Desipramine prevents stress-induced changes in depressive-like behavior and hippocampal markers of neuroprotection

Abstract

Extracellular signal-regulated kinases (ERKs) are widely implicated in multiple physiological processes. Although ERK1/2 has been proposed as a common mediator of antidepressant action in naive rodents, it remains to be determined whether the ERK1/2 pathway plays a role in depressive disorder. Here, we investigated whether chronic restraint stress (14 days) and antidepressant treatment [desipramine (DMI), 10 mg/kg intraperitoneally] induce changes in animal behavior and hippocampal levels of phospho-ERK1/2 and its substrate phospho-cAMP response element-binding protein (CREB). The results indicated that stress-induced depressive-like behaviors were correlated with an increase in P-ERK1/2 and P-CREB in the hippocampus evaluated by immunoblot analysis. As an indication of CREB activity, we evaluated changes in mRNA levels of its target genes. Brain-derived neurotrophic factor (BDNF) mRNA was reduced by stress, an effect prevented by DMI only in the CA3 area of hippocampus. Bcl-2 mRNA was reduced in all hippocampal regions by stress, an effect independent of DMI treatment. However, immunoblot from hippocampal extracts revealed that stress increased BCL-2 levels, an effect prevented by chronic DMI. These results suggest that ERKs and BDNF may be altered in depressive disorder, modifications that are sensitive to DMI action. In contrast, the stress-induced increase in BCL-2 may correspond to a neuroprotective response.

Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity

“…Our findings, therefore, seem to be in line with recent work suggesting that pERK activity in the amygdala is an inverse regulator of the animal's habituation to stress (Grissom and Bhatnagar, 2011). Following 2 weeks of exposure to restraint stress [a higher intensity stress protocol than CUS in terms of circuitry impact (Vyas et al, 2002)], stressinduced depression-like behaviors were correlated with an increase in pERK1/2 in the hippocampus (Bravo et al, 2009). The highest levels of pERK activation in the amygdala were found when the animals were submitted to uncontrollable stress, whereas it was reduced when they learn to control the stressor and were less anxious (Ilin and Richter-Levin, 2009).…”

Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: A role for hippocampal cell proliferation

“…This finding may seem counterintuitive given other reports that antidepressants including desipramine increase BDNF mRNA in the rat hippocampus (Nibuya et al, 1995;Jacobsen and Mork, 2004;Martinez-Turrillas et al, 2005;Dwivedi et al, 2006). However, negative findings have also been reported both at the mRNA level (Coppell et al, 2003;Vinet et al, 2004;Torregrossa et al, 2005;Bravo et al, 2009) and at the protein level (Altar et al, 2003;Jacobsen and Mork, 2004;Balu et al, 2008Balu et al, , 2009). Moreover, desipramine-induced decreases have also been reported by others (Torregrossa et al, 2005).…”

Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333

“…In addition, several neuroplasticity and proliferation related intracellular pathways appear to be involved in the mechanism of action of antidepressants, especially at the hippocampal level. They include BDNF (Bravo et al 2009 ;Duman & Monteggia, 2006), CREB (Malberg & Blendy, 2005 ;Tardito et al 2009), AKT (Mostany et al 2008 ;Soumier et al 2009) and b-catenin (Madsen et al 2003 ;Mostany et al 2008) pathways. Since chronic antidepressants have been reported to modulate 5-HT 4 receptor-coupled adenylate cyclase activity (Vidal et al 2009(Vidal et al , 2010, it would be of interest to analyse whether short-term administration of 5-HT 4 agonists results in the modification of this transductional signal.…”