Effects of the muscarinic M1 agonist VU0364572 and the M1/M4-prefering agonist xanomeline on cocaine choice in male and female rats

Abstract Cocaine use disorder (CUD) is a continuing threat to public health that lacks a Food and Drug Administration approved pharmacotherapy. However, there is evidence to suggest that muscarinic receptor activation may lead to reductions in cocaine taking, acquisition, and choice. Therefore, we use a cocaine-vs-food choice procedure in male and female Sprague-Dawley rats to evaluate the effectiveness of the bitopic M1/M4 preferring muscarinic agonist xanomeline and the M1 muscarinic agonist/positive allosteric modulator VU0364572 (VU’72). We found that repeated xanomeline did significantly attenuate cocaine choice while VU’72 failed to meaningfully alter cocaine choice across subjects. These results suggest that the mechanism by which muscarinic receptors modulate cocaine reinforcement may be mediated either by M4 muscarinic receptors specifically or a combination of both M1 and M4 muscarinic receptors acting in concert. Furthermore, there is evidence that xanomeline may prove a viable pharmacotherapy for treating CUD.