title: The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems.
abstract: Relapse to illicit drug-seeking following abstinence is a major challenge for the treatment of addiction as no effective pharmacotherapy is available. We have recently shown that activating the central oxytocinergic system prevents emotional impairment and stress-induced reinstatement associated with opioid withdrawal. Here, we investigated whether the oxytocin analogue carbetocin (CBT) is able to reverse morphine-primed reinstatement of conditioned-place preference (CPP) in mice. The mechanism underlining the behavioural effect of CBT was investigated by assessing the involvement of the striatal noradrenergic and dopaminergic systems in CBT reversal of priming- and stress-induced reinstatement of opioid CPP. In addition, given recent evidence suggesting the presence of oxytocin receptor (OTR)-μ-opioid receptor (MOPr) interactions in the brain, we further explored these interactions by carrying out OTR autoradiographic binding in brain of mice lacking MOPr. CBT administration prevented priming-induced reinstatement of morphine CPP. While an acute effect of CBT in enhancing dopamine turnover was observed following stress- and priming-induced reinstatement, CBT significantly decreased striatal noradrenaline turnover only following priming-induced reinstatement. Moreover, a significant brain region- specific increase in OTR binding was observed in MOPr knockout mice, indicating the presence of a possible OTR-MOPr interaction, which may be involved in the modulation of relapse. These results support the oxytocinergic system as a promising target for the prevention of relapse to opioid use and highlight the differential involvement of monoaminergic systems on the effects of OTR stimulation in preventing stress- and priming-induced reinstatement of opioid CPP behaviour.
authors.affiliation: Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK.
authors.forename: Polymnia
authors.initials: P
authors.lastname: Georgiou
authors.affiliation: Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Department of Pharmacology, School of Medicine, University of Murcia, Spain.
authors.forename: Juan-Antonio
authors.initials: JA
authors.lastname: Garcia-Carmona
authors.affiliation: Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Hourani
authors.affiliation: Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France; Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: Department of Pharmacology, School of Medicine, University of Murcia, Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Laorden
authors.affiliation: Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH Surrey, UK. Electronic address: a.bailey@surrey.ac.uk.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002228:Carbenicillin / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004298:Dopamine / Q000378:metabolism*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage*; D009638:Norepinephrine / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000378:metabolism; D012044:Regression Analysis
chemical_list: D017450:Receptors, Opioid, mu; D018045:Receptors, Oxytocin; D009020:Morphine; D002228:Carbenicillin; D004298:Dopamine; D003345:Corticosterone; D009638:Norepinephrine
keywords: Dopamine; MOPr; Morphine; Noradrenaline; Oxytocin; Reinstatement