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

Abstract

Motivated behavior can be characterized by behavioral activation and high work output. Moreover, people with depression and other disorders show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Effort-based decision making is studied using tasks offering choices between high effort options leading to highly valued reinforcers vs low effort/low reward options, and such tasks could be useful as animal models of motivational symptoms. In the present studies the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine (TBZ) were investigated. TBZ blocks vesicular storage and also produces depressive symptoms in humans. Moreover, TBZ alters effort-based choice in rats, biasing animals toward low effort alternatives. The present studies investigated the ability of acute administration of various monoamine uptake inhibitors to reverse the effects of TBZ. Effort-related effects of TBZ were attenuated by the catecholamine uptake inhibitor and antidepressant bupropion, and this effect of bupropion was reversed by either D1 or D2 family antagonism. The effort-related effects of TBZ were also attenuated by the selective dopamine uptake blocker GBR12909. The 5-HT uptake inhibitor fluoxetine and the norepinephrine uptake inhibitor desipramine failed to reverse the effects of TBZ, and higher doses of these drugs, given alone or in combination with TBZ, led to further behavioral impairments. These results indicate that drugs acting on dopamine transmission are relatively effective at reversing the effort-related effects of TBZ, and are consistent with the hypothesis that drugs that enhance dopamine transmission may be effective at treating effort-related psychiatric symptoms in humans.

Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington’s disease

“…Indeed, we have previously found that, while the Q175 HD mouse model employed in the current study exhibits diminished motivation, they do not display behaviors characteristic of depression [20]. In addition, antidepressant treatment may be problematic for apathy in HD because common antidepressants can suppress motivation by altering dopamine input to the NAc [56,57]. Moreover, the only FDAapproved treatment specifically for HD is TBZ, which reversibly inhibits the vesicular monoamine transporter-2 (VMAT-2) to suppress dopamine release [58].…”

Preference for Exercise vs. More Sedentary Reinforcers: Validation of an Animal Model of Tetrabenazine-Induced Anergia

“…Diverse tasks have been used in rodents for evaluating behavioral activation and effort-related decision making, including tasks that give animals the option of vigorously working (lever pressing or climbing a barrier) to obtain access to more highly valued reinforcers vs. approaching and consuming a less preferred reinforcer (Cousins et al, 1994;Salamone and Correa, 2002;Salamone et al, 2016;Mott et al, 2009;Mai et al, 2012;Pardo et al, 2012Pardo et al, , 2015Randall et al, 2012;Sommer et al, 2014;Yohn et al, 2015aYohn et al, , 2016bCorrea et al, 2018;SanMiguel et al, 2019). In these tasks, conditions that alter DA transmission, such as administration of DA antagonists or tetrabenazine (TBZ), can alter behavioral activation and reduce selection of high-effort choices in rats (Nunes et al, 2013;Randall et al, 2014;Hosking et al, 2015;Pardo et al, 2015;Yohn et al, 2015aYohn et al, , 2016aContreras-Mora et al, 2018;Rotolo et al, 2019). TBZ acts by inhibiting the vesicular monoamine transporter-type 2 (VMAT-2), which leads to a blockade of vesicular storage and a depletion of monoamines, with its greatest effects at low doses being on striatal DA in rats and mice (Pettibone et al, 1984;Nunes et al, 2013;López-Cruz et al, 2018).…”

A specific role for serotonin in overcoming effort cost

“…However, other studies also reported that SSRI treatments increase motivation or at least the sensitivity to reward (Tang et al, 2009; Stoy et al, 2012; Yuen et al, 2014). The related animal literature is also contradictory: some studies on cost/benefit trade-off showed reduced effort expenditure with SSRIs (Yohn et al, 2016) or no effect with serotonin blockers (Denk et al, 2005), while other studies reported increased motor activity induced by SSRI (Weber et al, 2009) or optogenetic stimulation of the dorsal raphe nucleus (Warden et al, 2012). …”