Novel insights into the role of the GABAB receptor in depression and anxiety

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dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.entireThesisEntire Thesis Restricted
dc.check.infoIndefiniteen
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorCryan, John F.en
dc.contributor.advisorO'Leary, Oliviaen
dc.contributor.authorFelice, Daniela
dc.contributor.funderEuropean Commissionen
dc.date.accessioned2014-01-20T16:49:05Z
dc.date.issued2013
dc.date.submitted2013
dc.description.abstractThe GABAB receptor is a functional heterodimer comprising the GABAB1 and GABAB2 subunits, with the GABAB1 subunit displaying two major isoforms, GABAB(1a) and GABAB(1b). Preclinical findings have strongly implicated the GABAB receptor in stress-related psychiatric disorders, however, the precise contribution of the GABAB receptor in depression and anxiety disorders remains unknown. Emerging data suggest that the interaction between adverse environmental conditions, such as early life stress, and a specific genetic composition can increase the risk to develop psychiatric disorders in adulthood. This thesis investigated the role of the GABAB receptor alone or in combination with early-life stress (maternal separation), in modulating antidepressant like and anxiety-related behaviours. Pharmacological blockade of the GABAB receptor with CGP52432 had antidepressant-like behavioural effects. Moreover, mice lacking the GABAB(1b) receptor subunit isoform exhibited antidepressant-like behaviours in adulthood but anxiety-like behaviour in early-life. In response to maternal separation, GABAB(1a)-/- mice exhibited early-life stress-induced anhedonia, a core symptom of depression, while GABAB(1b)-/- mice exhibited a more resilient phenotype. Moreover, when compared with wildtype or GABAB(1a)-/- mice, GABAB(1b)-/- mice that underwent maternal separation exhibited enhanced stressinduced neuronal activation in the hippocampus and in the nucleus accumbens (NAcc), a critical area for anhedonia thus suggesting that enhanced stress-induced neuronal activation in the hippocampus and NAcc in GABAB(1b)-/- mice may be important for their antidepressant-like phenotype and their resilience to stress-induced anhedonia. Pharmacological blockade of GABAB receptor and GABAB(1b) receptor subunit isoform loss of function increased adult hippocampal cell proliferation, thus suggesting that increased hippocampal neurogenesis could be a potential mechanism for the antidepressant-like effects of GABAB receptor antagonists and GABAB(1b) receptor subunit isoform disruption. Finally, this thesis investigated whether the expression of several genes involved in hippocampal neurogenesis or the antidepressant response were altered in the mouse hippocampus following chronic treatment with a GABAB receptor antagonist.en
dc.description.sponsorshipEuropean Commission (FP7/2007-2013, Grant Agreement 201714, Devanx Project )en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFelice, D. 2013. Novel insights into the role of the GABAB receptor in depression and anxiety. PhD Thesis, University College Cork.en
dc.identifier.endpage323
dc.identifier.urihttps://hdl.handle.net/10468/1310
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, Daniela Felice.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectGABAB receptoren
dc.subjectDepressionen
dc.subjectAnxietyen
dc.subjectAnti-depressantsen
dc.subjectEarly-life stressen
dc.subject.lcshDepression, Mental--Treatmenten
dc.subject.lcshAntidepressantsen
dc.subject.lcshAnxiety disorders--Treatmenten
dc.thesis.opt-outfalse*
dc.thesis.opt-outfalse*
dc.titleNovel insights into the role of the GABAB receptor in depression and anxietyen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorj.cryan@ucc.ie*
ucc.workflow.supervisorj.cryan@ucc.ie*
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