Bupropion Increases Selection of High Effort Activity in Rats Tested on a Progressive Ratio/Chow Feeding Choice Procedure: Implications for Treatment of Effort-Related Motivational Symptoms

Abstract

Background:Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology.Methods:Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber.Results:Bupropion (10.0–40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation.Conclusion:The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans.

Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior

“…This work was undertaken to focus on effort-related functions that may be highly relevant for understanding some of the motivational symptoms of depression and other disorders (Nunes et al, 2013a,b;Randall et al, 2014Randall et al, , 2015Treadway et al, 2012;Yohn et al, 2015). Rodent tests of effort-related dysfunction are likely to reflect a component of depression rather than a global measure, and possibly represent models of motivational symptoms that cross multiple diagnostic categories, rather than a model of a specific disorder .…”

“…Bupropion, a catecholamine reuptake blocker that elevates extracellular DA and norepinephrine (NE; Hudson et al, 2012;Randall et al, 2015), has been shown to reverse the effort related effects of TBZ (Nunes et al, 2013;Randall et al, 2014;Yohn et al, 2015).…”

Neurobiological basis of motivational deficits in psychopathology

“…Disruptions of effort-related decision making can be induced by several manipulations associated with depression, including stress (Shafiei et al, 2012), stimulation of muscarinic acetylcholine receptors in NAcc (Nunes et al, 2013a), and administration of the pro-inflammatory cytokine interleukin 1-β (Nunes et al, 2014). Recent studies also characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine (Nunes et al, 2013b;Randall et al, 2014). Tetrabenazine produces depressive symptoms in humans (Guay, 2010;Frank, 2009Frank, , 2010, and because of its selective inhibition of VMAT-2, it preferentially depletes striatal DA (Pettibone et al, 1984).…”

“…Tetrabenazine produces depressive symptoms in humans (Guay, 2010;Frank, 2009Frank, , 2010, and because of its selective inhibition of VMAT-2, it preferentially depletes striatal DA (Pettibone et al, 1984). Rats were tested on concurrent lever pressing/chow feeding choice tasks, and tetrabenazine shifted response choice from the high effort response (lever pressing) to the low effort alternative (approach and consumption of chow; Nunes et al, 2013b;Randall et al, 2014). Yet despite these effort-related impairments, tetrabenazine did not alter food intake or preference in parallel free-feeding choice studies.…”

Differential effects of bupropion on acquisition and performance of an active avoidance task in male mice

“…The doses employed in the current research were selected on the basis of previous studies about the effects of bupropion in NMRI mice (Carrasco et al, 2004(Carrasco et al, , 2013Gomez et al, 2009a,b;Redolat et al, 2005a,b) and are in the range of doses habitually used to assess behavioral effects of bupropion in rodents (Biała and Kruk, 2009;Lipina and Roder, 2010;Randall et al, 2014).…”