For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food, as well as drugs of abuse. Yet, several fundamental aspects of primary food reinforcement, motivation, and appetite are left intact after interference with accumbens DA transmission. Recent studies have shown that accumbens DA is involved in responsiveness to conditioned stimuli and activational aspects of motivation. In concurrent choice tasks, accumbens DA depletions cause animals to reallocate their choice behavior in the direction of instrumental behaviors that involve less effort. Also, an emerging body of evidence has demonstrated that the effects of accumbens DA depletions on instrumental food-seeking behavior can vary greatly depending upon the task. For example, some schedules of reinforcement are insensitive to the effects of DA depletions, whereas others are highly sensitive (e.g., large fixed ratios). Accumbens DA depletions slow the rate of operant responding, blunt the rate-facilitating effects of moderate-sized ratios, and enhance the rate-suppressing effects of very large ratios (i.e., produce ratio strain). Accumbens DA may be important for enabling rats to overcome behavioral constraints, such as work-related response costs, and may be critical for the behavioral organization and conditioning processes that enable animals to engage in vigorous responses, such as barrier climbing, or to emit large numbers of responses in ratio schedules in the absence of primary reinforcement. The involvement of accumbens DA in activational aspects of motivation has implications for energy-related disorders in psychiatry, as well as aspects of drug-seeking behavior.

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. inter-response 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.

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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.

Previous research suggests that cocaine dysregulates dopamine D 3 receptors. The present study examined the time course of changes in dopamine D 3 receptor binding after terminating a cocaine self-administration regimen.-tetralin was used to label dopamine D 3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31-32 days after their last cocaine self-administration session. The results indicated a timedependent increase in D 3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D 3 receptor binding in cocaine-experienced rats killed at the 2-or 8-day time points relative to controls, but there was an increase in D 3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31-to 32-day time point. In a subsequent experiment, we replicated the increase in D 3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D 3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.