Efeito de antagonistas do receptor NOP em Camundongos expostos ao modelo do desamparo aprendido

Abstract

The nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide being the endogenous ligand of a Gi protein-coupled receptor, named NOP receptor. Pharmacological and genetic evidence suggests potential antidepressant effect induced by the blockage of NOP receptor. The learned helplessness model (LH) employs uncontrollable and unpredictable electroshock in the animals' paws as a stressor to induce a depressive-like phenotype. This paradigm is based on the fact that after exposure to uncontrollable electric shock, animals develop deficits in avoidance behavior of electrified compartment, an event reversed by antidepressants. The LH is a well-validated model of depression compared with behavioral despair tests that are currently most used in the screening of new antidepressants. Thus, the present study aims to validate the helplessness learned model in our experimental conditions, and to evaluate the action of NOP receptor antagonists in animals that developed the helpless condition. For this study male mice went through three phases of the DA protocol (i.e., (1) induction, (2) screening, and (3) test). Animals that developed the depressive-like phenotype were subjected to the test session. In this phase it is possible to escape the chamber electroshock. Therefore, the latency to escape after the shock, and the frequency of failures (when the animal did not escape from the eletroshoch compartment) was recorded. The effect of the following treatments administered before the test session was evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, 60 min), both classical antidepressants, SB-612111 (1 to 10 mg/kg, ip, 30 min) and UFP-101 (1 to 10 nmol, icv, 5 min), both NOP antagonists. Still, to rule out possible false positives helpless kind of behavior, we evaluated the effect of these drugs on the motivational and cognitive components. Thus, it was shown that in animals that develop the depressive phenotype , nortriptyline, UFP-101 and SB-612111 were effective in reducing the escape latency and the frequency of failures without causing any change in motivational and cognitive components; the same is not true with fluoxetine administration, which does reverse helplessness behavior. In conclusion, acute treatment with NOP antagonists promotes a genuine antidepressant-like effect in mice submitted to the learned helplessness model.