John D. Salamone

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

BackgroundOver 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.ObjectiveThe present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry.ResultsThe 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.ConclusionsAlong 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.

Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine.

Although the Skinnerian Empirical Law of Effect does not directly consider the fundamental properties of stimuli that enable them to act as reinforcers, such considerations are critical for determining if nucleus accumbens dopamine systems mediate reinforcement processes. Researchers who have attempted to identify the critical characteristics of reinforcing stimuli or activities have generally arrived at an emphasis upon motivational factors. A thorough review of the behavioral literature indicates that, across several different investigators offering a multitude of theoretical approaches, motivation is seen by many as being fundamental to the process of reinforcement. The reinforcer has been described as a goal, a commodity, an incentive, or a stimulus that is being approached, self-administered, attained or preserved. Reinforcers also have been described as activities that are preferred, deprived or in some way being regulated. It is evident that this motivational or regulatory view of reinforcement has had enormous influence over the hypothesis that DA directly mediates reward or reinforcement processes. Indeed, proponents of the DA/reward hypothesis regularly cite motivational theorists and employ their language. Nevertheless, considerable evidence indicates that low/moderate doses of DA antagonists, and depletions of DA in nucleus accumbens, can suppress instrumental responding for food while, at the same time, these conditions leave fundamental aspects of reinforcement (i.e. primary or unconditioned reinforcement; primary motivation or primary incentive properties of natural reinforcers) intact. Several complex features of the literature on dopaminergic involvement in reinforcement are examined below, and it is argued that the assertions that DA mediates reward or reinforcement are inaccurate and grossly oversimplified. Thus, it appears as though it is no longer tenable to assert that drugs of abuse are simply turning on the brains natural reward system. In relation to the hypothesis that DA systems are involved in wanting, but not liking, it is suggested in the present review that wanting has both directional aspects (e.g. appetite to consume food) and activational aspects (e.g. activation for initiating and sustaining instrumental actions; tendency to work for food). The present paper reviews findings in support of the hypothesis that low doses of DA antagonists and accumbens DA depletions do not impair appetite to consume food, but do impair activational aspects of motivation. This suggestion is consistent with the studies showing that low doses of DA antagonists and accumbens DA depletions alter the relative allocation of instrumental responses, making the animals less likely to engage in instrumental responses that have a high degree of work-related response costs. In addition, this observation is consistent with studies demonstrating that accumbens DA depletions make rats highly sensitive to ratio requirements on operant schedules. Although accumbens DA is not seen as directly mediating appetite to consume food, principles of behavioral economics indicate that accumbens DA could be involved in the elasticity of demand for food in terms of the tendency to pay work-related response costs. Future research must focus upon how specific aspects of task requirements (i.e. ratio requirements, intermittence of reinforcement, temporal features of response requirements, dependence upon conditioned stimuli) interact with the effects of accumbens DA depletions, and which particular factors determine sensitivity to the effects of DA antagonism or depletion.

The involvement of nucleus accumbens dopamine in appetitive and aversive motivation.

In recent years, considerable emphasis has been placed upon the putative role of nucleus accumbens dopamine systems in appetitive motivation and positive reinforcement. However, considerable evidence indicates that brain dopamine in general, and nucleus accumbens dopamine in particular, is involved in aspects of aversive motivation. Administration of dopamine antagonists or localized interference with nucleus accumbens dopamine systems has been shown to disrupt active avoidance behavior. In addition, accumbens dopamine release and metabolism is activated by a wide variety of stressful conditions. A review of the literature indicates that there are substantial similarities between the characteristics of dopaminergic involvement in appetitive and aversive motivation. There is conflicting evidence about the role of dopamine in emotion, and little evidence to suggest that the profound and consistent changes in instrumental behavior produced by interference with DA systems are due to direct dopaminergic mediation of positive affective responses such as hedonia. It is suggested that nucleus accumbens dopamine is involved in aspects of sensorimotor functions that are involved in both appetitive and aversive motivation.

