Susana Mingote

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.

Nucleus Accumbens Adenosine A2A Receptors Regulate Exertion of Effort by Acting on the Ventral Striatopallidal Pathway

Goal-directed actions are sensitive to work-related response costs, and dopamine in nucleus accumbens is thought to modulate the exertion of effort in motivated behavior. Dopamine-rich striatal areas such as nucleus accumbens also contain high numbers of adenosine A2A receptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A2A receptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A2A receptors disrupted performance of an instrumental task with high work demands (i.e., an interval lever-pressing schedule with a ratio requirement attached) but had little effect on a task with a lower work requirement. Immunohistochemical studies revealed that accumbens neurons that project to the ventral pallidum showed adenosine A2A receptors immunoreactivity. Moreover, activation of accumbens A2A receptors by local injections of CGS 21680 increased extracellular GABA levels in the ventral pallidum. Combined contralateral injections of CGS 21680 into the accumbens and the GABAA agonist muscimol into ventral pallidum (i.e., “disconnection” methods) also impaired response output, indicating that these structures are part of a common neural circuitry regulating the exertion of effort. Thus, accumbens adenosine A2A receptors appear to regulate behavioral activation and effort-related processes by modulating the activity of the ventral striatopallidal pathway. Research on the effort-related functions of these forebrain systems may lead to a greater understanding of pathological features of motivation, such as psychomotor slowing, anergia, and fatigue in depression.

Accumbens dopamine and the regulation of effort in food-seeking behavior: modulation of work output by different ratio or force requirements.

It has been suggested that depletions of accumbens dopamine (DA) make rats more sensitive to work-related response costs. One way of controlling work costs in operant tasks has been to use fixed-ratio (FR) schedules with different ratio requirements. In addition to using ratio requirements to control response costs, investigators also can employ different force requirements. In the present study, different groups of rats were trained on two schedules (FR 1 and FR 5) and weights were placed on the levers 2 days each week. In the FR 5 studies, two different weights were used (32 or 64 g), while three different weights were used in the FR 1 studies (32, 64, or 96 g). After baseline training, rats received intra-accumbens injections of either 6-OHDA to deplete DA, or ascorbate vehicle as the control. The effects of DA depletions were highly schedule-dependent. DA-depleted animals on the FR 5 schedule showed reductions in responding across the different weight conditions. In contrast, DA depletion did not significantly suppress FR 1 responding under any conditions. Addition of weights to the levers reduced responding on the FR 1 and FR 5 schedules, but did not enhance sensitivity to DA depletion. Thus, rats with accumbens DA depletions were sensitive to different ratio requirements, yet they were relatively insensitive to different force requirements within the range tested. These studies indicate that DA depletions make animals sensitive to temporal or rate components of work that greatly influence responding on ratio schedules.

Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate

The typical response to acute peripheral administration of low to high doses of ethanol in rats is a dose-dependent depression of motor activity. Nevertheless, recent studies indicate that intraventricular (ICV) injections of ethanol can produce signs of behavioral activation. In addition, considerable evidence indicates that brain metabolism of ethanol is involved in modulating some of the behavioral effects of this drug, which suggests that ethanol may have active metabolites with central actions. The present study was undertaken to investigate the effects of ICV ethanol, and its two major metabolites acetaldehyde and acetate, on open field locomotor activity in rats. Male Sprague-Dawley rats received different doses of ethanol, acetaldehyde or acetate ICV and immediately were placed in an open field chamber in which locomotion was measured. Rats injected with ICV ethanol or acetaldehyde showed an inverted U-shaped dose-response curve, with moderate doses increasing motor activity. In contrast, acetate produced a dose-dependent decrease in motor activity. These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats, and suggest that acetaldehyde may be an active metabolite of ethanol that also can facilitate locomotor activity. Moreover, it is possible that some of the motor suppression or sedation produced by ethanol is due to the central actions of acetate.

Ratio and time requirements on operant schedules : effort- related effects of nucleus accumbens dopamine depletions

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. interresponse times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate‐enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work‐related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.

