Induction and Treatment of Motivational Dysfunctions in a Rodent Pharmacological Model of Effort-Related Choice Behavior: Evidence from Behavioral and Neurochemical Studies

The central aim of the present research was to develop animal models that are useful for characterizing potential treatments for the effort-related motivational symptoms of depression. Effort-based decision making in rats can be employed to study the effects of conditions associated with depression, and such procedures can assess the effects of potential therapeutic agents. Conditions associated with depression in humans, such as administration of the vesicular monoamine transport inhibitor tetrabenazine (TBZ), or inflammatory challenge, can shift effort-related choice behavior and reduce selection of high effort choices in rats. Experiment 1 characterized the effort-related effects of TBZ as measured by the T-maze barrier choice task, while experiments 2-7 employed operant choice procedures. Experiment 2 demonstrated that dopamine transport (DAT) blockers are effective at attenuating effort-related dysfunctions induced by TBZ. In contrast, inhibitors of 5-HT and norepinephrine uptake failed to reverse the effects of TBZ, and higher doses of these drugs led to further behavioral impairments. In experiment 3, the DAT blocker lisdexamfetamine significantly attenuated shifts in behavior induced by TBZ, the pro-inflammatory cytokine interleukin-1B, and the SERT inhibitor s-citalopram. Experiment 4 showed that the novel DAT blocker PRX-14040 reversed the effects of TBZ and increased selection of high effort lever pressing. Experiment group 5 revealed that either acute or chronic administration of the DAT blocker GBR-12909 could enhance effortful responding, while the 5-HT and norepinephrine transport inhibitors fluoxetine and desipramine could not. Experiment 6 found that the monoamine-oxidase B inhibitor deprenyl administered via systemic or local administration into the accumbens increased exertion of effort. Experimental group 7 revealed that administration of the pro-inflammatory cytokine interleukin-6 altered effort-related choice behavior, and that these behavioral effects can be attenuated by co-administration of the adenosine A2A antagonist MSX-3 or the major stimulant methylphenidate. Collectively, these studies demonstrate that drugs acting on dopamine transmission, as well as adenosine A2A antagonists that modify dopaminergic signaling, appear to be relatively effective at reversing the effort-related effects of TBZ and cytokines, and enhancing work related behavioral output. These results provide clues regarding the brain mechanisms involved in motivational psychopathologies, and may foster the development of novel treatment options