Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats

Abstract

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The "hunger hormone" ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs.

Keywords: Sprague-Dawley rat; cocaine; cue-reinforced drug seeking; growth hormone secretagogue receptor 1α (GHS1αR); oxycodone; self-administration.

FIGURE 1

JMV2959 does not alter cocaine intake (within-subjects, n = 7). (A) JMV2959 (0.5, 1, 2 mg/kg) does not reduce the total number of active (mean ± SEM/60 min) or inactive lever presses (mean ± SEM/60 min). (B) JMV2959 (0.5, 1, 2 mg/kg) failed to reduce the total number of cocaine infusions (mean ± SEM/60 min) relative to vehicle. (C) Latency to the first response is not significantly altered by JMV2959. All datapoints represent n = 7 rats (denoted by circles/squares) in a within-subjects design.

FIGURE 2

JMV2959 suppresses cue-reinforced cocaine-seeking (between-subjects, n = 5–6/treatment). (A) JMV2959 (2 mg/kg) decreases total number of previously active (circles), but not inactive lever presses (squares) assessed in the 60-min test session (mean ± SEM/60 min). (B) Latency to the first response is not significantly altered by JMV2959. *p < 0.05 vs. vehicle. All datapoints represent n = 17 rats (denoted by circles/squares) in a between-subjects design.

FIGURE 3

JMV2959 does not alter oxycodone intake (within-subjects, n = 10). (A) The total number of active (circles; mean ± SEM/180 min) and not inactive lever presses (squares; mean ± SEM/180 min) are presented. (B) JMV2959 (0.5, 1, 2 mg/kg) does not impact the total number of oxycodone infusions (mean ± SEM/180 min) relative to vehicle. (C) Latency to the first response is significantly increased by the highest dose of JMV2959 (2 mg/kg). *p < 0.05 vs. vehicle. All datapoints represent n = 10 rats (denoted by circles/squares) in a within-subjects design.

FIGURE 4

JMV2959 suppresses cue-reinforced oxycodone-seeking (between-subjects, n = 6/treatment). (A) JMV2959 (1 and 2 mg/kg) decreases total number of previously active lever presses (circles), but not inactive lever presses (squares) assessed in the 60-min test session (mean ± SEM/60 min). (B) Latency to the first response is not significantly altered by JMV2959. All datapoints represent n = 18 rats (denoted by circles/squares) in a between-subjects design. *p < 0.05 vs. vehicle.