A double-hit model of stress dysregulation: implications for HPA activity, limbic glucocorticoid receptors and anxiety under antidepressant treatment.

COTELLA, EVELIN M.; DURANDO, PATRICIA E.; SUÁREZ, MARTA M.

Dourado

Workshop; International Workshop of Neuroendocrinology; 2013

During early life, environment promotes different pathways of expression of molecules in the brain which will determine diverging responses to stress in adulthood. Alterations in the ability to respond to stressors can constitute a risk factor for disease, especially to emotional disorders such as depression. There are two types of receptors for glucocorticoids: the mineralocorticoid (MR) and the glucocorticoid (GR) receptors. They are involved in the negative feedback of glucocorticoids, adjusting the stress response. In our laboratory, we evaluate the long-term effects of early life adversity and its interaction with chronic stress during adulthood. We propose this as a model of vulnerability to dysregulation of the HPA axis. In the present study we assessed the effects on the HPA axis by measuring the basal secretion of corticosterone and ACTH after 24 d exposure to chronic variable stress (CVS) in rats previously subjected to early maternal separation (MS) for a period of 4.5 h for the first 3 weeks of life. We also identified the expression of GR and MR in the central and medial nuclei of amygdala, septohippocampal nucleus, lateral septum and dorsal hippocampus and analyzed the anxiety-like behavior. We also determined the effect of the tricyclic antidepressant amitriptyline (AMI) in such situations since this drug has been reported to correct HPA activity under certain circumstances. Our results showed that maternal separation induced several changes related to HPA axis control and behavior. Maternal separation evoked lower ACTH secretion and MR expression in the central amygdaloid nucleus. These changes were reverted by amitriptyline. Chronic variable stress evoked a rise in MR immunoreactivity in the hipocampal area CA2. It also evoked a rise in the anxiety behavior. All those effects were prevented by the antidepressant. When combined, maternal separation and chronic stress during adulthood, there was a rise in corticosterone secretion, prevented by amitriptyline. Nevertheless, there was also a reduction of the locomotor activity in the animals, with no corrective effect of the drug. This means that maternal separation would promote an alternative phenotype that in turn would evoke different responses later in life depending on the environment in which the animal lives.