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Role of serotonin- and glucocorticoid-mediated system in response to stressful situations

Abstract

Stress has been considered as one of the etiological factors in Psychiatric Disease, since it induces behavioural, neuroendocrine and cardiovascular changes, leading to an arousal state which in turn can be observed by changes in behaviour and central nervous system functioning. Such responses are coordinated by several brain structures such as prefrontal cortex (PFCx), hippocampus (dH), median raphe nucleus (MnRN) and amygdala, among the serotonergic system and glucocorticoids which interfere on the acquisition, consolidation/expression and extinction of these responses. Recent data suggest that the age at which the animals are exposed to stress is determinant to its consequences, thus suggesting that morfofunctional changes underlies these responses. Changes in the serotonergic neurotransmission and/or signalized by glucocorticoids attenuate the effects of stress, reinforcing the idea that such systems modulate the functioning of stress brain circuitry. However, the mechanisms underlying such changes have not been fully investigated yet. In the hippocampus and the MnRN activation of 5HT7 receptors seems to have a contradictory role in response to stress, increasing and attenuating its consequences. Therefore, new strategies employing different stressors would be valuable to clarify the role of 5HT7 in stress. Besides 5HT7, stress responses also seem to be modulated by activation of other serotonin receptors such as 5HT1a, 5-HT2 and 5-HT3 and also by glucocorticoid receptors such as the mineralocorticoid (MR) and glucocorticoid (GR) ones. Therefore, the aims of this project are to investigate: 1) if intra-hippocampal treatment with SB258741, a 5HT7 antagonist, would attenuate/prevent the effects of forced swim and/or footshocks stressors; 2) if subchronic treatment with metirapone (glucocorticoid synthesis inhibitor) and imipramine (tricyclic antidepressant) interferes on conditioned fear memories by changing the expression of serotonin transporter, its receptors and glucocorticoid receptors in brain structures responsive to stress; and 3) if these last behavioural changes are dependent on the amygdala-pre limbic cortex projections. We expect to contribute to the existent knowledge in the literature concerning the neurobiological substrates underlying stress responses, thus clarifying the effects of drugs acting on these substrates that are used in the treatment of the related psychiatric diseases. (AU)