeline, the putative M1-selective agonist McN-A-343, and the novel M1-selective agonist TBPB were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M1 subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M1 and M4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M1 receptor activation attenuates cocaine’s abuse-related effects, while non-M1/M4 receptors likely contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anti-cocaine effects of systemically applied, M1 receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on December 8, 2009 as DOI: 10.1124/jpet.109.162057 at A PE T Jornals on M ay 9, 2017 jpet.asjournals.org D ow nladed from