The GPR88 Agonist RTI-122 Reduces Alcohol-Related Motivation and Consumption

Abstract

GPR88, an orphan G protein-coupled receptor primarily expressed in the striatum, has emerged as a potential target for treating alcohol use disorder (AUD) due to its role in modulating reward and motivational pathways. In this study, we investigated the effects of the GPR88 agonist RTI-122 on alcohol intake and motivation to self-administer alcohol under different conditions. In mice, RTI-122 reduced alcohol consumption in a two-bottle choice paradigm, which was prevented by Gpr88 knockout, confirming a GPR88-specific effect on the attenuation of alcohol drinking. In rats, RTI-122 dose-dependently reduced operant alcohol self-administration and decreased motivation to self-administer alcohol in progressive ratio tasks, regardless of whether the alcohol was adulterated with quinine or not. Additionally, a high dose of RTI-122 reduced yohimbine-induced reinstatement. Importantly, RTI-122 did not affect water intake in mice or sucrose self-administration in rats, indicating receptor- and reward-specific modulation of alcohol intake. These findings suggest that RTI-122, through GPR88 agonism, effectively reduces alcohol consumption and motivation across various contexts, positioning it as a promising lead for the development of new AUD treatments.

FIGURE 1

RTI‐122 dose‐dependently reduced spontaneous locomotor activity in WT male mice. (A) Total distance travelled during the first 0–20 min, (B) during 20‐ to 40‐min time periods and (C) during 40‐ to 60‐min time periods of the test. Four doses of RTI‐122 were tested (2.5, 5, 10 and 20 mg/kg). RTI‐122 at 20 mg/kg strongly reduced spontaneous locomotion during the first 0–20 min (A) and 20–40 min (B) periods. RTI‐122 at 10 mg/kg reduced spontaneous locomotion transiently during the first time period (A). The 2.5 and 5 mg/kg doses of RTI‐122 do not alter spontaneous locomotion. Importantly, after 40 min, RTI‐122 does not show any effect on spontaneous locomotion (C). Data are presented as average of total distance ± S.E.M. Vehicle vs. RTI‐122 *p < 0.05, **p < 0.01 and ***p < 0.001, n = 12/group.

FIGURE 2

RTI‐122 reduced alcohol consumption in the two‐bottle choice test. Gpr88 knockout (Gpr88 KO) and control (Gpr88 WT) mice underwent the IA20%‐2bc procedure for 6 weeks. On test days, male (A–D) and female (E–H) mice received either vehicle or RTI‐122 at doses of 10 mg/kg (males: A–B; females: E–F) or 20 mg/kg (males: C–D; females: G–H), administered 60 min prior to the start of the 24‐h session. Alcohol intake was measured at 4 and 24 h. Data are presented as mean ± S.E.M. A–B, n = 31–37; C–D, n = 18–21; E–F, n = 6–9 G–H, n = 13–15. Treatment effect: *p < 0.05; **p < 0.01; genotype effect: ##p < 0.01, ###p < 0.001.

FIGURE 3

RTI‐122 reduced alcohol, but not sucrose, self‐administration. Doses of 5 and 10 mg/kg RTI‐122 reduced alcohol lever responses in 30‐min self‐administration sessions (A) and when data were split into 5‐min bins (B). The highest dose reduced locomotor rate during the session (C). RTI‐122 had no effects on sucrose self‐administration (D&E) and again the 10 mg/kg dose reduced locomotor rate (F). Males, n = 13; females, n = 8. *effect of treatment, ^effect of sex: p < 0.05.

FIGURE 4

RTI‐122 reduced breakpoint in both unadulterated and quinine adulterated alcohol. The 5 and 10 mg/kg doses of RTI‐122 significantly reduced break point (A) and total intake (B) in progressive ratio self‐administration sessions while also reducing locomotor rate at all doses tested (C). When alcohol was adulterated with quinine, the 5 mg/kg dose reduced break point (D). A significant interaction found that intake was reduced specifically in females (E). Locomotor activity was again generally reduced by RTI‐122 (F). Males, n = 13; females, n = 12. *effect of treatment, ^effect of sex: p < 0.05.

FIGURE 5

RTI‐122 reduced seeking and reinitiation of drinking in a two‐phase yohimbine‐induced reinstatement test. The 20 mg/kg dose of RTI‐122 reduced lever responses in the 15‐min seeking phase of the reinstatement test, akin to a traditional reinstatement test (A, middle panel). In the immediately subsequent 15‐min reinitiation of drinking phase where lever responding was reinforced, both the 10 and 20 mg/kg doses reduced lever responses (A, right panel). Locomotor rates were also reduced in the seeking phase (B, left panel) but not in the reinitiation phase (B, right panel). Males, n = 13; females, n = 12. *effect of treatment, #effect of dose in males, ! effect of dose in females, ^effect of sex: p < 0.05.