Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats.

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.

Selective involvement by the medial orbitofrontal cortex in biasing risky, but not impulsive, choice.

Separate regions of the orbitofrontal cortex (OFC) have been implicated in mediating different aspects of cost-benefit decision-making in humans and animals. Anatomical and functional imaging studies indicate that the medial (mOFC) and lateral OFC may subserve dissociable functions related to reward and decision-making processes, yet the majority of studies in rodents have focused on the lateral OFC. The present study investigated the contribution of the rat mOFC to risk and delay-based decision-making, assessed with probabilistic and delay-discounting tasks. In well-trained rats, reversible inactivation of the mOFC increase a risky choice on the probabilistic discounting task, irrespective of whether the odds of obtaining a larger/risky reward decreased (100-12.5%) or increased (12.5-100%) over the course of a session. The increase in risky choice was associated with enhanced win-stay behavior, wherein rats showed an increased tendency to choose the risky option after being rewarded for the risky choice on a preceding trial. In contrast, mOFC inactivation did not alter delay discounting. These findings suggest that the mOFC plays a selective role in decisions involving reward uncertainty, mitigating the impact that larger, probabilistic rewards exert on subsequent choice behavior. This function may promote the exploration of novel options when reward contingencies change.

Separate prefrontal-subcortical circuits mediate different components of risk-based decision making.

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.

Contributions of the nucleus accumbens and its subregions to different aspects of risk-based decision making.

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.

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 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-5'-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.

Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats.

BACKGROUND: The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state. METHODS: Rats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed for a number of other DSM-5-relevant addiction criteria following differential access conditions. Orexin system function was assessed by quantification of numbers and activity of orexin cells, pharmacological blockade of the orexin-1 receptor, and subregion-specific knockdown of orexin cell populations. RESULTS: IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than long access or short access. IntA was accompanied by an increase in number and activity of orexin-expressing neurons within the lateral hypothalamic subregion. This increase in orexin cell number and activity persisted during protracted withdrawal from cocaine for at least 150 days and was accompanied by enhanced incubation of craving in the same rats. Selective knockdown of lateral hypothalamic orexin neurons reduced motivation for cocaine, and orexin-1 receptor signaling played a larger role in drug seeking after IntA. CONCLUSIONS: 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.

Dopaminergic circuitry and risk/reward decision making: implications for schizophrenia.

Abnormal reinforcement learning and representations of reward value are present in schizophrenia, and these impairments can manifest as deficits in risk/reward decision making. These abnormalities may be due in part to dopaminergic dysfunction within cortico-limbic-striatal circuitry. Evidence from studies with laboratory animal have revealed that normal DA activity within different nodes of these circuits is critical for mediating dissociable processes that can refine decision biases. Moreover, both phasic and tonic dopamine transmission appear to play separate yet complementary roles in these processes. Tonic dopamine release within the prefrontal cortex and nucleus accumbens, serves as a "running rate-meter" of reward and reflects contextual information such as reward uncertainty and overt choice behavior. On the other hand, manipulations of outcome-related phasic dopamine bursts and dips suggest these signals provide rapid feedback to allow for quick adjustments in choice as reward contingencies change. The lateral habenula is a key input to the DA system that phasic signals is necessary for expressing subjective decision biases; as suppression of activity within this nucleus leads to catastrophic impairments in decision making and random patterns of choice behavior. As schizophrenia is characterized by impairments in using positive and negative feedback to appropriately guide decision making, these findings suggest that these deficits in these processes may be mediated, at least in part, by abnormalities in both tonic and phasic dopamine transmission.

Noradrenergic modulation of risk/reward decision making.

RATIONALE: Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. OBJECTIVES: The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. METHODS: We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 µg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. RESULTS: In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. CONCLUSIONS: These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

What's better for me? Fundamental role for lateral habenula in promoting subjective decision biases.

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.

Overriding phasic dopamine signals redirects action selection during risk/reward decision making.

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.

Receptor-specific modulation of risk-based decision making by nucleus accumbens dopamine.

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.

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists.

RATIONALE: Adenosine A(2A) antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. OBJECTIVE: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. METHODS: Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A(1) antagonists (DPCPX and CPT), and two adenosine A(2A) antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. RESULTS: Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A(2A) antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A(1) antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. CONCLUSIONS: These results suggest that adenosine A(2A) antagonists enhance operant response rates, but A(1) antagonists do not. The involvement of adenosine A(2A) receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.