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The Involvement of Oxytocin and μ-Opioid Receptor Systems in Drug Addiction.

Georgiou, Polymnia. (2014) The Involvement of Oxytocin and μ-Opioid Receptor Systems in Drug Addiction. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Relapse to illicit drug-seeking behaviour is a major challenge as no effective pharmacotherapy is currently available. Drug dependent individuals experience severe negative emotional withdrawal symptoms including anxiety, dysphoria, depression and social avoidance during abstinence from the drug, which may comprise a motivational trigger to re-administer the drug and relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well characterised. There is evidence suggesting that the oxytocin and u-opioid receptor (MOPr) system may be involved in the different stages of drug addiction. This work aimed to elucidate using a mouse model whether an acute administration of the oxytocin analogue carbetocin is able to reverse stress- and priming-induced reinstatement of opioid-seeking by using the conditioned place preference (CPP) paradigm. This thesis has also assessed the regulation of oxytocin receptor and MOPr density during acquisition, cocaine priming and cue-elicited reinstatement of cocaine-seeking via quantitative receptor autoradiography. Furthermore, the effect of chronic methamphetamine (MAP) administration and withdrawal on the oxytocin and MOPr systems was examined by means of quantitative receptor autoradiography and/or radioimmunoassay. Carbetocin reversed both the stress- and priming-induced reinstatement of morphine-seeking with a concomitant decrease in striatal noradrenaline levels by carbetocin following priming- but not stress induced reinstatement of morphine-seeking. A 4-day carbetocin treatment did not induce any rewarding or aversive effects. Cocaine self-administration induced a persistent increase in oxytocin receptor binding specifically in the central nucleus of amygdala compared with the saline controls. A significant reduction of MOPr binding was observed in the nucleus accumbens core and caudate putamen following cocaine self-administration and cue- but not priming-induced reinstatement of cocaine-seeking compared to saline controls. Cue-induced reinstatement of cocaine-seeking decreased MOPr binding in the nucleus accumbens and caudate putamen compared to cocaine-primed reinstatement. Chronic MAP administration induced a persistent increase in the OTR binding in the hippocampus. An increase in the OTR binding was observed following chronic MAP administration in the amygdala which was normalised following withdrawal, whilst MAP withdrawal induced a profound increase in the OTR binding in the lateral septum. With respect to the MOPr system, chronic MAP administration increased MOPr binding in the nucleus accumbens and caudate putamen which persisted during withdrawal. These receptor alterations occurred in parallel, with the emergence of anxiety-related symptoms during MAP withdrawal. Collectively, the results described in this thesis highlight the dysregulation of the oxytocinergic and MOPr systems in the amygdala and striatum respectively, induced by chronic psychostimulant and exposure, withdrawal and reinstatement. This brain region-specific dysregulation may at least partly underlie the emotional consequences of drug addiction. Additionally, this is the first study to support the oxytocinergic system as a novel target for the prevention of relapse and treatment of opioid addiction. Lastly, the results of this thesis point toward the existence of a possible OT-MOPr interaction which might underlie some of the effects observed.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Georgiou, Polymnia.
Date : 2014
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 2014.
Depositing User : EPrints Services
Date Deposited : 24 Apr 2020 15:26
Last Modified : 24 Apr 2020 15:26
URI: http://epubs.surrey.ac.uk/id/eprint/855252

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