TY - JOUR T1 - Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0153-18.2018 SP - ENEURO.0153-18.2018 AU - Jenni Kononoff AU - Marsida Kallupi AU - Adam Kimbrough AU - Dana Conlisk AU - Giordano de Guglielmo AU - Olivier George Y1 - 2018/06/25 UR - http://www.eneuro.org/content/early/2018/06/25/ENEURO.0153-18.2018.abstract N2 - GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the 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 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.Significance Statement GPR139 has been identified as a receptor with high expression in a key brain region for addiction, the habenula. However, no studies have yet provided causal evidence of the role of GPR139 in brain dysfunction. This study found that GPR139 receptor activation reduced alcohol self-administration in alcohol-dependent rats with compulsive-like drinking and decreased withdrawal-induced hyperalgesia. Importantly, we found that the habenula but not interpeduncular nucleus was a mediator of the observed effects. These results represent an important advance in the field because they are the first to demonstrate a role for GPR139 in addiction-related behaviors. ER -