Discriminating evidence - use and misuse of the drug-discrimination test in abuse potential assessment of novel CNS drugs

Abstract

Nonclinical testing to predict the abuse potential of central nervous system (CNS) drug candidates is a mandatory part of the safety pharmacology assessment for medications seeking approval for human use. In the "standard model," the drug candidate is tested to determine whether its psychoactive effects generalize to the discriminative cue of an abused drug that animals have been trained to recognize. However, CNS drugs with novel pharmacological mechanisms are challenging, and in response, the regulatory agencies have recommended alternative experimental designs. Variant 1: test the drug candidate in a series of drug-discrimination experiments that exemplify the major classes of abused drugs. Variant 2: use the drug candidate as a training cue. Back-test examples from established classes of abused drugs to see if they generalize to the drug candidate's cue. We critically assessed the pharmacological and translational validity of these protocols. The standard model is underpinned by decades of research and refinement and has the highest degree of translational validity. Question marks exist over the validity of substitution results when the drug candidate has no affinity for known abuse-related targets. Published research does not support the use of either of the alternative models. On the contrary, these models have no pharmacological rationale and, consequently, no translational validity. The review contains a decision tree on the appropriate application of the standard drug-discrimination model, together with recommendations for adapting the test when characterizing the psychoactive properties of drug candidates acting on novel CNS targets.

Keywords: CNS drugs; Drug discrimination; methodology; predictive validity; rats; translational validity.

Figure 1.

Drug-discrimination testing based on the pharmacological characteristics of the drug candidate. The drug candidate is pharmacologically characterized to define its proposed therapeutic mode of action and possible off-target interactions with targets mediating the actions of known substances of abuse. Drug-discrimination testing is performed using a representative substance of abuse as the training cue from the pharmacological class that is a “hit” for the drug candidate.

Figure 2.

Alternative experimental design 1. Multiple drug-discrimination tests recommended when the therapeutic mechanism of the drug candidate is not linked with the pharmacology of known substances of abuse and screening for off-target effects yields no “hits.”

Figure 3.

Alternative experimental design 2. Drug-discrimination test using animals that have been trained to discriminate the drug candidate from vehicle. Experimental design recommended when the therapeutic mechanism of the drug candidate is not linked with the pharmacology of known substances of abuse and screening for off-target effects yields no “hits.” Animals are trained to recognize the interoceptive cue produced by the drug candidate (positive control) and discriminate it from vehicle (negative control). Representatives of the major types of substances of abuse are tested to determine whether they substitute for the drug candidate in the model.

Figure 4.

Pharmacological validation of speculative hits from drug-discrimination tests that have been obtained Alternative experimental design 1 or 2 (see text for details). ¹Full generalization ⩾80% or ⩾75% substitution according to the model used. ²High-level partial generalization ⩾60% substitution. ³Low-level partial generalization <60% substitution. ⁴Pharmacological validation of a speculative hit that has been generated in a test where the drug candidate and any major metabolites have no affinity for the molecular target that produces the psychoactive effects of the substance of abuse used as the positive control.

Figure 5.

Recommendations for decisions on drug-discrimination tests based on pharmacological profiling of the drug candidate.