Characterization of the Behavioral Phenotypes Underlying the Reinforcing Effects of Cannabinoid Receptor Agonists in Rhesus Monkeys

Abstract

The lack of a widespread, suitable method to establish robust levels of Δ9‐tetrahydrocannabinol (THC) self‐administration (SA) remains an impediment for developing treatments for human marijuana abuse. Therefore, the major objective of this study was to establish the experimental conditions necessary for demonstrating intravenous SA of THC as well as the cannabinoid receptor (CBR) agonist CP 55,940 in rhesus monkeys. In addition, behavioral phenotypes underlying the individual differences in CBR agonist SA were characterized in order to determine critical variables that could be modified to optimize the procedure. Rhesus monkeys (n=8), implanted with indwelling intravenous catheters, served as subjects and were trained to respond under a fixed‐ratio 10 schedule of food presentation, with a 60‐second timeout after each reinforcer. Once responding was stable, saline was substituted for food pellets for at least 5 consecutive sessions and until responding was extinguished (>80% reduction in responding for 3 consecutive sessions). After re‐establishing food‐maintained responding, CP 55,940 (0.005–1.0 μg/kg) and THC (0.03–10 μg/kg) were substituted for food pellets, with each dose available for at least 5 sessions and until responding was deemed stable. There was a return to food‐maintained responding, for at least 3 sessions, between different CBR agonist doses. CP 55,940 functioned as a reinforcer in three of eight rhesus monkeys at doses lower than previously tested in monkeys. Interestingly, in those three monkeys, non‐contingent administration of CP 55,940 was least potent in decreasing food‐maintained responding indicating an inverse relationship between the rate‐decreasing effects and reinforcing effects (r=0.81, p<0.05). No relationship was found between the reinforcing effects and CP 55,940‐induced hypothermia nor the unconditioned behavioral effects of the dopamine D2/D3 receptor agonist quinpirole. In those monkeys for which CP 55,940 functioned as a reinforcer, THC (0.03–3.0 μg/kg per injection) did not maintain responding higher than vehicle. Therefore, future experiments will determine if tolerance to the rate‐decreasing effects of THC will enhance the reinforcing effects of THC. Such an outcome would suggest that preclinical models require a period of repeated drug treatment before assessing THC SA.Support or Funding InformationSupported by DA06634 and T32AA007565.