ABSTRACT
Androgenic-anabolic steroid (AAS) misuse has been associated with depression. It has been proposed that stress has a role in depression and that serotonin is involved in both endocrine responses to stress and depressive physiopathology. Although reports demonstrate that AAS chronic administration modifies components of stress-responsive hypothalamic-pituitary-adrenal axis (HPAA), no study has evaluated AAS effect on the response to stressful stimuli. We studied the effects of the subchronic administration (once a day for 14 days in rats) of a supratherapeutical dose of nandrolone decanoate (ND) on HPAA and cortical serotoninergic system response to acute restraint stress (RS). Acute RS produced the following effects: increase in CORT (in blood) and ACTH (both in blood and in pituitary corticotropes), GR depletion in hippocampus and hypothalamus cytosol and GR translocation in hippocampus nuclear fraction, cortical serotonin re-uptake stimulation and hippocampus cytosolic ERK2 activation. ND by itself, i.e. in non-stressed rats, did not modify these parameters, except for a decrease of plasma CORT and ACTH levels and an increase in hippocampus cytosolic phospho-ERK1/2. On the contrary, in stressed rats ND affected stress-induced plasma ACTH increase and prevented all other above reported stress effects, except the increase in pituitary ACTH positive cell density. Our results show that the prolonged administration of a supratherapeutical dose of ND in rats, albeit did not affect in a notable way HPAA and serotonin transporter activity in the absence of stress, may deregulate the stress-induced hormonal cascade which plays a crucial role in depressive psychopathology.
Subject(s)
Adaptation, Psychological/drug effects , Hormones/metabolism , Nandrolone/pharmacology , Stress, Psychological/metabolism , Adaptation, Psychological/physiology , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/metabolism , Anabolic Agents/administration & dosage , Anabolic Agents/pharmacology , Animals , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/metabolism , Hormones/blood , Hydrocortisone/blood , Hydrocortisone/metabolism , Male , Nandrolone/administration & dosage , Pituitary Gland/drug effects , Pituitary Gland/metabolism , Rats , Rats, Sprague-Dawley , Stress, Psychological/blood , Time FactorsABSTRACT
The forced swim test (FST) can lead to stress-related diseases such as depression, through activation of hypothalamic-pituitary-adrenal axis (HPAA) and corticosteroid disregulation. Among the proopiomelanocortin (POMC)-derived peptides, alpha-melanocyte-stimulating hormone (alpha-MSH) has been shown to regulate long-lasting behavioral responses. Moreover, serotonergic pathways in various brain areas are activated by stressors, a feature that suggests a role for serotonin in both stress-induced HPAA disregulation and depressive physiopathology. Taking all together these data, we investigated the effects of the FST exposure and the effects of pre-treatment with alpha-MSH on cortical synaptosomal serotonin transporter (SERT) activity, corticosterone (CORT) plasma levels and on glucocorticoid receptor (GR) occupancy and expression in rat hippocampus. Young male rats were divided into three groups treated with saline or with alpha-MSH at doses of 1 or 4 microg/rat, 15 min prior to FST. Our data show that FST increased CORT secretion; GR levels in hippocampus decreased in density after stress without variations in affinity; GR redistributed from the cytosolic to the nuclear tissue fraction; finally, SERT activity strongly increased. All these effects were blocked by pre-treatment with alpha-MSH at the higher dose.
