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

Jenni Kononoff, Marsida Kallupi, Adam Kimbrough, Dana Conlisk, Giordano de Guglielmo, Olivier George
eNeuro. 2018-05-01; 5(3): ENEURO.0153-18.2018
DOI: 10.1523/ENEURO.0153-18.2018

PubMed
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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.

 

Auteurs Bordeaux Neurocampus