Self-administration of cannabinoids by experimental animals and human marijuana smokers

Abstract

Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-naïve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.

Figure 1

Average plasma levels (± SD) of Δ⁹-THC in two groups of marijuana smokers (heavy and light users) after intravenous administration of Δ⁹-THC (5 mg; panel A) and after smoking a marijuana cigarette (heavy: 12.7 ± 1.3 mg of THC smoked; light: 13.4 ± 1.6 mg of THC smoked; panel B). See Lindgren et al., 1981 for more detailed information on methods and plasma levels. Modified from Lindgren et al., 1981.

Figure 2

Schematic drawing of a squirrel monkey sitting in a self-administration chair. During daily one-hour sessions, monkeys sat inside the experimental chamber, restrained in the seated position by a waist lock on the Plexiglas chair. At the start of each session, a white-house light was turned off and a green stimulus light was turned on; ten lever presses turned off the green light and produced a 2-s amber light paired with i.v. injection of THC (0.2 ml in 0.2 s) delivered from a syringe pump outside the chamber. There was a 60-s time-out period after each injection, during which the chamber was dark and lever presses had no programmed consequences (a 10-response, fixed-ratio schedule of i.v. THC injection with a 60-s time-out; FR 10, TO 60 s).

Figure 3

THC dose-response curves in squirrel monkeys with no history of exposure to other drugs (n = 3) and in squirrel monkeys with a history of cocaine self-administration (n = 4). Numbers of injections per session (left panel), overall rates of responding in the presence of a green light signalling THC availability (middle panel) and total THC intake per session (right panel) are presented as a function of injection dose of THC. Each symbol represents the mean (± S.E.M.) of the last three sessions under each THC injection dose condition and under a vehicle condition from three or four monkeys, with the exception of the values for the 1 μg/kg/injection dose of THC, which represent mean results from two monkeys. *P < 0.05, **P < 0.01 post-hoc comparisons with the vehicle conditions after significant one-way ANOVA for repeated measures main effect, Dunnett’s test. Modified from Tanda et al., 2000 and Justinova et al., 2003.

Figure 4

A. Intravenous self-administration of WIN 55,212-2 by rats. Each bar represents the mean ± S.E.M number of injections per session during 6 consecutive sessions immediately after 3 days of stable responding (n = 12-14). Doses are expressed as μg/kg per injection. **P<0.01 and *P<0.05 significant difference from vehicle group. Modified from Fattore et al., 2001. B. Effects of acute priming injections of WIN 55,212-2, heroin or cocaine on reinstatement of cannabinoid-seeking behavior following prolonged abstinence. Each bar represents the mean ± S.E.M of active nose-pokes over the last 3 days of cannabinoid self-administration (training), over the last five consecutive sessions of extinction (EXT) and during reinstatement test sessions (priming). Doses are expressed as mg/kg (i.p.). *P<0.001 vs respective EXT; ^#P<0.05, ^##P<0.01 and ^###P<0.001 vs respective training; ^§P<0.05 between primings of the two doses of WIN 55,212-2. ANOVA followed by post hoc test (n=7-8). Modified from Spano et al., 2004.

Figure 5

Effects of pretreatment with 0.03 and 0.1 mg/kg naltrexone on self-administration responding maintained by THC over consecutive sessions. Number of injections per session during THC (4 μg/kg/injection) self-administration sessions after pretreatment with vehicle (sessions 1-3 and 9-11) or naltrexone (sessions 4-8), and numbers of injections per session during self-administration sessions when saline was substituted for THC (sessions 4-8) are shown. Symbols represent the means (± S.E.M.) of injections per session from 4 monkeys. **P<0.01, post-hoc comparisons with the last THC session before naltrexone pretreatment or saline substitution (session 3) after significant one-way ANOVA for repeated measures main effect, Dunnett’s test. Modified from Justinova et al., 2004.