Florey Department of Neuroscience and Mental Health - Research Publications
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ItemStress Controversies: Post-Traumatic Stress Disorder, Hippocampal Volume, Gastroduodenal Ulceration*Fink, G (WILEY, 2011-02-01)Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Increased activity of these two systems induces behavioural, cardiovascular, endocrine and metabolic cascades that enable the individual to fight or flee and cope with the stress. Our understanding of stress and stress-response mechanisms is generally robust. Here, however, we review three themes that remain controversial and perhaps deserve further scrutiny and investigation before they achieve canonical status. The themes are, first, hypocortisolaemia in post-traumatic stress disorder (PTSD). A reduction rather than a stress-induced increase in adrenal glucocorticoid levels, as seen in major depressive disorder (MDD), is puzzling and furthermore is not a consistent feature of PTSD. Overall, studies on PTSD show that glucocorticoid levels may be normal or higher or lower than normal. The second theme concerns the reduction in volume of the hippocampus in MDD attributed to the neurotoxicity of hypercortisolaemia. Again, as for hypocortisolaemia in PTSD, reduced hippocampal volume in MDD has been found in some but not all studies. Third, the discovery of a causal association between Helicobacter pylori and peptic ulcers apparently brought to an end the long-held view that peptic ulceration was caused predominantly by stress. However, recent studies suggest that stress can cause peptic ulceration in the absence of H. pylori. Predictably, the aetiological pendulum of gastric and duodenal ulceration has swung from 'all stress' to 'all bacteria' followed by a sober realisation that both factors may play a role. This raises the question as to whether stress and H. pylori interact, and if so how? All three controversies are of clinical significance, pose fundamental questions about stress mechanisms and offer important areas for future research.
ItemClozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugsPereira, A ; Sugiharto-Winarno, A ; Zhang, B ; Malcolm, P ; Fink, G ; Sundram, S (CAMBRIDGE UNIV PRESS, 2012-09-01)Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapine's action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile.