Cannabinoids: A Preclinical Study

Much of the information we know regarding the abuse-related effects of cannabinoids comes from preclinical studies using the drug discrimination procedure (Balster and Prescott, 1992; Wiley, 1999). The drug discrimination procedure is based on the ability of a drug to induce a specific set of interoceptive stimulus conditions perceived by animals that might be predictive of the subjective reports of perceptions/feelings induced by the same drug in humans. As a result, the drug discrimination procedure does not measure reinforcing/rewarding effects of drugs; however, there is usually a good correlation between those drugs belonging to a particular pharmacological class that serve as reinforcers and those that produce subjective/discriminative
effects characteristic of that pharmacological class (Schuster and Johanson, 1988). Therefore, studies of the subjective effects of new drugs in both humans and animals have been relatively good predictors of whether or not a drug will be abused.
Animal drug discrimination procedures consist of an initial period of training that consists of alternating the administration of either a specific drug dose or the drug's vehicle before each session.
Typically, sessions take place within an experimental chamber, which has two different response manipulandum. Animals learn to make a response on one manipulandum when sessions are preceded by injection of the training drug and make a response on the other manipulandum during sessions preceded by a vehicle injection. In order to maintain this behavior, responding is intermittently reinforced by food pellets or by postponement or escape from electric shocks. Once subjects reach a criterion level of correct performance (e.g. 80% drug appropriate responding), test sessions are occasionally scheduled, during which they receive either the training drug at a different dose or a different drug, to test whether or not such a drug/dose will produce a discriminative stimulus effect similar to the training drug. Generally, if the training drug is an agonist, only agonist drugs belonging to the same pharmacological class will produce full generalization to the training stimulus and only antagonists belonging to the same pharmacological class will selectively block the training stimulus.
Cannabinoid drugs, indeed, show a pharmacological specificity in this behavioral procedure. For example, in animals trained to discriminate injections of THC from injections of its vehicle, only drugs that selectively
activate CB1 receptors fully generalize to the THC training stimulus (Wiley et al. 1993a, 1993b, 1995c; Barret et al. 1995). Furthermore, CB1 receptor agonists have been shown to substitute for the THC training stimulus with a potency that is consistent with their in vitro affinity for the CB1 receptors (Balster and Prescott 1992; Gold et al. 1992; Wiley et al. 1995b).
In addition to THC, other cannabinoid CB1 receptor agonists have also been used as the training stimulus (Wiley et al.
1995a, 1995b; Perio et al. 1996; Järbe et al. 2001). For example, Wiley et al. (1995b) trained rats to discriminate the synthetic CB1 receptor agonist CP 55,940 from saline and it was found that THC, the synthetic CB1 receptor agonist WIN 55,212-2, and cannabinol all generalized to the CP 55,940 training stimulus and did so at potencies similar to those that displace CP 55,940 in binding studies. Similarly, other studies have trained rats to discriminate WIN 55,212-2 from vehicle (Perio et al. 1996), and it has been found that THC and CP 55,940 produce complete generalization. Moreover, the discriminative stimulus effects of THC and other synthetic CB1 agonists have been shown to be antagonized by the selective CB1 receptor antagonist SR 141716A, further demonstrating that the cannabinoid discrimination is mediated by CB1 receptors (Mansbach et al. 1996; Perio et al. 1996). Further, it has been demonstrated that this is a centrally mediated behavior through studies showing that a selective CB1 receptor antagonist that does not cross the blood-brain barrier, SR 140098, does not antagonize the discriminative stimulus effects of cannabinoids (Perio et al.
1996).