The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models

Abstract

Rationale: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

Objectives: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

Results: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

Conclusion: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

Keywords: Agonist; Alcohol; Elevated plus-maze; Nociception/orphanin FQ; Operant; Reinstatement; Wistar rat.

Fig. 1

Behavioral screening for effective dose using the elevated plus-maze (a) and testing for reversal of alcohol-induced hangover anxiety (b). a Pre-treatment with SR-8993 at a dose of 1 mg/kg bodyweight had a pronounced anxiolytic-like effect on the elevated plus-maze during baseline, non-stressful conditions. Data presented is percent time spent on the open arm out of time spent on any arm (100 % × (open/(open + closed)). b The same dose was effective in reversing the anxiogenic effects of an acute administration of a high dose of alcohol. Withdrawal anxiety was induced by an acute administration of alcohol (i.p., 3.5 g/kg) at 12 h prior to testing using the elevated plus-maze, and the pre-treatment with SR 8993 (1 mg/kg) was administered 45 min prior to plus-maze exposure. Data presented is percent time spent on the open arm out of time spent on any arm (100 % × (open/(open + closed)) as well as the number of closed arm entries, a measure of locomotor activity. All values are given as mean ± SEM. a * p < 0.05 vs. vehicle, ** p < 0.01 vs. vehicle. b * p < 0.05 vs. vehicle, ## p < 0.01 vs. non-alcohol control, ** p = 0.01 vs. withdrawal

Fig. 2

Alcohol intake (a) but not water intake (b) in a non-operant, two-bottle choice—paradigm was significantly attenuated by pre-treatment with SR-8993. Animals were given access to two bottles, one with alcohol solution and one with water, for 4 h starting 1 h into the dark phase. Measures are shown as intake at 90 min, intake between minute 90 and minute 240, and total intake during the session. a Alcohol intake was significantly suppressed at all timepoints examined. b Water intake (ml/kg bodyweight) was not affected by pre-treatment with SR-8993 at any timepoint. All values are given as mean ± SEM. ** p < 0.01 vs. vehicle, *** p < 0.001 vs. vehicle

Fig. 3

SR-8993 suppresses alcohol self-administration (a), decreases motivation to work for alcohol (b), and prevents both cue- (c) and stress-induced relapse-like behavior (d). a Operant self-administration of alcohol (10 % v/v) was significantly attenuated by pre-treatment with 1 and 3 mg/kg SR-8993. b Pre-treatment with SR-8993, significantly decreased motivation to work for alcohol delivery as measured using progressive-ratio responding. Breakpoint is defined as the highest number of lever presses the animals performed to receive one dose of alcohol in the drinking cup. c Exposure to alcohol-associated cues (light/orange odor) induced reinstatement of lever pressing at the lever previously paired with alcohol delivery (extinction vs. vehicle bars). Pre-treatment with SR-8993 (1 mg/kg) completely blocked this cue-induced reinstatement (vehicle vs. 1.0 mg/kg bars). d Similar to what was observed for cue-induced reinstatement, yohimbine-induced reinstatement was blocked by pre-treatment with SR-8993. All values are given as mean ± SEM. ** p < 0.01 vs. vehicle, *** p < 0.001 vs. vehicle

Fig. 4

Effects of SR-8993 on alcohol intake (a) and operant responding (b) in animals with escalated alcohol consumption. Animals were allowed intermittent (24 h, three times per week) access to 20 % alcohol for 15 weeks. a During the intermittent access to 20 % alcohol, SR-8993 at 1 and 3 mg/kg significantly attenuated consumption over the 24 h time period. b In operant self-administration, a significant escalation of responding from baseline prior to intermittent access to re-training after the intermittent access paradigm was seen (baseline vs. vehicle bars). Pre-treatment with SR-8993 (1 mg/kg) significantly attenuated responding. Baseline indicates responding prior to 15 weeks of intermittent access to 20 % alcohol. The line indicating “Escalation” points to responding after intermittent access following either vehicle or SR-8993 (1 mg/kg) treatment. All values are given as mean ± SEM. a *** p < 0.001 vs. vehicle, b ### p < 0.001 vs. extinction, *** p = 0.01 vs. vehicle