Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue-induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil.

Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of orexin-1 receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

The role of orexin-1 receptor signaling in demand for the opioid fentanyl.

The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Qo (drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α) for fentanyl without affecting Qo. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.

Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement.

Psychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. It has recently been appreciated that reinforcement may be separated into consummatory (hedonic), motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, motivation to avoid or escape foot shock or to acquire sucrose was not altered by mTBI. Our results suggest that individuals experiencing mTBI find avoidance of aversive events less reinforcing, and therefore are less apt to utilize proactive control of stress.

Corrigendum: Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement.

[This corrects the article on p. 77 in vol. 11, PMID: 28270744.].

Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement.

Abnormal motivation and hedonic assessment of aversive stimuli are symptoms of anxiety and depression. Symptoms influenced by motivation and anhedonia predict treatment success or resistance. Therefore, a translational approach to the study of negatively motivated behaviors is needed. We describe a novel use of behavioral economics demand curve analysis to investigate negative reinforcement in animals that separates hedonic assessment of footshock termination (i.e., relief) from motivation to escape footshock. In outbred Sprague Dawley (SD) rats, relief increased as shock intensity increased. Likewise, motivation to escape footshock increased as shock intensity increased. To demonstrate the applicability to anxiety disorders, hedonic and motivational components of negative reinforcement were investigated in anxiety vulnerable Wistar Kyoto (WKY) rats. WKY rats demonstrated increased motivation for shock cessation with no difference in relief as compared to control SD rats, consistent with a negative bias for motivation in anxiety vulnerability. Moreover, motivation was positively correlated with relief in SD, but not in WKY. This study is the first to assess the hedonic and motivational components of negative reinforcement using behavioral economic analysis. This procedure can be used to investigate positive and negative reinforcement in humans and animals to gain a better understanding of the importance of motivated behavior in stress-related disorders.