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

Abstract

AbstractBackgroundStudies have shown that ‘satiety’ agents such as exendin-4 (a glucagon-like peptide-1 analog) reduce responding for addictive drugs (e.g., cocaine, nicotine, alcohol). In this study we tested the effect of exendin-4 on cue-induced and drug-induced reinstatement of heroin seeking behavior in rats.MethodsThis study consisted of three phases: In Phase 1, 55 male Sprague-Dawley rats had 15 daily pairings of saccharin with heroin self-administration. In Phase 2, rats experienced a 16-day home cage abstinence period and daily treatment with vehicle or exendin-4. On day 17, an extinction/reinstatement test was performed to assess drug seeking. In Phase 3, rats experienced 9 days of extinction followed by a reinstatement only test. Finally, expression of mRNA for various receptors in the nucleus accumbens shell (NAcS) was measured using RTqPCR.ResultsIn Phase 1, rats that avoided intake of the heroin-paired saccharin cue exhibited shorter latency to obtain the first infusion. In Phase 2, treatment with exendin-4 decreased cue-induced, but not drug-induced heroin seeking. In Phase 3, saccharin avoiders previously treated with exendin-4 increased acceptance of saccharin, and 1-hour pretreatment with Exendin-4 abolished drug-induced heroin seeking. Finally, exendin-4 treatment increased expression of mRNA for the Orexin 1 receptor (OX1) in the NAcS, but did not affect expression of dopamine D2 receptors, GLP-1 receptors, or leptin receptors in this same structure.ConclusionExendin-4 reduced cue- and drug-induced heroin seeking and increased acceptance of the drug-associated saccharin cue. These changes in behavior were accompanied by an increase in the expression of the OX1 receptor in the NAcS.