Improvements on the unpredictable chronic mild stress (UCMS) model for anti-depressive testing

• Grant number: 15/08098-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2015
• End date: June 30, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Cristoforo Scavone
• Grantee: Adriana de Toledo Ramos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Depression is an incapacitating and hardly treated psychiatric condition so the development of new drugs has been a priority for big pharmaceutical companies and academics. New molecular entities with antagonistic action on CRHR1 and V1b receptors have been developed by Sanofi-Aventis and Pfizer and showed antidepressant activities in pre-clinical models. We investigated the effectiveness of these compounds on neuro-endocrine responses to stress and as antidepressants describing that these compounds used simultaneously are very effective at blocking the neuro-endocrine response to stress but were not additive regarding the anti-depressant action pointing towards a non-hypothalamic site of action. Inasmuch, subsequent failures at clinical phase II tests exposed the poor predictive capacity of the most commonly used pre-clinical tests for anti-depressives. Considering the need for better pre-clinical models in this field, we propose the present investigation on the unpredictable chronic mild stress (UCMS) model based on induction of anhedonia (sucrose preference), the most remarkable symptom of major depression. Current literature reports that induction of anhedonia is subject to failures and we repute such failure to be attributed to the misuse of different stress modalities in inducing anhedonia, i. e., a mix of physical and processive stresses. It is well known that stress modalities may differentially alter brain circuits; we intend to specifically investigate which of these two stress modalities can induce anhedonia. Such difference could lead to the proposal of a more efficient and reliable model of anhedonia for pre-clinical screening of new drug candidates with important economical consequences. As a complementary investigation we propose the study of the neural circuits involved in anhedonia by means of rat brain deoxy-glucose and cytochrome-oxidase activity in rats. This mapping will then be compared to human depressive brain mapping activity obtained by f-PET and other methods, already described in the literature, in order to increase our understanding of the brain circuitry involved in this disease. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RAMOS, ADRIANA T.; TUFIK, SERGIO; TRONCONE, LANFRANCO R. P.. Control of Stress-Induced ACTH Secretion by Vasopressin and CRH: Additional Evidence. NEUROPSYCHOBIOLOGY, v. 73, n. 3, p. 184-190, 2016. (15/08098-5, 98/14303-3, 13/18897-7)

RAVELLI, KATHERINE GARCIA; RAMOS, ADRIANA DE TOLEDO; GONCALVES, LUANA BARACHO; MAGNOLI, FABIO CARLOS; PAOLO TRONCONE, LANFRANCO RANIERI. Phoneutria nigriventer spider toxin Tx2-6 induces priapism in mice even after cavernosal denervation. Toxicon, v. 130, p. 29-34, MAY 2017. (15/08098-5)