Bupropion Displays both Stimulant-like and Antidepressant-like Profiles in the Differential Reinforcement of Low Rate (DRL) 72 sec Operant Task

Abstract ID 99122 Poster Board 310 Preclinical models investigating antidepressants and depression have predominantly relied on their predictive validity derived from serendipitously discovered monoamine antidepressants, employing a reverse translational approach. Among these models, the Differential Reinforcement of Low rate (DRL) operant task stands out. Both at 72s and 36s intervals, this task has demonstrated high predictive validity for screening antidepressant drugs, based on the acute effects of traditional antidepressants and ketamine. However, the consistent insensitivity of this task to one antidepressant, bupropion, challenges its comprehensive applicability. The DRL task has primarily been used to study the acute behavioral effects of drugs (e.g., traditional antidepressants). Yet, there exists a gap in understanding repeated treatments with the same medications in the DRL task. The present study examined the acute, subchronic (3 treatments within 24 hours), and repeated (14 consecutive days) administration of desipramine and bupropion in male and female stress-vulnerable Wistar Kyoto rats in the DRL 72 sec operant task. Our findings confirmed earlier observations that acute and subchronic treatment with desipramine led to an increase in earned reinforcers and a decrease in responses (i.e., an antidepressant-like effect). Conversely, bupropion resulted in a decrease in earned reinforcers and an increase in responses (i.e., a stimulant-like effect). However, the most intriguing findings emerged from the repeated treatment procedure. Bupropion exhibited an increase in reinforcers and a decrease in responses (i.e., an antidepressant-like profile); whereas, desipramine did not produce any changes in DRL 72 sec behavior after 15 days of repeated dosing. Clinically, treatment with both desipramine and bupropion typically require consistent daily administration for weeks before therapeutic effects manifest. If the DRL test accurately measures the therapeutic impact of antidepressants, it should demonstrate sensitivity to their repeated treatment. Bupropion demonstrated an antidepressant-like profile under the repeated dosing paradigm, while desipramine did not. These results demonstrated that the DRL task is not only dependent on the interval length, but also on the drug administration regimen. Short DLR intervals have traditionally been used to study the stimulant-like effects of drugs, while longer intervals have been used to study the antidepressant-like effects of drugs. However, bupropion displayed stimulus-like effects with acute and subchronic administration, but antidepressant-like effects with repeated dosing – both with the longer 72 sec interval length. The stimulus-like effects under acute and subchronic administration for bupropion also reinforces the use of the DRL task as a valid measure for measuring impulsivity-like behaviors. Interestingly, bupropion has been used clinically for Attention-deficit/hyperactivity disorder (ADHD) treatment, reducing impulsive behaviors.