We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.

The nucleus accumbens (NAc) has been implicated in mediating different forms of decision making in humans and animals. In the present study, we observed that inactivation of the rat NAc, via infusion of GABA agonists, reduced preference for a large/risky option and increased response latencies on a probabilistic discounting task. Discrete inactivations of the NAc shell and core revealed further differences between these regions in mediating choice and response latencies, respectively. The effect on choice was attributable to reduced win-stay performance (i.e., choosing risky after a being rewarded for a risky choice on a preceding trial). Moreover, NAc inactivation altered choice only when the large/risky option had greater long-term value, in terms of the amount of food that could be obtained over multiple trials relative to the small/certain option. Inactivation of the NAc or the shell subregion also slightly reduced preference for larger rewards on a reward magnitude discrimination. Thus, the NAc seems to play a small role in biasing choice toward larger rewards, but its contribution to behavior is amplified when delivery of these rewards is uncertain, helping to direct response selection toward more favorable outcomes.

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.

Phasic increases and decreases in dopamine (DA) transmission encode reward prediction errors thought to facilitate reward-related learning, yet how these signals guide action selection in more complex situations requiring evaluation of different reward remains unclear. We manipulated phasic DA signals while rats performed a risk/reward decision-making task, using temporally discrete stimulation of either the lateral habenula (LHb) or rostromedial tegmental nucleus (RMTg) to suppress DA bursts (confirmed with neurophysiological studies) or the ventral tegmental area (VTA) to override phasic dips. When rats chose between small/certain and larger/risky rewards, LHb or RMTg stimulation, time-locked to delivery of one of these rewards, redirected bias toward the alternative option, whereas VTA stimulation after non rewarded choices increased risky choice. LHb stimulation prior to choices shifted bias away from more preferred options. Thus, phasic DA signals provide feedback on whether recent actions were rewarded to update decision policies and direct actions toward more desirable reward.

Choosing between smaller, assured rewards or larger, uncertain ones requires reconciliation of competing biases towards 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 towards 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.

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 A 2A receptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A 2A receptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5Ј-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A 2A 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 A 2A receptors immunoreactivity. Moreover, activation of accumbens A 2A 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 GABA A 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 A 2A 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.

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/smaller rewards of equal cost. Thus, instead of serving as an aversion center, the evolutionarily-conserved LHb acts as preference center integral for expressing subjective decision biases.

No abstract