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 cueinduced seeking and drug-induced reinstatement of heroin seeking. As such, a GLP-1R agonist may serve as an effective treatment for OUD in humans. Behavioural

Background

Protamine stimulates guinea-mesenteric mast cells in a concentration-dependent manner, both histamine release and mast cell degranulation being correlated. Mast cell stimulation is blocked by 2,4-DNP (0.03 mM), low (0 degrees C) and high (45 degrees C) temperature. The inhibitory effect by 2,4-DNP is reversed by glucose (5.0 mM), while incubation at 37 degrees reverses that by low and high temperature. Lack of calcium from the incubation medium does not influence mast cell stimulation by protamine. However calcium chelation with EDTA (2.0 mM) or EGTA (2.0 mM) blocks mast cell stimulation. Addition of calcium (0.9 mM) reverses this inhibition. These observations indicate that guinea-pig mast cell stimulation by protamine is a nonlytic, energy and calcium dependent process, similar to anaphylaxis, but different from that of other basic compounds which induce mast cell lysis.