Acute glucagon-like peptide-1 receptor agonist liraglutide prevents cue-, stress-, and drug-induced heroin-seeking in rats.

Substance use disorder is challenging to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there currently are only three effective, yet not ideal, treatments to prevent relapse to opioids. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin, and nicotine when administered over several days or weeks. This may serve as an effective adjuvant during treatment; however, whether it would be effective when used acutely to bridge a patient between cessation of use and onset of medication for the treatment of an opioid addiction is unknown. Here, we tested the acute effects of the longer acting GLP-1 analog, liraglutide, on heroin-seeking. In rats with heroin self-administration experience, we found that subcutaneous administration of an acute dose of 0.3-mg/kg liraglutide was effective in preventing drug-seeking after exposure to three major precipitators: drug-associated cues, stress (yohimbine-induced), and the drug itself. Finally, we confirmed that the reduction in drug-seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, acute use of GLP-1 analogs may serve as a new and effective nonopioid bridge to treatment.

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

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.

Dose titration with the glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats.

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.