Regulatory agencies require that any drug (parent or major metabolite) that penetrates the brain and has CNS activity, regardless of its therapeutic indication, be assessed for that drug’s abuse potential. In this series on Assessing Potential Drug Abuse, we are sharing how the team designs and setup accurate and valid nonclinical GLP abuse liability assessment study types required by regulatory agencies: self-administration, drug discrimination and physical dependency studies. For the first in this series, we will explore how to design and develop a comprehensive self-administration study to test for a drug’s potential abusive or addictive nature.
About the Self-Administration Study – Evaluation of the Reinforcing Effects of Test Drugs
A self-administration study assesses the potential of a drug to maintain lever-pressing behavior due to its positive reinforcing effects. According to the 2017 FDA Guidance for Industry Assessment, “if animals actively work at a behavioral task to receive a dose of the drug, it is likely that the drug will [also] be rewarding in humans.”
Study Phases for the Self-Administration Drug Abuse Liability Study
Using examples and in-house data, this article explores the following phases in designing and implementing a valid abuse liability study that will meet regulatory agencies requirements:
- Training-drug/self-administration phase: in which research models are trained to press a lever in order to receive an infusion of the training drug (reward) under a fixed ratio (FR) schedule of reinforcement appropriate to the training drug.
- Saline extinction phase: in which the training drug is replaced with saline to extinguish the lever pressing behavior.
- Test drug substitution phase: in which saline is replaced with the test drug reacquisition of and lever pressing behavior is evaluated, under the schedule of reinforcement used for the training and extinction phases.
- Progressive ratio (PR) schedule of reinforcement: will be conducted whenever assessment of the reinforcing efficacy of the test drug is deemed necessary to compliment the results obtained under a FR schedule.
This article will also share in-house data on self-administration studies completed related to drugs like ketamine, heroin and amphetamine.
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