Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress

This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after 2 weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving 2 weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal–cingulate cortex and brainstem nuclei linked to depression (e.g., habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal–cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action.

Research Highlights
► Fluoxetine antidepressant action was tested in learned helpless Holtzman rats.
► Holtzman rats are novelty reactive and susceptible to stress-induced depression.
► Fluoxetine exerted a protective effect against forced swim induced immobility.
► Fluoxetine reduced cytochrome oxidase in accumbens shell and ventral hippocampus.
► Prefrontal–cingulate cortex and brainstem networks were also affected by fluoxetine.