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

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

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression

Anterior cingulate cortex supports effort allocation towards a qualitatively preferred option

The anterior cingulate cortex (ACC) is known to be involved in effortful choice, yet its role in cost-benefit evaluation of qualitatively different rewards (more/less preferred), beyond magnitude differences (larger/smaller), is poorly understood. Selecting between qualitatively different options is a decision type commonly faced by humans. Here, we assessed the role of ACC on a task that has primarily been used to probe striatal function in motivation. Rats were trained to stable performance on a progressive ratio schedule for sucrose pellets and were then given sham surgeries (control) or excitotoxic NMDA lesions of ACC. Subsequently, a choice was introduced: chow was concurrently available while animals could work for the preferred sucrose pellets. ACC lesions produced a significant decrease in lever presses for sucrose pellets compared to control, whereas chow consumption was unaffected. Lesions had no effect on sucrose pellet preference when both options were freely available. When laboratory chow was not concurrently available, ACC-lesioned rats exhibited similar lever pressing as controls. During a test under specific satiety for sucrose pellets, ACC-lesioned rats also showed intact devaluation effects. The effects of ACC lesions in our task are not mediated by decreased appetite, a change in food preference, a failure to update value or a learning deficit. Taken together, we found that ACC lesions decreased effort for a qualitatively preferred option. These results are discussed with reference to effects of striatal manipulations and our recent report of a role for basolateral amygdala in effortful choice

Effects of SKF-83566 and haloperidol on performance on progressive ratio schedules maintained by sucrose and corn oil reinforcement: quantitative analysis using a new model derived from the Mathematical Principles of Reinforcement (MPR)

Rationale Mathematical models can assist the interpretation of the effects of interventions on schedule-controlled behaviour and help to differentiate between processes that may be confounded in traditional performance measures such as response rate and the breakpoint in progressive ratio (PR) schedules. Objective The effects of a D1-like dopamine receptor antagonist, 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide (SKF-83566), and a D2-like receptor antagonist, haloperidol, on rats’ performance on PR schedules maintained by sucrose and corn oil reinforcers were assessed using a new model derived from Killeen’s (Behav Brain Sci 17:105–172, 1994) Mathematical Principles of Reinforcement. Method Separate groups of rats were trained under a PR schedule using sucrose or corn oil reinforcers. SKF-83566 (0.015 and 0.03 mg kg−1) and haloperidol (0.05 and 0.1 mg kg−1) were administered intraperitoneally (five administrations of each treatment). Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model’s parameters were compared between treatments. Results Haloperidol reduced a (the parameter expressing incentive value) in the case of both reinforcers, but did not affect the parameters related to response time and post-reinforcement pausing. SKF-83566 reduced a and k (the parameter expressing sensitivity of post-reinforcement pausing to the prior inter-reinforcement interval) in the case of sucrose, but did not affect any of the parameters in the case of corn oil. Conclusions The results are consistent with the hypothesis that blockade of both D1-like and D2-like receptors reduces the incentive value of sucrose, whereas the incentive value of corn oil is more sensitive to blockade of D2-like than D1-like receptors

Dopamine/adenosine interactions involved in effort-related aspects of food motivation

Nucleus accumbens dopamine (DA) is involved in effort-related aspects of food motivation. Accumbens DA depletions reduce the tendency of rats to work for food, and alter effort-related choice, but leave other aspects of food motivation and appetite intact. DA and adenosine receptors interact to regulate effort-related processes. Adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and intra-accumbens injections of a adenosine A2A agonist produce effects that are similar to those produced by accumbens DA depletion or antagonism. These studies have implications for understanding the neurochemical interactions that underlie activational aspects of motivation. © 2009 Elsevier Ltd. All rights reserved

Selection of sucrose concentration depends on the effort required to obtain it: studies using tetrabenazine, D₁, D₂, and D₃ receptor antagonists

RationaleLow doses of dopamine (DA) antagonists and accumbens DA depletions reduce food-reinforced instrumental behavior but do not impair primary food motivation, causing animals to reallocate behavior away from food-reinforced tasks with high response requirements and select less effortful alternatives. However, it is uncertain if this same pattern of effects would occur if sucrose was used as the reinforcer. Objectives These experiments studied the impact of DA depletion and antagonism on performance of an effort-related choice task using sucrose as the reinforcer, as well as sucrose consumption, preference, and taste reactivity tests. Methods The effects of DA manipulations were assessed using a task in which rats chose between lever pressing on a fixed ratio 7 schedule for 5.0 % sucrose versus freely consuming a less concentrated solution (0.3 %). Results The DA depleting agent tetrabenazine shifted effort-related choice, decreasing lever pressing for 5.0 % sucrose but increasing intake of the concurrently available 0.3 % sucrose. Tetrabenazine did not affect sucrose appetitive taste reactivity, or sucrose consumption or preference, in free consumption tests. The D1 antagonist ecopipam and the D2 antagonist haloperidol also shifted choice behavior at doses that did not alter sucrose consumption or preference. In contrast, sucrose pre-exposure reduced consumption across all conditions. D3 antagonism had no effects. Conclusions D1 and D2 receptor blockade and DA depletion reduce the tendency to work for sucrose under conditions that leave fundamental aspects of sucrose motivation (intake, preference, hedonic reactivity) intact. These findings have implications for studies employing sucrose intake or preference in animal models of depression