ANIMAL MODELS OF DEPRESSION, ACTION OF ANTIDEPRESSANTS

WIKINSKI S

Huerta Grande, Córdoba

Workshop; First Joint Meeting of the Argentine Society for Neurosciences and the Argentine Workshop in Neurosciences; 2009

Taller Argentino de Neurociencias y Sociedad Argentina de Neurociencias

Animal models of depression, action of antidepressants   Silvia Wikinski. Instituto de Investigaciones Farmacològicas (UBA-CONICET)     Depression is a highly prevalent disorder all over the World. The World Health Organization estimates that more than 120 million people are currently affected and that, by 2020 it will be the second cause of burden due to health problems. Although since 1950 many antidepressant drugs were developed, according with the latest evidences, significant proportions of patients do not respond to treatment or relapse in the short term. It remains necessary to reach new insights on the neurobiology of depression in order to be able to design new pharmacological treatments. Depression is undoubtedly a human disease, but for the investigation of the potential utility of new compounds several animal models are employed. Additionally, supported on some similarities between the symptoms of depression and behavioral parameters in rodents, some other approaches are used to investigate the neurobiology of the disease. In this lecture the most frequently employed models of depression will be presented and their advantages and limitations will be discussed. Focus will be put on the stress-based experimental models: chronic mild stress, chronic restraint stress and the learned helplessness paradigm. Mechanism of action of antidepressant drugs is still controversial. Since the ’80, when the monoaminergic theory of depression and of the action of antidepressants were proposed several other theories have been presented. Currently the neurotrophic and the neurogenic hypotheses are the most cited. I will present evidencies supporting each of these hypothesis, as well as their pitfalls. I will also present the results from our laboratory concerning the plastic changes induced by exposure to inescapable stress in the learned helplessness paradigm and by the chronic treatment with the glucocorticoid corticosterone. There will be also shown the effects of the treatment with the antidepressant fluoxetine, the mood stabilizer valproic acid and those obtained by the exposure to an enriched environment. Our results show that inescapable stress induces a long lasting diminution of synaptic and cytoskeletal markers in the hippocampus, that chronic treatment with corticosterone deeply affects intermediate neurofilaments and MAP2 in the same area, and that all these changes are accompanied by alterations in the in vitro glutamate release. While fluoxetine reverses behavioral and synaptic parameters, it fails to correct the cytoskeletal alterations. Valproic acid and enriched environment, on the contrary, exert a corrective effect on these parameters too. Preliminary results which could explain the mechanism by which cytoskeletal proteins are affected upon stress, together with the modifications in the CRF signaling cascade in animals exposed to learned helplessness will be also presented.