Investigating the ability of the Norepinephrine-Dopamine Reuptake Inhibitor Nomifensine to Reverse the Effort-related Effects of Tetrabenazine in Female Rats

Anergia, lassitude, and psychomotor retardation are core symptoms of motivational dysfunction that often accompany Major Depressive Disorder (MDD). While selective serotonin reuptake inhibitors effectively alleviate mood and anxiety symptoms, they remain relatively ineffective at alleviating motivational deficits. Compounds that elevate extracellular dopamine (DA) have shown promise in addressing these symptoms. Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), increases DA and is effective at attenuating motivational symptoms in patients. Another NDRI, nomifensine, has demonstrated potential antidepressant properties in preclinical research. Effort-based choice tasks, such as the FR5/chow choice task, serve as animal models for studying motivational dysfunction. Rats choose between exerting effort to obtain a preferred food (high-carbohydrate pellets) via lever pressing or consuming freely available less preferred chow. Tetrabenazine (TBZ), a dopamine-depleting agent, shifts behavior toward the low-effort option, modeling motivational impairments seen in MDD. Previous studies in male rats have shown that nomifensine effectively reverses the TBZ-induced behavioral effects, however the effects in female rats are unknown. Given the higher prevalence of depression in women and sex differences in symptomatology, the present study examined whether nomifensine could reverse TBZ-induced low-effort bias in female. Nomifensine partially restored lever pressing and dose-dependently reversed the effects of TBZ on chow intake. These findings support the efficacy of NDRIs in mitigating motivational deficits and highlight the importance of exploring sex-specific responses to antidepressant treatments.