title: GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response.
abstract: Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioural changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.
authors.affiliation: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Gunn
authors.affiliation: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Cunningham
authors.affiliation: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Mitchell
authors.affiliation: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Swinny
authors.affiliation: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.affiliation: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Electronic address: d.belelli@dundee.ac.uk.
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
mesh_terms: D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A
keywords: Allopregnanolone; Depression; Early-life stress; GABA(A) receptor; HPA axis