Behavioural pharmacology

The contiguity between the physiological and behavioural consequences of drug intake provides for a convenient operational basis to define and characterise a drug’s functional properties. MPI Research’s Dr. David Gauvin discusses predictive methodologies to identify and characterise potential abuse liability issues.

In 1971 an international treaty entitled “The Convention on Psychotropic Substances” was signed by many nations to establish suitable controls over the manufacture, distribution, transfer and use of certain psychoactive substances. In the US, the obligation to the Psychotropic Convention formed the framework for the Comprehensive Drug Abuse and Control Act, also known as the Controlled Substances Act. In accordance with current federal policy, it is the Administrator of the Drug Enforcement Administration (DEA) alone who sets the exact placement of a new chemical entity into the schedule of control set forth within the CSA and based upon eight separate factors evaluated for each compound. Among these factors for consideration in the question of drug scheduling is any scientific evidence suggesting abuse liability. It is within the purview of the Food and Drug Administration (FDA) to require pharmaceutical companies to supply such science-based information which then may be evaluated among other factors by the DEA in arriving at a scheduling decision.

Due to the innovative and pioneering efforts of specialists in the field of behavioural pharmacology since the 1960s, predictive methodologies have been developed and elaborated to identify and characterise potential abuse liability issues. It is now understood that the contiguity between the physiological and behavioural consequences of drug intake provides for a convenient operational basis to define and characterise a drug’s functional properties, and for differentiating between its dependence potential and expected abuse liability. A convenient perspective for such evaluation focuses on the changes or events preceding the repeated drug taking on the one hand, and those following it on the other. Operationally, assessment of the biochemical, physiological, and behavioural changes which follow the repeated drug intake provides an effective means to address the drug’s dependence potential. Conversely, measures of antecedent drug-seeking and drug discriminating behaviours which occur prior to habitual use can reliably be used as an index of the drug’s abuse liability.

The methodological and operational basis for development of laboratory procedures for behavioral pharmacological assessment within the framework of the pharmaceutical industry has been provided by the systematic analyses of two major stimulus properties of drugs:

• the reinforcing properties, which are operationally defined using self-administration paradigms in which an animal receives a single bolus of drug following successful completion of a scheduled-controlled behavioural operant.
• the discriminative or subjective properties, which may be objectively defined using a two-lever operant free-choice drug discrimination procedure.

Appropriate implementation of the most suitable experimental contingencies, together with proper data analyses, is the key to successful application of these methods to generating useful conclusions as to the specific abuse liability of a given compound.

The European Union (EU) and Japan have clearly indicated abuse liability studies to be performed within the GLP environment. In view of the general admonition contained within international harmonised regulations to conduct definitive safety pharmacology studies to the greatest extent possible under GLPs, abuse liability and dependence potential assays should be conducted in full compliance with the GLPs as part of the normal compliment of Safety Pharmacology studies completed towards a New Drug Application (NDA). Generally, abuse/dependence liability assessment should be conducted around the time at which the compound has been confirmed as a target for an NDA, if not sooner.

Certainly, the appropriate methods and GLP status of abuse and dependence liability studies are not in question, although time will tell the extent to which regulatory agencies, in particular, the FDA, will require their performance for new drugs in development for various therapeutic areas. Compounds that cross the blood-brain barrier and that have the potential for interacting with the central nervous system in a manner similar to known exemplars of drugs of abuse, or via a novel mechanism of action, would often need to be evaluated for some element(s) of abuse and/or dependence liability. Although no universal standard currently exists for determining the need for, or specific approaches to, abuse liability and dependence potential testing, careful review of existing data in consultation with internal and external industry experts, including the applicable regulatory agency, is a prudent approach to successfully negotiating the issue.

BIO

Dr. David Gauvin is a Senior Principal Study Director in Safety Pharmacology at MPI Research. He received his PhD in behavioural pharmacology from Wayne State University and has focused on drug abuse liability research for much of his career. Formerly a Drug Science Officer with the DEA, Gauvin’s expertise was utilised in federal drug scheduling decisions.