RATIONALE - 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.
OBJECTIVE - This study aims to elucidate the respective contributions of M(1) and M(4) receptors to this effect.
METHODS - 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).
RESULTS - 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.
CONCLUSIONS - 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.