Behavioral Determinants of Cannabinoid Self-Administration in Old World Monkeys

Abstract

Reinforcing effects of Δ⁹-tetrahydrocannabinol (THC), the primary active ingredient in marijuana, as assessed with self-administration (SA), has only been established in New World primates (squirrel monkeys). The objective of this study was to investigate some experimental factors that may enhance intravenous SA of THC and the cannabinoid receptor (CBR) agonist CP 55 940 in Old World monkeys (rhesus and cynomolgus), a species that has been used extensively in biomedical research. In one experiment, male rhesus monkeys (N=9) were trained to respond under a fixed-ratio 10 schedule of food presentation. The effects of CP 55 940 (1.0-10 μg/kg, i.v.) and THC (3.0-300 μg/kg, i.v.) on food-maintained responding and body temperature were determined in these subjects prior to giving them access to self-administer each drug. Both drugs dose-dependently decreased food-maintained responding. CP 55 940 (0.001-3.0 μg/kg) functioned as a reinforcer in three monkeys, whereas THC (0.01-10 μg/kg) did not have reinforcing effects in any subject. CP 55 940 was least potent to decrease food-maintained responding in the monkeys in which CP 55 940 functioned as a reinforcer. Next, THC was administered daily to monkeys until tolerance developed to rate-decreasing effects. When THC SA was reexamined, it functioned as a reinforcer in three monkeys. In a group of cocaine-experienced male cynomolgus monkeys (N=4), THC SA was examined under a second-order schedule of reinforcement; THC functioned as reinforcer in two monkeys. These data suggest that SA of CBR agonists may be relatively independent of their rate-decreasing effects in Old World monkeys. Understanding individual differences in vulnerability to THC SA may lead to novel treatment strategies for marijuana abuse.

Figure 1

Effects of CP 55 940 (circles) and Δ⁹-tetrahydrocannabinol (THC) (triangles) on food-maintained responding (filled symbols) and body temperature (open symbols) in individual rhesus monkeys (n=9). CP 55 940 and THC were administered non-contingently 1 min prior to the start of the session and body temperature was recorded prior to each injection and then again 60 min following the start of the session. Tolerance to the rate-decreasing effects of THC on food-maintained responding was developed by repeated administration across consecutive sessions (filled squares). Abscissae: Dose of CP 55 940 and THC in μg/kg. Left ordinate: Mean (±SD) response rate expressed as a percentage of baseline. Right ordinate: Mean (±SD) change in body temperature expressed in °C.

Figure 2

Self-administration dose-response curves for CP 55 940 (filled circles), THC (closed triangles) and Δ⁹-tetrahydrocannabinol (THC) after the development of tolerance to rate-decreasing effects on food-maintained responding (open triangles). Abscissae: Unit dose (μg/kg/injection) available for self-administration. Ordinate: Number of injections earned in the 60-min session. Data represent mean±SD of last three sessions. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared with vehicle.

Figure 3

THC self-administration under a second-order [FI 600-s (FR 30:S)] schedule of reinforcement. Each dose was studied for a minimum of 7 sessions and until responding was stable. Data represent mean (±SD) response rates for Δ⁹-tetrahydrocannabinol (THC) (filled triangles) and cocaine (open squares) during last 3 sessions of substitution. Abscissae: Unit dose (μg/kg/injection) available for self-administration. Ordinate: Mean overall rate of responding (responses/sec). C-7427: F(4,8)=14.94, p<0.001; C-6526: F(4,8)=41.72, p<0.001. Post-hoc: *p<0.05, ***p<0.001, ****p<0.0001.