Progressive ratio responding in an obese mouse model: Effects of fenfluramine

Abstract

The progressive ratio schedule of operant responding is a well utilised task for assessing the rewarding aspects of abused drugs and natural rewards including food. Interestingly, progressive ratio paradigms have mainly been neglected in the field of animal research in obesity. Among the most widely studied mouse models of obesity is the leptin-deficient ob/ob mouse, characterised by hyperphagia and obesity. To date there are no studies on the behaviour of these mice in progressive ratio responding, thus we sought to validate the utility of the progressive ratio paradigm in obese mice and demonstrate its sensitivity to an anorectic drug challenge. Ob/ob mice and their lean controls were tested in fixed ratio paradigms of different demand, extinction learning, and progressive ratio schedules with linear and exponential increments, followed by an anorectic drug challenge with fenfluramine (5 and 10 mg/kg). Obese animals showed equal fixed ratio-acquisition and -responding for ratios 1 and 3, but displayed lower responding in ratios 6 and 9. Interestingly, obese animals showed equal motivation to respond in progressive ratio schedules. Fenfluramine dose-dependently induced anorectic effects in both genotypes and reduced progressive ratio responding significantly. This study, for the first time, describes motivational food intake in an operant progressive ratio paradigm in ob/ob mice. Leptin deficiency did not alter appetitive learning or motivation in the progressive ratio. The utility and sensitivity of the progressive ratio task for studies on motivational food intake was demonstrated by a challenge with the anorectic agent fenfluramine.