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Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long‐ or intermittent access self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking. Because the orexin‐1 receptor antagonist SB‐334867 (SB) is particularly effective at reducing drug‐seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self‐administration ('baseline α') was positively correlated with α assessed after 2w of long‐ or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug‐seeking in initial abstinence and cued reinstatement following long‐, intermittent‐ or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin‐based therapies for the treatment of addiction. [ABSTRACT FROM AUTHOR]

The nucleus accumbens (NAc) serves as an integral node within cortico-limbic circuitry that regulates various forms of cost-benefit decision making. The dopamine (DA) system has also been implicated in enabling organisms to overcome a variety of costs to obtain more valuable rewards. However, it remains unclear how DA activity within the NAc may regulate decision making involving reward uncertainty. This study investigated the contribution of different DA receptor subtypes in the NAc to risk-based decision making, assessed with a probabilistic discounting task. In well-trained rats, D1 receptor blockade with SCH 23 390 decreased preference for larger, uncertain rewards, which was associated with enhanced negative-feedback sensitivity (ie, an increased tendency to select a smaller/certain option after an unrewarded risky choice). Treatment with a D1 agonist (SKF 81 297) optimized decision making, increasing choice of the risky option when reward probability was high, and decreasing preference under low probability conditions. In stark contrast, neither blockade of NAc D2 receptors with eticlopride, nor stimulation of these receptors with quinpirole or bromocriptine influenced risky choice. In comparison, infusion of the D3-preferring agonist PD 128 907 decreased reward sensitivity and risky choice. Collectively, these results show that mesoaccumbens DA refines risk-reward decision biases via dissociable mechanisms recruiting D1 and D3, but not D2 receptors. D1 receptor activity mitigates the effect of reward omissions on subsequent choices to promote selection of reward options that may have greater long-term utility, whereas excessive D3 receptor activity blunts the impact that larger/uncertain rewards have in promoting riskier choices. [ABSTRACT FROM AUTHOR]

Choosing between smaller, assured rewards or larger, uncertain ones requires reconciliation of competing biases toward more certain or riskier options. We used disconnection and neuroanatomical techniques to reveal that separate, yet interconnected, neural pathways linking the medial prefrontal cortex (PFC), the basolateral amygdala (BLA), and nucleus accumbens (NAc) contribute to these different decision biases in rats. Disrupting communication between the BLA and NAc revealed that this subcortical circuit biases choice toward larger, uncertain rewards on a probabilistic discounting task. In contrast, disconnections between the BLA and PFC increased choice of the Large/Risky option. PFC-NAc disconnections did not affect choice but did increase choice latencies and trial omissions. Neuroanatomical studies confirmed that projection pathways carrying axons from BLA-to-PFC transverse a distinctly different route relative to PFC-to-BLA pathways (via the ventrolateral amydalofugal pathway and ventromedial internal capsule, respectively). We exploited these dissociable axonal pathways to selectively disrupt bottom-up and top-down communication between the BLA and PFC. Subsequent disconnection studies revealed that disruption of top-down (but not bottom-up) information transfer between the medial PFC and BLA increased choice of the larger, riskier option, suggesting that this circuit facilitates tracking of actions and outcomes to temper urges for riskier rewards as they become less profitable. These findings provide novel insight into the dynamic competition between these cortical/ subcortical circuits that shape our decision biases and underlie conflicting urges when evaluating options that vary in terms of potential risks and rewards. [ABSTRACT FROM AUTHOR]

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 adenosineA2A 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. [ABSTRACT FROM AUTHOR]

The lateral habenula (LHb) is believed to convey an aversive or 'anti-reward' signal, but its contribution to reward-related action selection is unknown. We found that LHb inactivation abolished choice biases, making rats indifferent when choosing between rewards associated with different subjective costs and magnitudes, but not larger or smaller rewards of equal cost. Thus, instead of serving as an aversion center, the evolutionarily conserved LHb acts as a preference center that is integral for expressing subjective decision biases. [ABSTRACT FROM AUTHOR]