Methamphetamine Self‐Administration History May Increase the Reinforcing Effects of Cannabinoid Receptor Agonists in Rhesus Monkeys

Abstract

Animal models of drug self‐administration (SA) are a predictive measure of abuse liability. While Δ9‐tetrahydrocannabinol (THC) remains one of the most commonly abused drugs among humans, it has been an on‐going challenge to establish animal models of intravenous SA of THC. In a recent study (John et al., 2017), we found that THC did not function as a reinforcer in rhesus monkeys responding under a fixed‐ratio (FR) 10 schedule of reinforcement, but the cannabinoid receptor (CBR) agonist CP 55,940 was reinforcing in 3 of 8 monkeys; these 3 monkeys all had a previous methamphetamine (MA) SA history. In an effort to increase THC SA in those 8 monkeys, we treated them chronically with THC and found that THC functioned as a reinforcer in 3 monkeys (only 1 of which CP 55,940 had reinforcing effects). The goals of the present study were to (1) evaluate how chronic THC treatment affected CP 55,940 in those 3 monkeys and (2) examine whether exposure to MA would enhance CP 55,940 SA. After a year of abstinence from chronic THC treatment, CP 55,940 (0.001–0.04 μg/kg/injection) no longer functioned as a reinforcer at doses previously identified as reinforcing in those 3 monkeys. To test the hypothesis that the MA history had influenced the reinforcing effects of CP 55,940, these three monkeys and a fourth animal with no previous MA history, were given access to 0.03 mg/kg/injection MA for 8 sessions and then CP 55,940 was re‐evaluated under an FR 10 reinforcement schedule. Following a brief re‐exposure to MA, resulting in intakes ranging from 2.90–6.3 mg/kg, CP 55,940 functioned as a reinforcer in 2 of the 3 monkeys relative to their previous baselines; in the previously MA‐naïve monkey, this history did not increase the reinforcing effects of CP 55,940. CP 55,940 did function as a reinforcer in the monkey with the highest MA intake (6.3 mg/kg), but the sample size is too small to know if there is a direct relation between MA intake and CBR agonist reinforcement. Additional studies are underway to determine if the chronic MA history affected dopamine D3 receptor availability and if this transient increase was necessary for the CBR agonist to have reinforcing effects. Ultimately, our goal is to identify conditions that will permit CBR agonists to function as reinforcers in Old World monkeys.Support or Funding InformationDA06634