Drug Abuse Liability – Drug Discrimination
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, as did the stimulant medication modafinil. Serotonin and noradrenaline reuptake inhibition failed to mimic the cocaine discriminative stimulus. (B) Response rate data provide a measure of potential non-specific locomotor effects of the test compound.
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In addition to assessing potential abuse liability, the DD assay is a valuable assay of in vivo pharmacological mechanism(s) of action. For example, various GABAA receptor legends exhibited distinct profiles in rats trained to discriminate chlordiazepoxide (CDP) or zolpidem from vehicle.
Rats were trained to discriminate CDP (5 mg/kg IP; A) or zolpidem (2.5 mg/kg IP; B) from vehicle. Subsequently, a range of GABAA receptor ligands were tested in both sets of rats. Zolpidem, selective for the GABAA alpha subunit, failed to fully substitute for the non-selective ligands, chlordiazepoxide. TPA023, that lacks activity at the alpha subunit, substituted for CDP it did not substitute for zolpidem.
Finally, the DD assay may also be used to assess pharmacodynamic profiles of novel compounds. For example, the time-course of the nicotine discriminative stimulus was assessed in rats trained to discriminate nicotine (0.4 mg/kg IP) from saline when administered 10 minutes before testing.
As shown in Panel A, prolonged pretreatment times were associated with diminished DS properties of nicotine. At a 10 minute pretreatment time, response rates were increased at higher doses. At longer pretreatment times, response rates were unaffected by dose (B).
