Impact of Fluoxetine on Behavioral Invigoration of Appetitive and Aversively Motivated Responses: Interaction With Dopamine Depletion

Impaired behavioral activation and effort-related motivational dysfunctions like fatigue and anergia are debilitating treatment-resistant symptoms of depression. Depressed people show a bias towards the selection of low effort activities. To determine if the broadly used antidepressant fluoxetine can improve behavioral activation and reverse dopamine (DA) depletion-induced anergia, male CD1 mice were evaluated for vigorous escape behaviors in an aversive context (forced swim test, FST), and also with an exercise preference choice task [running wheel (RW)-T-maze choice task]. In the FST, fluoxetine increased active behaviors (swimming, climbing) while reducing passive ones (immobility). However, fluoxetine was not effective at reducing anergia induced by the DA-depleting agent tetrabenazine, further decreasing vigorous climbing and increasing immobility. In the T-maze, fluoxetine alone produced the same pattern of effects as tetrabenazine. Moreover, fluoxetine did not reverse tetrabenazine-induced suppression of RW time but it reduced sucrose intake duration. This pattern of effects produced by fluoxetine in DA-depleted mice was dissimilar from devaluing food reinforcement by pre-feeding or making the food bitter since in both cases sucrose intake time was reduced but animals compensated by increasing time in the RW. Thus, fluoxetine improved escape in an aversive context but decreased relative preference for active reinforcement. Moreover, fluoxetine did not reverse the anergic effects of DA depletion. These results have implications for the use of fluoxetine for treating motivational symptoms such as anergia in depressed patients.