Utility of Progressive Ratio Schedules of Reinforcement in Abuse Potential Assessments

Abstract Abuse potential assessments are recommended by regulatory agencies for all new pharmaceuticals that are active in the central nervous system prior to approval. The self-administration assay is a nonclinical model that determines a drug's reinforcing potential. In this model, animals are provided the opportunity to self-administer a drug by performing an operant task. This chapter describes two methodologies used in self-administration: the fixed ratio and progressive ratio (PR) schedules of reinforcement. The focus of the chapter is to present study design considerations and discuss data interpretations when PR schedules are employed in self-administration, as well as physical dependence and withdrawal, studies. Standard diagnostic tests of binary classification were used to determine whether the use of PR schedules in nonhuman primate and/or rat self-administration studies correctly predicted human abuse outcomes. A full discussion on the value that PR schedules bring to safety pharmacology and abuse potential assessments is included.