Effects of nonpharmacological manipulations and repeated xanomeline treatment on methamphetamine-vs-food choice in Sprague Dawley and Long Evans rats

Abstract

The absence of Food and Drug Administration (FDA)-approved pharmacotherapies for methamphetamine use disorder (MUD) highlights the need for preclinical research to understand both the basic biological mechanisms of methamphetamine reinforcement and evaluate novel MUD pharmacotherapies. Recent studies demonstrated that repeated treatment with the muscarinic M1/M4 receptor agonist xanomeline attenuated cocaine self-administration. Whether these xanomeline treatment effects extend to methamphetamine self-administration remains unknown. The first aim established the economic substitutability between methamphetamine and liquid food (i.e., Ensure(R)) using a methamphetamine-vs-food choice procedure in male and female Sprague Dawley (SD) and Long Evans (LE) rats. A within-session methamphetamine choice dose-effect function (0.032-0.32 mg/kg/infusion) was determined daily, and food reinforcer magnitude was manipulated weekly by changing the concentration (0, 10, 32, and 100%) of vanilla-flavored Ensure. Additionally, methamphetamine response requirement (i.e., fixed ratio (FR) 1, 5, 25, 125) was manipulated each week while holding the food FR constant. The second aim determined the effectiveness of repeated 5-day xanomeline (3.2-10 mg/kg, SC) to attenuate methamphetamine choice. Both increasing Ensure concentrations and methamphetamine FR values resulted in rightward shifts in the methamphetamine choice dose-effect function in both SD and LE rats. Repeated 5-day xanomeline treatment significantly decreased methamphetamine choice across all doses tested in LE, but not SD, rats. Time course of xanomeline treatment effectiveness revealed effects were greatest during the first 30 min of choice session. These results demonstrate that methamphetamine and food function as economic substitutes and that xanomeline may warrant further consideration as a MUD pharmacotherapy.