Behavioral functions of nucleus accumbens dopamine : Empirical and conceptual problems with the anhedonia hypothesis

Nucleus accumbens (DA) has been implicated in a number of different behavioral functions, but most commonly it is said to be involved in reward or reinforcement. In the present article, the putative reinforcement functions of accumbens DA are summarized in a manner described as the General Anhedonia Model. According to this model, the DA innervation of the nucleus accumbens is conceived of as a crucial link in the reward system, which evolved to mediate the reinforcing effects of natural stimuli such as food. The reward system is said to be activated by natural reinforcing stimuli, and this activation mediates the reinforcing effects of these natural stimuli. According to this view, other stimuli such as brain stimulation and drugs can activate this system, which leads to these stimuli being reinforcing as well. Interference with DA systems is said to blunt the reinforcing effects of these rewarding stimuli, leading to extinction. This general model of the behavioral functions of accumbens DA is utilized widely as a theoretical framework for integrating research findings. Nevertheless, there are several difficulties with the General Anhedonia Model. Several studies have observed substantial differences between the effects of extinction and the effects of DA antagonism or accumbens DA depletions. Studies involving aversive conditions indicate that DA antagonists and accumbens DA depletions can interfere with avoidance behavior, and also have demonstrated that accumbens DA release is increased by stressful or aversive stimuli. Although accumbens DA is important for drug abuse phenomena, particularly stimulant self-administration, studies that involve other reinforcers are more problematic. A large body of evidence indicates that low doses of dopamine antagonists, or depletions of accumbens DA, do not impair fundamental aspects of food motivation such as chow consumption and simple instrumental responses for food. This is particularly important, in view of the fact that many behavioral researchers consider the regulation of food motivation to be a fundamental aspect of food reinforcement. Finally, studies employing cost/benefit analyses are reviewed, and in these studies considerable evidence indicates that accumbens DA is involved in the allocation of responses in relation to various reinforcers. Nucleus accumbens DA participates in the function of enabling organisms to overcome response costs, or obstacles, in order to obtain access to stimuli such as food. In summary, nucleus accumbens DA is not seen as directly mediating food reinforcement, but instead is seen as a higher order sensorimotor integrator that is involved in modulating response output in relation to motivational factors and response constraints. Interfering with accumbens DA appears to partially dissociate the process of primary reinforcement from processes regulating instrumental response initiation, maintenance and selection.

Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure.

Two experiments were conducted to study the role of dopamine in the performance of a novel cost/benefit procedure. Rats were trained on a T-maze task in which one arm contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). Different groups of rats were trained either with unobstructed access to both arms from the start area, or under a condition in which a large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the first experiment, rats trained under each procedure received injections of 0.1 mg/kg haloperidol and tartaric acid vehicle as a control procedure. Analysis of variance indicated that there was a significant effect of the barrier on maze arm choice, a significant effect of haloperidol, and a significant drug x barrier interaction. Haloperidol did not affect arm choice in rats tested without the barrier present, but this drug significantly reduced the number of selections of the arm with high reinforcement density when the barrier was present. In the second experiment, groups of rats were trained as described above, and then received intraaccumbens injections of 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions produced by 6-hydroxydopamine decreased the number of selections of the arm with high reinforcement density when the barrier was present, but had no effect on arm choice when the barrier was not present.(ABSTRACT TRUNCATED AT 250 WORDS)

Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure

An important aspect of motivated behavior is that organisms will perform complex instrumental behaviors to gain access to stimuli such as food. In the present study, food-deprived rats were tested in an operant chamber in which the animals had a choice between pressing a lever to obtain a more-preferred food (Bioserve pellets), or free feeding on a less-preferred food (lab chow). Typically, rats pressed the lever to obtain the preferred food pellets, and ate little of the less-preferred food even though it was freely available. Pre-fed rats showed suppression of both lever pressing and feeding. Systemic administration of 0.1 mg/kg haloperidol (HP) led to a dramatic shift in the behavior of these rats, such that the number of lever presses was substantially reduced, but the amount of less-preferred food consumed showed a significant increase. This result occurred if the rats pressed a lever on either a CRF or FR5 schedule. Injection of 3.5–7.0 µg HP directly into the nucleus accumbens, or intra-accumbens injections of 6-hydroxy-dopamine, also decreased lever pressing for food and increased feeding on laboratory chow. Thus, interference with brain dopamine suppressed a highly active instrumental response for food, although the behavior of the animal was still directed towards food acquisition and consumption.

Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task.

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.

