Aldosterone Signals the Onset of Depressive Behaviour in a Female Rat Model of Depression along with SSRI Treatment Resistance

Abstract

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-<smlcap>D</smlcap>-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.

Effect of Physical Exercise and Acute Escitalopram on the Excitability of Brain Monoamine Neurons: In Vivo Electrophysiological Study in Rats

“…Almost all known antidepressant drugs stimulate 5-HT transmission, either directly or indirectly (Dremencov, 2009; Pavlovicova et al, 2015). Accordingly, tryptophan depletion and the subsequent decrease in 5-HT bioavailability leads to the onset of the symptoms of depression (Delgado et al, 1994, 1999; Franklin et al, 2015). Since increased excitability of 5-HT neurons leads to the increased synaptic levels of 5-HT in the brain, it is possible that the anxiolytic and antidepressant effect of physical exercise, reported in previous studies in animal models (Greenwood et al, 2003; Lapmanee et al, 2012; Chen et al, 2016) and human subjects (Kvam et al, 2016) is mediated, at least in part, via increased excitability of 5-HT neurons in the DRN.…”

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

“…For example, childhood adversity is associated with altered cortisol and DHEA secretion 55 , which in turn increases the risk of depression 65,66 . Furthermore, aldosterone induces depressive symptoms in animals 64,67 . On the other hand, depression itself can alter steroid hormone concentrations.…”

View on Aldosterone and the Brain Revisited

“…We showed that aldosterone secretion had increased already after 4 days of tryptophan depletion, prior to the rise in serum corticosterone. This finding suggests that aldosterone may be more important than corticosterone in the development of a depression-like state and aldosterone may constitute an early marker for the onset of depression-like behavior [30].…”

“…We have established a new and novel animal model of depression based on diet-induced tryptophan depletion in female rats [29]. Diet-induced tryptophan depletion resulted in a significant reduction of brain serotonin and induction of depressionlike behavior manifested by increased immobility in the forced swim test [30]. Interestingly, the depression-like state was associated with a significant increase in serum aldosterone concentrations.…”