Rats are trained to discriminate between a drug of abuse (e.g., cocaine) and vehicle in a two- lever food-reinforced procedure. Following training, rats are tested with an experimental drug to determine whether generalization ('substitution') to the drug of abuse cue occurs, indicative of potential abuse liability and a shared pharmacological target. Alternatively, rats could be trained to discriminate between an experimental compound and vehicle, and substitution tests with various drugs of abuse (cocaine, d-amphetamine, etc.) could be run for generalization. An experimental compound that substitutes but is not self-administered could indicate a possible treatment for addiction.

Rats were trained to discriminate cocaine (10 mg/kg) from saline. (A) d-Amphetamine and the selective dopamine reuptake inhibitor GBR12909 fully substituted for cocaine, but morphine and nicotine did not. (B) Response rate data provide a measure of potential non-specific locomotor effects of the test compound.