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

GPR139 receptor agonist JNJ-63533054 reverses the escalation of alcohol self-administration in alcohol-dependent rats, with no effect in nondependent rats. A, Rats in the alcohol-dependent group were made dependent by chronic intermittent alcohol vapor exposure. Once the animals were made alcohol-dependent and escalated their alcohol intake [****p < 0.0001, pre-vapor baseline (BSL) vs escalated baseline (ESC)], the effect of JNJ-63533054 on alcohol self-administration was evaluated using a within-subjects design (n = 17). One hour before the session, the rats were orally administered a single dose of JNJ-63533054. JNJ-63533054 significantly reduced alcohol self-administration at a dose of 30 mg/kg (**p < 0.05). Water intake was unaffected by JNJ-63533054 treatment. B, The median number of reinforced responses for alcohol in alcohol-dependent rats was 50 after escalation. C, Once a stable baseline of alcohol intake was reached (±10% over the last three sessions), the effect of JNJ-63533054 on alcohol intake was tested in nondependent rats. One hour before the session, the rats were orally administered a single dose of JNJ-63533054 in a within-subjects design (n = 12). JNJ-63533054 did not significantly affect alcohol self-administration in nondependent rats. Water self-administration was unaffected by JNJ-63533054 treatment. D, The effect of JNJ-63533054 (30 mg/kg, p.o.) on 0.04% (w/v) saccharin self-administration was tested in a separate cohort of rats that were made alcohol dependent by chronic intermittent alcohol vapor exposure. Both saccharin and water self-administration was unaffected by vapor exposure or JNJ-63533054.

GPR139 agonist decreases withdrawal-induced hyperalgesia without affecting somatic signs of withdrawal. A, JNJ-63533054 (30 mg/kg, p.o.) increased paw withdrawal thresholds compared with vehicle-treated rats in the mechanical nociceptive von Frey test (**p < 0.05), indicating an increase in pain thresholds during alcohol withdrawal. B, JNJ-63533054 did not affect the number of somatic signs of alcohol withdrawal; n = 8–9/group. VLR: ventromedial limb retraction, VOC: vocalization, TR: tail rigidity, AG: abnormal gait, and BT: body tremors.

Dependent rats that exhibit high alcohol drinking exhibit high compulsive-like alcohol drinking. A, Two distinct subgroups of rats in the alcohol-dependent group were identified according to the median of 50 alcohol-reinforced responses during baseline alcohol self-administration after escalation. Baseline alcohol intake was significantly higher in high-compulsive rats compared with low-compulsive rats (***p < 0.001, n = 8–9). B, To further test the compulsivity of alcohol intake, the rats in the low- and high-compulsive subgroups underwent the quinine adulteration test. The rats were subjected to operant alcohol self-administration sessions with increasing concentrations of quinine that were added to the alcohol solution. The data are expressed as the percentage change relative to the escalated baseline (i.e., lever presses for alcohol alone before quinine adulteration). High-compulsive rats maintained their alcohol drinking despite the aversive, bitter taste of quinine in the alcohol solution (i.e., they were high-compulsive alcohol drinkers). Low-compulsive rats decreased their alcohol intake (>20% from baseline) starting with the lowest concentration of quinine (0.005 g/l; i.e., they were low-compulsive), whereas only the highest quinine concentration (0.05 g/l) decreased alcohol intake in high-compulsive rats; #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001, significant difference compared with own baseline; *p < 0.05, ***p < 0.001, significant difference between low-compulsive rats and high-compulsive rats. C, The intake of quinine (0.025 g/l)-adulterated water was not different between low-compulsive and high-compulsive rats.

JNJ-63533054 decreases alcohol intake in high-compulsive alcohol-dependent rats but has no effect on alcohol intake in low-compulsive alcohol-dependent rats. A, Rats in the high-compulsive subgroup of alcohol-dependent rats (n = 9) escalated their alcohol intake [****p < 0.0001, pre-vapor baseline (BSL) vs escalated baseline (ESC)]. JNJ-63533054 (30 mg/kg, p.o.) significantly decreased alcohol intake in high-compulsive rats (**p < 0.01). Rats in the low-compulsive subgroup escalated their alcohol intake after alcohol vapor exposure (*p < 0.05), but JNJ-63533054 had no effect on alcohol intake in low-compulsive rats (n = 8). B, JNJ-63533054 (30 mg/kg) decreased (>30% reduction) alcohol self-administration in high-compulsive rats (***p < 0.0001) but had no effect in low-compulsive rats.