The effects of acute and repeated M1 agonist VU0364572 administration on cocaine-vs-food choice in male and female Sprague-Dawley rats.

Abstract

Cocaine use disorder (CUD) represents a public health crisis for which there are currently no pharmacotherapies. Repeated administration of the muscarinic agonist xanomeline significantly decreased cocaine self-administration. However, the pharmacological mechanisms mediating xanomeline effects on cocaine reinforcement remain to be determined. The present aim was to determine whether selective M1 receptor activation with the M1 agonist VU0364572 was sufficient to attenuate cocaine-vs-food choice in male and female rats. Rats were trained to respond under a concurrent fixed-ratio (FR)5:FR5 schedule of intravenous cocaine infusions and liquid food during daily 2h sessions. VU0364572 (0.32-10mg/kg, IP) or vehicle was administered acutely before the cocaine choice session and VU034572 effects were observed for two-to-four weeks. Additionally, VU0364572 was administered using a 5-day dosing regimen to model clinical aspects of substance use disorder medication dosing regimens. During saline administration, cocaine maintained a dose-dependent increase in percent cocaine choice. Neither acute nor repeated VU0364572 administration up to 10mg/kg significantly altered cocaine choice in male and female rats. These results do not support VU0364572 as a candidate CUD pharmacotherapy and further suggest that xanomeline effectiveness to attenuate cocaine choice is not exclusively mediated by M1 receptors.