Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats

Abstract

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.

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

“…Similarly, specific expression of GPR139 was observed, in agreement with rat and human expression patterns ( Liu et al, 2015 ) (75th and 168th most specific gene the lateral and medial habenula, respectively). A recent study demonstrated that activation of GPR139 reduces alcohol intake in alcohol-dependent rats ( Kononoff et al, 2018 ). Transient Receptor Potential Cation Channel Subfamily M Member 8 ( TRPM8 ), was highly expressed in both the lateral and medial habenula (ranked 3rd and 8th in the medial and lateral divisions, respectively).…”

Depletion of the Microbiome Alters the Recruitment of Neuronal Ensembles of Oxycodone Intoxication and Withdrawal

“…Mechanical nociception, reflected by hindpaw withdrawal thresholds, was determined by an observer who was blind to the experimental groups using von Frey filaments that ranged from 3.63 to 281.838 g as previously reported (Dixon, 1965;Kononoff et al, 2018). A test session began after 10 min of habituation to the testing environment immediately following the subcutaneous injection of naloxone (WD, WD1ABX, and SAL groups) or saline (OXY and OXY1ABX groups).…”

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies

“…Glutamatergic neurotransmission and hyperexcitability of the LHb is manifest during withdrawal, and this process appears to be driven by enhanced functions of TRPV1 vanilloid receptors (Gregor et al, ) and suppression of M‐type potassium channels (Kang et al, ). One viable therapeutic target in the LHb‐mediating AUD symptoms is the orphan G protein–coupled receptor GPR139 (Kononoff et al, ). Antagonism of GPR139 with JNJ‐63533054 reduced both escalated drinking and hyperalgesia symptoms in alcohol‐dependent rats.…”