Over the last decade oxycodone has become one of the most widely abused drugs. The emergence of oxycodone dependence as a serious health crisis has prompted a major need for animal models of oxycodone dependence with face and predictive validity. Oxycodone use in humans is more prevalent in women (Administration, 2014) and leads to pronounced hyperalgesia and irritability. However, it is unclear if the current animal model of oxycodone self-administration recapitulates these characteristics. We assessed the face validity of an extended access oxycodone self-administration model in rats by examining escalation of oxycodone intake and behavioral symptoms of withdrawal including irritability like behavior and mechanical nociception in male and female rats. We found that male and female rats escalated oxycodone intake over the course of 14 self-administration sessions, however, female rats escalated took more drug than male rats once escalated. When we assessed irritability-like behavior we found no differences between baseline or withdrawal, however when tested immediately after a 12-h self-administration session rats showed a decreased number of aggressive responses and a increased number of defensive responses. When tested for mechanical threshold during withdrawal rats showed pronounced hyperalgesia that was only partially reversed by oxycodone self-administration. The results of the present study demonstrate the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and demonstrating pronounced changes to pain and affective states.

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GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior.

Background In humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression-like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests that measure withdrawal in animal models is they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropin-releasing factor (CRF)-CRF1 receptor system has been suggested to be critical for the emergence of anxiety-like behavior in ethanol dependence, but the role of this system in irritability-like behavior has not been characterized. Methods The present study compared the effects of chronic intermittent ethanol vapor exposure (CIE)-induced ethanol dependence on irritability-like behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naive, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 h and 2 weeks into abstinence from ethanol. Separate cohorts of dependent and nondependent rats were used to examine the effect of the specific CRF1 receptor antagonist R121919 on irritability-like behavior. Results Dependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time-points of abstinence, ethanol-dependent rats exhibited increased aggressive-like responses compared with naive and nondependent rats. R121919 reduced irritability-like behavior in both dependent and nondependent rats, but dependent rats were more sensitive to R121919. Conclusions Irritability-like behavior is a clinically relevant and reliable measure of negative emotional states that is partially mediated by activation of the CRF-CRF1 system and remains elevated during protracted abstinence in ethanol-dependent rats.

Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 g/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.