Nucleus Accumbens Dopamine and the Forebrain Circuitry Involved in Behavioral Activation and Effort-Related Decision Making: Implications for Understanding Anergia and Psychomotor Slowing in Depression

The notion that motivated behaviors having an energetic or activational component is an old one, and there are numerous examples of this idea from the literatures of psychology and ethology. Behavioral researchers have demonstrated that vigor or persistence of work output in stimulus-seeking behavior is a fundamental aspect of motivation. In addition, psychiatrists and clinical psychologists have come to emphasize the importance of energy-related dysfunctions, such as psychomotor slowing and apathy, in various clinical syndromes. Because of the potential scientific importance and clinical relevance of behavioral activation processes, it is critical to determine the brain mechanisms that are involved. Considerable evidence indicates that DA in nucleus accumbens is involved in activational aspects of motivation. Accumbens DA depletions decrease spontaneous, stimulant-induced, and food-induced motor activity. In addition, the effects of accumbens DA depletions on food-seeking behavior depend greatly upon the response requirements of the task. Research involving concurrent choice tasks has shown that rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead select a less-effortful type of food-seeking behavior. Rats with accumbens DA depletions are particularly sensitive to lever pressing schedules with high ratio requirements (i.e., a large number of lever presses must be emitted for reinforcement to occur). Together with studies of frontal cortex function in animals, and clinical studies on neurochemical and other functional changes in the human brain, this line of research could have implications for understanding the brain circuitry involved in energy-related psychiatric disorders such as psychomotor slowing in depression, anergia, fatigue and apathy.

Dopamine Neurons Control Striatal Cholinergic Neurons via Regionally Heterogeneous Dopamine and Glutamate Signaling

Midbrain dopamine neurons fire in bursts conveying salient information. Bursts are associated with pauses in tonic firing of striatal cholinergic interneurons. Although the reciprocal balance of dopamine and acetylcholine in the striatum is well known, how dopamine neurons control cholinergic neurons has not been elucidated. Here, we show that dopamine neurons make direct fast dopaminergic and glutamatergic connections with cholinergic interneurons, with regional heterogeneity. Dopamine neurons drive a burst-pause firing sequence in cholinergic interneurons in the medial shell of the nucleus accumbens, mixed actions in the accumbens core, and a pause in the dorsal striatum. This heterogeneity is due mainly to regional variation in dopamine-neuron glutamate cotransmission. A single dose of amphetamine attenuates dopamine neuron connections to cholinergic interneurons with dose-dependent regional specificity. Overall, the present data indicate that dopamine neurons control striatal circuit function via discrete, plastic connections with cholinergic interneurons.

Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior.

Organisms often make effort-related choices based upon assessments of motivational value and work requirements. Nucleus accumbens dopamine is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior. Rats with accumbens dopamine depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead they select a less-effortful type of food-seeking behavior. The ventral pallidum is a brain area that receives substantial GABAergic input from nucleus accumbens. It was hypothesized that stimulation of GABA(A) receptors in the ventral pallidum would result in behavioral effects that resemble those produced by interference with accumbens dopamine transmission. The present studies employed a concurrent choice lever pressing/chow intake procedure; with this task, interference with accumbens dopamine transmission shifts choice behavior such that lever pressing for food is decreased but chow intake is increased. In the present experiments, infusions of the GABA(A) agonist muscimol (5.0-10.0 ng) into the ventral pallidum decreased lever pressing for preferred food, but increased consumption of the less preferred chow. In contrast, ventral pallidal infusions of muscimol (10.0 ng) had no significant effect on preference for the palatable food in free-feeding choice tests. Furthermore, injections of muscimol into a control site dorsal to the ventral pallidum produced no significant effects on lever pressing and chow intake. These data indicate that stimulation of GABA receptors in ventral pallidum produces behavioral effects similar to those produced by accumbens dopamine depletions. Ventral pallidum appears to be a component of the brain circuitry regulating response allocation and effort-related choice behavior, and may act to convey information from nucleus accumbens to other parts of this circuitry. This research may have implications for understanding the brain mechanisms involved in energy-related psychiatric dysfunctions such as psychomotor retardation in depression, anergia, and apathy.

Noradrenaline and Dopamine Efflux in the Prefrontal Cortex in Relation to Appetitive Classical Conditioning

We trained rats to learn that an auditory stimulus predicted delivery of reward pellets in the Skinner box. After 2 d of training, we measured changes in efflux of noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex using microdialysis on the third day. Animals were subjected to a normal rewarded session and an extinction session, in which the auditory stimulus was presented alone. In the rewarded session, both NA and DA efflux were increased, but in extinction, only NA was activated. The data suggest that NA has a role in the reaction to reward-predicting stimuli, which complements that of DA.

Dopamine/adenosine interactions related to locomotion and tremor in animal models: Possible relevance to parkinsonism

Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function.