Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice

We previously showed that muscarinic agonists with M-1 and/or M-4 receptor affinities attenuated cocaine discrimination and self-administration in wild-type mice but not in M-1/M-4 double-knockout mice. This study aims to elucidate the respective contributions of M-1 and M-4 receptors to this effect. Knockout mice lacking either the M-1 subtype (M (1) (-/-) ) or the M-4 subtype (M (4) (-/-) ) and wild-type mice were trained to discriminate 10 mg/kg cocaine from saline. Muscarinic ligands were tested for modulation of cocaine discrimination: xanomeline (M-1/M-4-preferring agonist), VU0357017 (M-1-selective partial agonist), 77-LH-28-1 (M-1 agonist), and BQCA (M-1-selective positive allosteric modulator). Xanomeline produced rightward shifts in the cocaine dose-effect curve in all three genotypes, but most robustly in wild-type mice. VU0357017 produced rightward shifts in the cocaine dose-effect curve in wild-type and M (4) (-/-) mice, but not in M (1) (-/-) mice. Response rates were suppressed by xanomeline in wild-type and M (1) (-/-) but not in M (4) (-/-) mice and were unaltered by VU0357017. 77-LH-28-1 and BQCA also showed evidence of attenuating cocaine's discriminative stimulus, but at doses that suppressed responding or had other undesirable effects. Intriguingly, both VU0357017 and 77-LH-28-1 exhibited U-shaped dose-effect functions in attenuating cocaine discrimination. None of the drugs substituted for the cocaine stimulus. Attenuation of the cocaine stimulus by VU0357017 depended upon M-1 receptors, and full effects of xanomeline depended upon both M-1 and M-4 receptors. Therefore M-1-selective agonists and mixed M-1/M-4 agonists may be promising leads for developing medications that block cocaine's effects.