Different effects of nucleus accumbens and ventrolateral striatal dopamine depletions on instrumental response selection in the rat

This experiment was undertaken to investigate dopaminergic involvement in food-related instrumental behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or feeding upon a less preferred food (lab chow). The lever-pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever-pressing schedule. The neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial striatum, or ventrolateral striatum to determine the effects of dopamine depletion on the performance of this task. Depletion of dopamine in the nucleus accumbens led to a dramatic shift in behavior in which there was a significant decrease in lever pressing but a significant increase in consumption of lab chow. The shift away from lever pressing and towards chow consumption in rats with accumbens DA depletions was significantly correlated with a decrease in spontaneous locomotor activity. Dopamine depletions in the medial striatum did not significantly affect lever pressing or chow consumption. Ventrolateral striatal dopamine depletions decreased lever pressing but also tended to reduce consumption of lab chow. Rats with ventrolateral striatal dopamine depletions also showed profound deficits in home-cage feeding, and these rats had to receive wet mash or tube feeding to maintain body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus Accumbens Dopamine Depletions in Rats Affect Relative Response Allocation in a Novel Cost/Benefit Procedure

Rats were tested on days 1, 3, and 5 of a 5-day test week in an operant chamber in which they could either lever press on a fixed-ratio 5 (FR5) schedule to obtain food pellets (Bioserve) or approach and consume lab chow that was also available in the chamber (Teklad Premier). Rats typically pressed at high rates to obtain the food pellets and ate little of the lab chow. On days 2 and 4 of each week lab chow was not concurrently available, and rats could only lever press on the FR5 schedule for pellets to obtain food. Dopamine depletions produced by intraaccumbens injections of the neurotoxic agent 6-hydroxydopamine produced a dramatic decrease in lever pressing and increase in chow consumption on days when lab chow was available. Lever pressing was not significantly reduced in dopamine-depleted rats on days when chow was not available, although there was a significant correlation between lever pressing and accumbens dopamine levels. These results suggest that nucleus accumbens dopamine depletions do not produce a general deficit in food motivation. Moreover, accumbens dopamine depletions do not appear to produce severe deficits in fine motor control that impair the execution of individual motor acts involved in lever pressing. Rather, the present results are consistent with the notion that accumbens dopamine sets constraints upon which food-related response is selected in a particular situation, and that these depletions alter the relative allocation of food-related responses.

The Role of Accumbens Dopamine in Lever Pressing and Response Allocation: Effects of 6-OHDA Injected into Core and Dorsomedial Shell

Three experiments investigated the behavioral effects of injections of the neurotoxic agent 6-hydroxydopamine (6-OHDA) into the core or shell of the nucleus accumbens. In the first experiment, it was observed that injections of 6-OHDA into either core or shell had no significant effect on variable interval 30-s responding. In Experiment 2, responding on a fixed ratio 5 (FR5) schedule was impaired by 6-OHDA injections in the core, but not the shell. Rats with core injections of 6-OHDA showed significant alterations in the relative distribution of interresponse times, which were indicative of reductions in the maximal rate of responding and increases in the number of pauses. In the third experiment, rats were tested using a lever-pressing/chow-feeding procedure, in which a preferred food (Bioserve pellets) was available by pressing a lever on a FR5 schedule, but a less preferred food (lab chow) was also available concurrently in the test chamber. Untreated rats usually pressed the lever at high rates to obtain the food pellets and ate little of the lab chow. After training, dopamine depletions were produced by injections of 6-OHDA directly into the core or dorsomedial shell subregions. Injections of 6-OHDA into the core significantly decreased lever pressing for food pellets, increased lab chow consumption, and decreased the relative amount of food obtained by lever pressing. Dorsomedial shell injections of 6-OHDA had no significant effects on either lever pressing or lab chow consumption. Neurochemical results indicate that injections of 6-OHDA in the shell produced substantial depletions in the shell that were somewhat selective; however, injections of 6-OHDA into the core tended to deplete both core and shell. Correlational analyses revealed that decreases in FR5 lever pressing were associated with dopamine levels in the core, but not the shell. The present results indicate that substantial depletions of dopamine in the dorsomedial shell are not sufficient for suppressing reinforced lever pressing, and indicate that dopamine depletions must include the core area to impair performance on these tasks. The lack of effect of accumbens dopamine depletions on VI30 responding are consistent with the notion that accumbens dopamine depletions affect responding on schedules that generate a high rate of responding (FR5), but not those that generate a moderate rate of responding (e.g., VI30 s). The results of the concurrent FR5/chow-feeding experiment indicate that rats with accumbens dopamine depletions remain directed towards the acquisition and consumption of food. These results suggest that dopamine in the core region of accumbens sets constraints upon the selection of food-related behaviors, and that core dopamine depletions alter the relative allocation of food-related responses.