Novel roles for the GABAB receptor in anxiety and cocaine addiction

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dc.contributor.advisor Cryan, John F. en
dc.contributor.author Sweeney, Fabian
dc.date.accessioned 2014-03-19T15:57:49Z
dc.date.available 2014-03-19T15:57:49Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation Sweeney, F. 2013. Novel roles for the GABAB receptor in anxiety and cocaine addiction. PhD Thesis, University College Cork. en
dc.identifier.endpage 278
dc.identifier.uri http://hdl.handle.net/10468/1473
dc.description.abstract The GABAB receptor has been postulated as a possible drug target in the treatment of anxiety disorders and cocaine addiction. Indeed, a wealth of preclinical data is emerging that has shown that mice lacking functional GABAB receptors display a highly anxious behaviour across a range of behavioural models of anxiety. Additionally, novel compounds that act by altering the allosteric conformation of the GABAB receptor to a more active state; the GABAB receptor positive modulators, have been repeatedly demonstrated to have anxiolytic effects in animals. In addition to being a putative anxiolytic drug target, the GABAB receptor has been identified as a novel target for antiaddictive therapies. Indeed GABAB receptor positive modulators have been demonstrated to have anti-addictive properties across a broad variety of behavioural paradigms. Despite these findings, several gaps in our knowledge of the role played by the GABAB receptor in both anxiety and drug abuse disorder exist. The aim of this thesis was to use preclinical animal models in an effort to further probe the role played by the GABAB receptor in anxiety and addiction. Our studies initially examined the role played by the GABAB receptor in the neurodevelopmental processes underpinning of anxiety. Our studies demonstrated that treating mouse pups in early life with the GABAB receptor agonist baclofen produced an anxious phenotype in adult life, whereas treatment with the GABAB receptor antagonist CGP52432 produced no effects on adult behaviour. Further to this, we examined whether the anxious behaviour induced by early life blockade of the serotonin reuptake transporter was dependant on alterations in GABAB receptor function. Our studies however revealed no effect of early life selective serotonin reuptake inhibitor treatment on adult life baclofen sensitivity. The next issue addressed in this thesis is the characterization of the effects of a GABAB receptor positive modulator and a GABAB receptor antagonist in a behavioural model of conditioned fear behaviour. These novel classes of GABAB receptor ligands have been considerably less well characterized in this facet of preclinical anxiety behaviour than in terms of innate anxiety behaviour. Our study however revealed that the GABAB receptor positive modulator GS39783 and the GABAB receptor antagonist CGP52432 were without effect on the acquisition, expression or extinction of conditioned fear in our model. The next element of this thesis dealt with the characterization of a novel mouse model, the GABAB(2)- S892A mouse. This mouse has been engineered to express a form of the GABAB(2) receptor subunit wherein the function determining serine phosphorylation site cannot be phosphorylated. We initially tested this mouse in terms of its GABAB receptor function in adult life, followed by testing it in a battery of tests of unconditioned and learned anxiety behaviour. We also examined the behavioural and molecular responses of the GABAB(2)-S892A mouse to cocaine. All of our studies appear to show that the GABAB(2)-S892A mouse is indistinguishable from wildtype controls. The final aim of the thesis was to investigate the behavioural and molecular sensitivity of the GABAB(1) subunit isoform null mice, the GABAB(1a) -/- and GABAB(1b) -/- mice to cocaine. Our studies revealed that these mice display differing behavioural responses to cocaine, with the GABAB(1a) -/- mouse displaying a hypersensitivity to the acute locomotor effects of cocaine, while the GABAB(1b) -/- displayed blunted locomotor sensitisation to cocaine. en
dc.description.sponsorship European Commission (FP7 DEVANX – HEALTH-F2-2007-201714) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Fabian Sweeney en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject GABAB en
dc.subject Cocaine addiction en
dc.subject Anxiety en
dc.subject.lcsh Cocaine abuse--Treatment en
dc.subject.lcsh Anxiety disorders--Treatment en
dc.subject.lcsh Molecular neurobiology en
dc.title Novel roles for the GABAB receptor in anxiety and cocaine addiction en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.contributor.funder European Commission en
dc.description.status Not peer reviewed en
dc.internal.school Pharmacology and Therapeutics en
dc.internal.school Pharmacy en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor j.cryan@ucc.ie
dc.internal.conferring Spring Conferring 2014 en


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