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Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin-seeking behavior in rats.

ABSTRACT: Opioid use disorder (OUD) causes the death of nearly 130 Americans daily. It is evident that new avenues for treatment are needed. To this end, studies have reported that 'satiety' agents such as the glucagon-like peptide-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), decreases responding for addictive drugs such as cocaine, nicotine, alcohol, and oxycodone, but no work has been done with heroin. In this study, we used a reward devaluation model in which rats avoid ingesting a saccharin solution that predicts drug availability to test the effects of 2.4 μg/kg Ex-4 on responding for a natural reward cue (i.e., saccharin) and on cue- and drug-induced heroin seeking. The results showed that treatment with Ex-4 during the 16-day abstinence period and on the test day decreased cue-induced heroin seeking. Drug-induced heroin seeking also was reduced by Ex-4, but only when using a 1 h, but not a 6 h, pretreatment time. Treatment with Ex-4 did not alter intake of the saccharin cue when the drug was on board, but a history of treatment with Ex-4 increased acceptance of the saccharin cue in later extinction trials. Finally, treatment with Ex-4 did not alter body weight, but was associated with increased Orexin 1 receptor (OX1) mRNA expression in the nucleus accumbens shell. Taken together, these findings are the first to show that treatment with a GLP-1R agonist can reduce both cue-induced seeking and drug-induced reinstatement of heroin seeking. As such, a GLP-1R agonist may serve as an effective treatment for OUD in humans.

SUBMITTER: Douton JE

PROVIDER: S-EPMC8119287 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.

Project description:Recovery from opioid use disorder (OUD) and maintenance of abstinence from opioid use is hampered by perseverant drug cravings that may persist for months after cessation of drug use. Drug cravings can intensify during the abstinence period, a phenomenon referred to as the 'incubation of craving' that has been well-described in preclinical studies. We previously reported that animals that self-administered heroin at a dosage of 0.075 mg/kg/infusion (HH) paired with discrete drug cues displayed robust incubation of heroin craving behavior after 21 days (D) of forced abstinence, an effect that was not observed with a lower dosage (0.03 mg/kg/infusion; HL). Here, we sought to elucidate molecular mechanisms underlying long-term heroin seeking behavior by profiling microRNA (miRNA) pathways in the orbitofrontal cortex (OFC), a brain region that modulates incubation of heroin seeking. miRNAs are small noncoding RNAs with long half-lives that have emerged as critical regulators of drug seeking behavior but their expression in the OFC has not been examined in any drug exposure paradigm. We employed next generation sequencing to detect OFC miRNAs differentially expressed after 21D of forced abstinence between HH and HL animals, and proteomics analysis to elucidate miRNA-dependent translational neuroadaptations. We identified 55 OFC miRNAs associated with incubation of heroin craving, including miR-485-5p, which was significantly downregulated following 21D forced abstinence in HH but not HL animals. We bidirectionally manipulated miR-485-5p in the OFC to demonstrate that miR-485-5p can regulate long-lasting heroin seeking behavior after extended forced abstinence. Proteomics analysis identified 45 proteins selectively regulated in the OFC of HH but not HL animals that underwent 21D forced abstinence, of which 7 were putative miR-485-5p target genes. Thus, the miR-485-5p pathway is dysregulated in animals with a phenotype of persistent heroin craving behavior and OFC miR-485-5p pathways may function to support long-lasting heroin seeking.

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Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin-seeking behavior in rats.

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