The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 μg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

Depression is a serious condition that occurs more frequently in women and is often associated with treatment resistance. The main hypotheses of this study are that (a) aldosterone is an early marker of depression onset and (b) a tryptophan (TRP) depletion model of depression previously validated in male rats is treatment resistant in females. To explore possible underlying mechanisms, we have focused on factors shown to be altered in patients with treatment-resistant depression. Female Sprague-Dawley rats were treated with a control or low-TRP-containing diet for various time periods up to 21 days. The results show that aldosterone secretion increased after 4 days of TRP depletion and prior to corticosterone. Optimal effects of TRP depletion occurred at 14 days. In addition to neurochemical and behavioural changes observed previously in males, TRP depletion in females was associated with a significant decline in serum magnesium concentrations, increased serum interleukin-6, enhanced gene expression of orexin A in the frontal cortex and induced a rise in N-methyl-D-aspartate (NMDA) receptor B_max in the amygdala. Depression-like behaviour, NMDA receptor upregulation, enhancement of the kynurenine-to-kynurenic acid ratio and magnesium were resistant to paroxetine treatment (10 mg/kg/day in drinking water for 14 days). In conclusion, aldosterone may represent an important early marker for the onset of depression-like behaviour. With respect to treatment resistance, the underlying mechanisms may involve pro-inflammatory cytokines, the kynurenine pathway, magnesium, glutamate neurotransmission and the orexin pathway. This model of treatment-resistant depression may be useful for the future development of new compounds with novel antidepressant properties.

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