Document Type



Physiology & Neurobiology


Prof. John Salamone, Dept. of Psychological Sciences


Cognitive Neuroscience | Neuroscience and Neurobiology | Psychology | Social and Behavioral Sciences


Serotonin-selective reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications. Despite their popularity, they remain relatively ineffective at treating effort-related motivational symptoms of depression such as fatigue and anergia. Increasing research on triple reuptake inhibitors (TRIs) that target three neurotransmitters—dopamine, serotonin, and norepinephrine—has suggested that TRIs could have efficacy in targeting motivational dysfunction due to their dopaminergic effects. Previous research has shown that the dopamine depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards low-effort behavior in effort-based choice tasks, and provide a validated approach to creating a model of motivational dysfunction. This is consistent with human studies showing that people with major depression exhibit a bias toward low-effort activities. Diclofensine is a TRI with a relatively high affinity for the dopamine transporter and, therefore, it was hypothesized that this drug could improve motivational symptoms. The present study analyzed the ability of diclofensine to treat motivational deficits of depression through a rodent model of effort-based choice, the fixed ratio 5/chow feeding choice task. Diclofensine demonstrated the ability to partially reverse the effort-related effects of tetrabenazine; it increased selection of high-effort FR5 lever pressing in rats at the 10.0 mg/kg dose and decreased chow intake at the 5.0 mg/kg and 10.0 mg/kg doses. Given the devastating impact to society, families, and individuals of inadequately treated depressive disorders, it is imperative that there is continued investment in the discovery of highly efficacious and tolerable antidepressants. This study contributes to the understanding and possible utility of TRIs as a treatment of motivational dysfunctions involved in depression in humans.