Glucagon-Like Peptide-1 Receptor Agonist Treatment Does Not Reduce Abuse-Related Effects of Opioid Drugs

Abstract

Dependence on opioids and the number of opioid overdose deaths are serious and escalating public health problems, but medication-assisted treatments for opioid addiction remain inadequate for many patients. Glucagon-like pepide-1 (GLP-1) is a gut hormone and neuropeptide with actions in peripheral tissues and in the brain, including regulation of blood glucose and food intake. GLP-1 analogs, which are approved diabetes medications, can reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine, and nicotine in rodents. Investigations on effects of GLP-1 analogs on opioid reward and reinforcement have not been reported. We assessed the effects of the GLP-1 receptor agonist Exendin-4 (Ex4) on opioid-related behaviors in male mice, i.e., morphine-conditioned place preference (CPP), intravenous self-administration (IVSA) of the short-acting synthetic opioid remifentanil, naltrexone-precipitated morphine withdrawal, morphine analgesia (male and female mice), and locomotor activity. Ex4 treatment had no effect on morphine-induced CPP, withdrawal, or hyperlocomotion. Ex4 failed to decrease remifentanil self-administration, if anything reinforcing effects of remifentanil appeared increased in Ex4-treated mice relative to saline. Ex4 did not significantly affect analgesia. In contrast, Ex4 dose dependently decreased oral alcohol self-administration, and suppressed spontaneous locomotor activity. Taken together, Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction. This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central stimulants, and nicotine.

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

“…Several recent studies in rodents have highlighted the role of the GLP-1 system in regulating addictive behaviors related to different drugs of abuse, including nicotine, cocaine, opioids, and alcohol, suggesting a new and promising pharmacotherapeutic target for drug addiction ( Egecioglu et al, 2013a , b ; Graham et al, 2013 ; Shirazi et al, 2013 ; Harasta et al, 2015 ; Suchankova et al, 2015 ; Sørensen et al, 2015 ; Sirohi et al, 2016 ; Vallöf et al, 2016 , 2019b , 2020 ; Fortin and Roitman, 2017 ; Tuesta et al, 2017 ; Bornebusch et al, 2019 ; Zhang et al, 2020 ). Here, we described, for the first time, that liraglutide and semaglutide had similar transient inhibitory effects on EtOH intake, but different effects on EtOH preference.…”

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

“…Exogenous treatment with Ex-4 also has been observed to reduce conditioned place preference (CPP) and accumbens dopamine release by nicotine, cocaine and amphetamine; and to reduce cocaine self-administration and seeking in rats [44][45][46][47][48][49] and relapse-like drinking in mice [50]. Thus far, only one study investigated the effect of GLP-1R agonists on opioid addiction [51], finding Ex-4 not to be effective in reducing abuse-related effects of the opioid remifentanil in mice.…”

Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol

“…Among the drugs of abuse that have been studied, cocaine (Egecioglu et al, 2013b ; Graham et al, 2013 ; Harasta et al, 2015 ; Sørensen et al, 2015 ; Reddy et al, 2016 ; Schmidt et al, 2016 ; Sirohi et al, 2016 ; Fortin and Roitman, 2017 ; Hernandez et al, 2018 , 2019 ; Bornebusch et al, 2019 ; You et al, 2019 ; Łupina et al, 2020 ), amphetamine (Lautar et al, 2005 ; Erreger et al, 2012 ; Egecioglu et al, 2013b ; Sirohi et al, 2016 ), opioids (Bornebusch et al, 2019 ; Łupina et al, 2020 ; Zhang et al, 2020 ), alcohol (Egecioglu et al, 2013c ; Shirazi et al, 2013 ; Sirohi et al, 2016 ; Sørensen et al, 2016 ; Vallöf et al, 2016 , 2019a , b , 2020 ; Thomsen et al, 2017 , 2019 ; Abtahi et al, 2018 ; Dixon et al, 2020 ), and nicotine (Egecioglu et al, 2013a ; Tuesta et al, 2017 ) were found. All preclinical studies that assessed the association between GLP-1 and drugs of abuse are presented in Supplementary Table 2 .…”

“…Contrary to this finding, in mice, Ex-4 did not impact morphine-induced CPP, morphine withdrawal, or hyperlocomotion. Ex-4 also did not reduce remifentanil (a synthetic opioid) self-administration (Bornebusch et al, 2019 ). However, both systematic and intra-NAc shell Ex-4 successfully decreased oxycodone self-administration and cue priming-induced reinstatement of oxycodone seeking-behavior in mice without causing adverse feeding behaviors or changing analgesic effects of oxycodone (Zhang et al, 2020 ).…”

“…In rats, Ex-4 successfully reduced ethanol intake dose-dependently and reduced spontaneous locomotion (Bornebusch et al, 2019 ). Ex-4 reduced alcohol intake and alcohol-seeking behavior in rats after 8 months of alcohol use (Egecioglu et al, 2013c ).…”