Differential-Reinforcement-of-Low-Rate Behavior in Rodents as a Screen for Antidepressant Efficacy

Differential-reinforcement-of-low-rate (DRL) is an operant conditioning schedule that requires behavioral inhibition for a given length of time, known as the interresponse time (IRT), in order to receive reinforcement. For rodents under a DRL 36 or 72-s schedule, antidepressant treatment results in an increased reinforcement rate, decreased response rate, and a rightward shift in the IRT histogram distribution. While these characteristic changes are seen following a wide variety of clinically proven antidepressant treatments, including selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, atypical antidepressants, electroconvulsive shock, and numerous putative antidepressants, these changes are not seen with other psychotherapeutic drug classes including anxiolytics, stimulants, antihistamines, anticholinergics, opioids, or sedative-hypnotics. Due to the increasing popularity and utility of genetic engineering, mouse DRL is an essential tool for not only the identification of antidepressant efficacy of new compounds but also for the identification of underlying neurochemical and neuroanatomical mechanisms involved in the onset of antidepressant effects. When properly implemented, the DRL protocol has high predictive validity and reliability as a screen for antidepressant efficacy.