Abstract
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.
Highlights
Motivational symptoms such as psychomotor retardation, anergia, lack of energy, lassitude, fatigue, and reduced exertion of effort are common and critical in major depressive disorder (Stahl, 2002; Demyttenaere et al, 2005; Salamone et al, 2007; Treadway and Zald, 2011)
The present experiments evaluated the ability of the 5-HT uptake inhibitor fluoxetine to produce antidepressant effects on the classical rodent paradigm, the forced swim test (FST), and its potential to reverse the depression-like effects of the DA depleting agent TBZ in this paradigm (Carratalá-Ros et al, 2020)
We confirmed that administration of a range of doses of fluoxetine significantly increased the time mice spent climbing and swimming, reducing the time animals spent immobile in the FST (Figure 1)
Summary
Motivational symptoms such as psychomotor retardation, anergia, lack of energy, lassitude, fatigue, and reduced exertion of effort are common and critical in major depressive disorder (Stahl, 2002; Demyttenaere et al, 2005; Salamone et al, 2007; Treadway and Zald, 2011). Conditions associated with depression, including stress (Shafiei et al, 2012; Bryce and Floresco, 2016, 2019) and pro-inflammatory cytokines (Nunes et al, 2014; Goldsmith et al, 2016; Yohn et al, 2016a), as well as dopamine (DA) receptor antagonism (Pardo et al, 2012, 2015; Yohn et al, 2015a; Correa et al, 2016; Yang et al, 2020) or DA depletion (Nunes et al, 2013; Randall et al, 2014; Yohn et al, 2015b; López-Cruz et al, 2018; Rotolo et al, 2019; Carratalá-Ros et al, 2020) can affect effort-related decision-making and bias animals towards the low effort options These results obtained from animal studies are consistent with clinical data showing a reduced selection of high effort alternatives in depressed people tested on tasks of effort-based choice (Treadway et al, 2012; Chong et al, 2016). We have demonstrated that TBZ induces depressive symptoms in the forced swim test (FST); mice show less vigorous scaping behaviors and increase immobility (Carratalá-Ros et al, 2020)
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