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

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dc.contributor.advisor Cryan, John F. en
dc.contributor.advisor O'Leary, Olivia en
dc.contributor.author Felice, Daniela
dc.date.accessioned 2014-01-20T16:49:05Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation Felice, D. 2013. Novel insights into the role of the GABAB receptor in depression and anxiety. PhD Thesis, University College Cork. en
dc.identifier.endpage 323
dc.identifier.uri http://hdl.handle.net/10468/1310
dc.description.abstract The 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.sponsorship European Commission (FP7/2007-2013, Grant Agreement 201714, Devanx Project ) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Daniela Felice. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject GABAB receptor en
dc.subject Depression en
dc.subject Anxiety en
dc.subject Anti-depressants en
dc.subject Early-life stress en
dc.subject.lcsh Depression, Mental--Treatment en
dc.subject.lcsh Antidepressants en
dc.subject.lcsh Anxiety disorders--Treatment en
dc.title Novel insights into the role of the GABAB receptor in depression and anxiety en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text not available en
dc.check.info Indefinite en
dc.check.date 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder European Commission en
dc.description.status Not peer reviewed en
dc.internal.school Pharmacy en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false *
dc.thesis.opt-out false *
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Both hard copy thesis and e-thesis en
ucc.workflow.supervisor j.cryan@ucc.ie *
ucc.workflow.supervisor j.cryan@ucc.ie *
dc.internal.conferring Summer Conferring 2013 en


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© 2013, Daniela Felice. Except where otherwise noted, this item's license is described as © 2013, Daniela Felice.
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