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

Abstract

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.

Keywords: Addiction; GLP-1RA; Heroin; Liraglutide; Opioids; Rats; Relapse; Self-administration.

Figure 1:. Outline for Experiments 1 and 2.

After jugular catheter implantation surgery, recovery, and habituation, the rats had 11 days of saline or heroin self-administration (SA). On the 12^th day, the rats had a first test day (Test Day 1) to assess cue-induced seeking during extinction and drug-induced reinstatement. After Test Day 1, the rats had 2 weeks of abstinence in their home cage and were treated with the titrated doses of liraglutide or saline. The dose starts at 0.06 mg/kg and goes up every three days until it reaches the maximum (0.6 mg/kg for Experiment 1 and 0.3 mg/kg for Experiment 2). Thereafter, that dose is given for the remaining days of abstinence. After two weeks of abstinence and titrated dosing with liraglutide or saline, the rats received a second test day (Test Day 2) to test the effect of the titrated dose of liraglutide on cue-induced seeking and drug-induced reinstatement of heroin seeking. For Experiment 1, the rats had an additional three days of abstinence and daily saline or 0.3 mg/kg of liraglutide treatment before going through a similarly conducted Test Day 3. Figure created with BioRender.com.

Figure 2:. A. Heroin or Saline Acquisition Over 11 Trials; B. Cue-induced Seeking and Drug-induced Reinstatement Test 1.

A) Acquisition: Mean (+/− SEM) number of infusions/6 hours across 11 daily trials for heroin high drug takers (blue), heroin low drug takers (orange), and saline controls. B) Test Day 1: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 of extinction for heroin high takers (blue), heroin low takers (orange) and saline controls (black). A single iv infusion of heroin was administered at the end of Hour 3. Cue-induced heroin seeking was assessed in Hour 1; Drug-induced reinstatement of heroin seeking was assessed in Hour 4. Symbols denote significance between groups (*=p<0.05 for her/high vs. sal; ^a= p<0.05 for her/low vs. sal; °=p<0.05 for her/high vs. her/low).

Figure 3:. Cue-induced Seeking and Drug-induced Reinstatement After Chronic Liraglutide Titrated to 0.6 mg/kg.

A) Low Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for low heroin takers and saline self-administering controls treated with vehicle (saline) or 0.6 mg/kg liraglutide during abstinence and prior to test. B) High Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for high heroin takers and saline self-administering controls treated with vehicle (saline) or 0.6 mg/kg liraglutide during abstinence and prior to test (*=p<0.05 for her/veh vs. sal/veh; ª=p<0.05 for her/lir vs. sal/lir).

Figure 4:. Cue-induced Seeking and Drug-induced Reinstatement after 3 days of Vehicle or 0.3 mg/kg Liraglutide Treatment.

A) Low Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for low heroin takers and saline self-administering controls treated with vehicle (saline) or 0.3 mg/kg liraglutide during 3 days of abstinence and 6 h prior to test. B) High Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for high heroin takers and saline self-administering controls treated with vehicle (saline) or 0.3 mg/kg liraglutide during 3 days of abstinence and 6 h prior to test. Symbols denote significance between groups (*=p<0.05 for her/veh vs. sal/veh; °=p<0.05 for her/veh high (or low) vs. her/lir high (or low)).

Figure 5:. A. Heroin or Saline Acquisition Over 11 Trials; B. Cue-induced Seeking and Drug-induced Reinstatement Test 1 for Experiment 2.

A) Acquisition: Mean (+/− SEM) number of infusions/6 hours across 11 daily trials for heroin high drug takers (blue), heroin low drug takers (orange), and saline controls. B) Test Day 1: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 of extinction for heroin high takers (blue), heroin low takers (orange) and saline controls (black). A single iv infusion of heroin was administered at the end of Hour 3. Cue-induced heroin seeking was assessed in Hour 1; Drug-induced reinstatement of heroin seeking was assessed in Hour 4. Symbols denote significance between groups (*=p<0.05 for her/high vs. sal; ^a= p<0.05 for her/low vs. sal; °=p<0.05 for her/high vs. her/low).

Figure 6:. Cue-induced Seeking and Drug-induced Reinstatement After Chronic Liraglutide Titrated to 0.3 mg/kg.

A) Low Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for low heroin takers and saline self-administering controls treated with vehicle (saline) or 0.3 mg/kg liraglutide during abstinence and prior to test. B) High Drug Takers: Mean (+/− SEM) number of infusion attempts across Hours 1 – 4 for high heroin takers and saline self-administering controls treated with vehicle (saline) or 0.3 mg/kg liraglutide during 3 days of abstinence and prior to test (*=p<0.05 for her/veh vs. sal/veh; °=p<0.05 for her/veh high (or low) vs. her/lir high (or low); ª=p<0.05 for her/lir vs. sal/lir).

Figure 7:. Glucose and Insulin Levels After Liraglutide Treatment.

There is no significant decrease or increase in (A) glucose, (B) insulin, (C) total glucose (p=0.324 one-way repeated measures ANOVA), and (D) total insulin levels (p=0.431 one-way repeated measures ANOVA) following the administration of a range of doses of liraglutide (0.06, 0.1, 0.3, 0.6, and 1.0 mg/kg). AUC = Area Under the Curve.