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Neuropharmacology. 2019 May 15;150:192-199. doi: 10.1016/j.neuropharm.2018.12.023. Epub 2018 Dec 19.

The active heroin metabolite 6-acetylmorphine has robust reinforcing effects as assessed by self-administration in the rat.

Author information

1
Sussex Addiction Research and Intervention Centre (SARIC), School of Psychology, University of Sussex, Brighton, UK.
2
Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway; Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
3
Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway; Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Norway.
4
Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
5
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Norwegian Institute of Public Health, Oslo, Norway.
6
Sussex Addiction Research and Intervention Centre (SARIC), School of Psychology, University of Sussex, Brighton, UK; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. Electronic address: Aldo.Badiani@sussex.ac.uk.
7
Section for Drug Abuse Research, Department of Forensic Sciences, Oslo University Hospital, Norway. Electronic address: fernando.boix.escolan@ous-hf.no.

Abstract

Previous studies have suggested that at least some of the behavioral effects of heroin might be mediated by its active metabolite 6-acetylmorphine (6-AM). The aim of the present study was to investigate the reinforcing effects of 6-AM and its role in mediating those of heroin. We used an intravenous self-administration procedure in male Sprague-Dawley rats including four phases: acquisition, extinction, reinstatement of drug-seeking, and re-acquisition. Independent groups of rats readily learned to self-administer equimolar doses (0.135 μmol/kg) of either 6-AM (44.3 μg/kg) or heroin (50 μg/kg). Under a fixed ratio 1 (FR1) schedule of reinforcement, the rate of responding was the same for 6-AM and heroin, but it was significantly higher for 6-AM than for heroin under a FR2 schedule. A non-contingent infusion ('priming') of 0.068 μmol/kg of either 6-AM or heroin reinstated non-reinforced drug-seeking (relapse). The rats readily re-acquired self-administration behaviour when given access to one of two doses (0.068 and 0.135 μmol/kg) of 6-AM or heroin. Pretreatment with a specific monoclonal antibody (mAb) against 6-AM blocked the priming effect of 6-AM, and modified the rate of lever-pressing on re-acquisition of 6-AM self-administration in a manner compatible with a shift to the right of the dose-effect curve. The mAb did not affect heroin responding. The present results show that 6-AM possesses reinforcing effects similar to those of heroin. The lack of effect of 6-AM mAb on heroin priming and heroin self-administration calls for further studies to clarify the role of heroin and its metabolites in heroin reward. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

KEYWORDS:

6-Acetylmorphine; Heroin; Reinforcement; Self-administration

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