Acromegaly is associated with an increased prevalence and a specific pattern of affective disorders. Greater emphasis on diagnosing and treatment of mental disorders in acromegalic patients might improve the disease management.

Although long-term exposure of the brain to increased GH/IGF-1 likely influences cerebral functions, no in vivo studies have been directed towards changes of the brain structure in acromegaly. Here, we used high resolution magnetic resonance images to compare volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of forty-four patients with acromegaly to an age and gender matched, healthy control group (n = 44). In addition, white matter lesions (WMLs) were quantified and graded. Patients exhibited larger GM (?3.7% compared with controls, P = 0.018) and WM volumes (?5.1%, P = 0.035) at the expense of CSF. Differences of WML counts between patients and controls were subtle, however, showing more patients in the 21-40 lesions category (P = 0.044). In conclusion, this MRI study provides first evidence that acromegalic patients exhibit disturbances of the macroscopic brain tissue architecture. Furthermore, acromegalic patients may have an increased risk of neurovascular pathology, likely due to secondary metabolic and vascular comorbidities.

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.

Using adult heterozygous zebrafish, we show that ELC S195 phosphorylation is pivotal for adaptation of cardiac function to augmented physical stress and we provide novel mechanistic insights into the pathogenesis of ELC-linked cardiomyopathy.

SummaryThere is strong evidence for a pivotal interaction of corticosteroid signalling and behavioral adaptation to stress. To further elucidate this relation, we monitored the dynamics of free corticosterone in the murine hippocampus of two inbred mouse strains using in vivo microdialysis. C57BL/6JOlaHsd (C57BL/6) and DBA/2OlaHsd (DBA/2) inbred mouse strains have been shown to differ in their anxiety-related and depression-like behavior and provide, thus, an interesting animal model to study the stimulus-response profile of the hypothalamus-pituitary-adrenocortical (HPA) system as a function of emotional and physical load. We, first, compared peripheral and intracerebral concentration patterns of corticosterone by simultaneous microdialysis of the jugular vein and the hippocampus in anesthetized mice and found strain differences in blood versus intracerebral free corticosterone concentrations. C57BL/6 showed almost the same steroid levels in either compartment, whereas DBA/2 mice displayed higher glucocorticoid levels in the circulation than in the hippocampus. This data suggest a strain difference in the tissue environment influencing the amount of biological active corticosterone at the receptor site. Measurements of intrahippocampal corticosterone in freely moving mice revealed that DBA/2 display a prolonged glucocorticoid increase in response to a single forced swimming stress (FST), as compared to C57BL/6 mice indicating a reduced inhibitory HPA axis feedback. Exposure to a novel environment (NE) induced a desensitization of the HPA system in DBA/2 animals as they show an attenuated intracerebral corticosterone dynamics after a subsequent FST. Testing animals in an elevated plus-maze (EPM), however, did not significantly stimulate coriticosterone release in either strain. The analysis of the area under the curve revealed a high amount of corticosterone released through FST and a low glucocorticoid release after NE or EPM exposure that are independent of the strain. This data indicate a strong stimulus dependency of corticosterone secretion that is strain independent, whereas the dynamics and feedback of the HPA axis is different between both inbred strains. Behavioral phenotyping of animals revealed a strong impact of microdialysis procedure on FST and EPM performance. Innate emotionality differences of both strains, however, were not affected. Though descriptive in nature, the present results suggest an altered corticosteroid signalling in the DBA/2 strain compared to C57BL/6 mice. Whether this observation causally underlies the differences in anxiety-related and depression-like behavior has to be further experimentally validated. In addition, our study highlights the use of in vivo microdialysis to assess the neuroendocrine endophenotype of animal models via profiling of stimulus-response patterns of stress hormones. ARTICLE IN PRESS