Role of the Endocannabinoid System in Extinction of Learned Behaviours Motivated by Opioid-Induced Reward and Aversion in Rats

dc.contributor.advisorCholeris, Elena
dc.contributor.advisorMallet, Paul
dc.contributor.authorManwell, Laurie
dc.date.accessioned2013-08-26T18:07:27Z
dc.date.available2013-08-26T18:07:27Z
dc.date.copyright2013
dc.date.created2013-08-19
dc.date.issued2013-08-26
dc.degree.departmentDepartment of Psychologyen_US
dc.degree.grantorUniversity of Guelphen_US
dc.degree.nameDoctor of Philosophyen_US
dc.degree.programmePsychologyen_US
dc.description.abstractRecent evidence suggesting that the endogenous cannabinoid (ECB) system can be selectively manipulated to facilitate or impair the extinction of learned behaviours — specifically regarding drug-induced aversive memories — has important consequences for research on opiate withdrawal and abstinence. Data presented here support and expand previous findings that the ECB system has an important function in the extinction of aversively motivated behaviors and is mediated by i) an increase in available endogenous CB1 receptor agonists, primarily anandamide, and ii) the exogenous CB1 receptor agonist Δ9-THC, in a manner that is dependent upon both the dose and route of administration. Experiments demonstrated that the fatty acid amide hydrolase (FAAH) inhibitor, URB597, which blocks deactivation of endogenous CB1 ligands, such as anandamide, significantly facilitated extinction of naloxone-precipitated morphine withdrawal-induced conditioned cue aversion, whereas the CB1 receptor antagonist/inverse agonist SR141716 significantly impaired extinction. Several experiments demonstrated that neither the CB1 antagonist AM251 nor the FAAH inhibitor URB597 had any effect on extinction learning for morphine-induced conditioned cue preference. A method was developed for analysing cannabinoid levels in blood by liquid chromatography/mass spectrometry (LC/MS) to compare bioavailable levels of Δ9-THC and its primary psychoactive metabolite. Experiments were designed to meet three primary objectives: 1) to provide further support for the role of the ECB system in the extinction of aversively-motivated behaviours, 2) to compare bioavailable levels of Δ9-THC and its primary psychoactive metabolite, 11-OH-Δ9-THC, after pulmonary and parenteral administration, and 3) to demonstrate that the route of administration of Δ9-THC can have a significant impact on whether or not it facilitates or impairs extinction learning. Results showed that inhaled Δ9-THC dose- and time-dependently facilitated rates of extinction learning of the conditioned aversion whereas injected Δ9-THC significantly impaired extinction. These data suggest that the route of administration of Δ9-THC has important consequences for its resulting pharmacokinetic and behavioural effects, specifically, that pulmonary exposure facilitates, whereas parenteral exposure impairs, rates of extinction learning for conditioned cue aversion. Thus, pulmonary administration of Δ9-THC may prove more beneficial for pharmacological potentiation of extinction learning for aversive memories, such as those supporting drug-craving/seeking in opiate withdrawal-syndrome.en_US
dc.description.sponsorshipNatural Sciences and Engineering Research Council of Canada
dc.description.sponsorshipOntario Graduate Studies
dc.identifier.urihttp://hdl.handle.net/10214/7415
dc.language.isoenen_US
dc.publisherUniversity of Guelphen_US
dc.rightsAttribution-NoDerivs 2.5 Canada*
dc.rights.urihttp://creativecommons.org/licenses/by-nd/2.5/ca/*
dc.subjectendocannabinoiden_US
dc.subjectextinction learningen_US
dc.subjectrewarden_US
dc.subjectaversionen_US
dc.subjectΔ9-tetrahydrocannabinolen_US
dc.subject11-OH-Δ9-tetrahydrocannabinolen_US
dc.subjectCB1en_US
dc.subjectopioiden_US
dc.subjectpulmonary administrationen_US
dc.subjectfatty acid amide hydrolase (FAAH)en_US
dc.subjectURB597en_US
dc.subjectroute of administrationen_US
dc.subjectmorphine withrawalen_US
dc.subjectraten_US
dc.titleRole of the Endocannabinoid System in Extinction of Learned Behaviours Motivated by Opioid-Induced Reward and Aversion in Ratsen_US
dc.typeThesisen_US

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