Effect of dopamine agonists and fenfluramine on discriminative behavior in obese and lean Zucker rats

Dopamine agonists and fenfluramine were used as pharmacological probes to investigate the possible difference in sensitivity and time course of drug action in genetically obese Zucker rats and their lean littermates. All rats were trained to discriminate between the stimulus properties of 0.6 mg/kg d-amphetamine and its vehicle in a two-lever, food-motivated operant task. Once trained, both groups of rats showed a dose-related decrease in discriminative performance with lower amphetamine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.17 mg/kg and for the lean group of 0.14 mg/kg. Administration of 0.3-1.2 mg/kg l-amphetamine and 2.5-10.0 mg/kg cocaine produced a pattern of responding similar to that observed with d-amphetamine. In contrast, 0.08-mg/kg apomorphine produced saline-appropriate responding and 1.5-2.5 mg/kg fenfluramine produced intermediate results in both groups. Time-course experiments indicated that the lean rats maintain errorless discriminative performance through 90 min post-injection, whereas the obese rats discriminate d-amphetamine significantly less at that post-administration time. The results suggest a similar sensitivity to d-amphetamine and other dopaminergic agonists in obese and lean rats with a difference in the time-course of d-amphetamine's action between these two groups.