Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse

Abstract

Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.

Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects

“… 110 Several non‐peptide small molecules, including JMV2959, AZ‐GHS‐38, JMV 3002, and others were under investigation for obesity in the preclinical development phases. 92 , 111 Current investigations are focused on peptide‐based molecules such as liver‐expressed antimicrobial peptide 2 (LEAP2), initially described by their antimicrobial properties, but recently recognized as an inverse GHSR agonist and a reversible ghrelin antagonist. 112 Given that LEAP2 opposes ghrelin, there is optimism that increasing the LEAP‐2/ghrelin ratio could be an effective approach to combat obesity.…”

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

“…JMV2959 pretreatement significantly attenuated ongoing fentanyl self-administration, and also reduced fentanyl-seeking/relapse-like behavior tested in rats tested on the 12th day of the forced abstinence period [ 206 ]. A recent study that used a modification of the rat CPP test indicated that GHS-R1A antagonism might effectively prevent the morphine-induced memory reconsolidation and the relapse-like behavior [ 209 ]. One day after the last drug conditioning, a high JMV2959 dose (6 mg/kg) was administered immediately after the rat re-exposure to the morphine-paired chamber (drug-memory reactivation) and the CPP was retested 1 day and 7 days after the memory reactivation.…”