Efeitos do bloqueio da síntese da corticosterona sobre o congelamento condicionado de machos e fêmeas em diferentes fases do ciclo estral

Abstract

Metyrapone, an inhibitor of adrenal corticosteroid synthesis, has been associated with alterations in the conditioned freezing response in male rats. However, the effects of metyrapone on aversive conditioning in females, whose brain operates in a context of cyclic variation of sexual hormones, remain underexplored. Simultaneously, previous studies have demonstrated poorer performance in contextual fear extinction in females, suggesting a potential relationship between sex differences and conditioned fear. Thus, the overall aim of this study was to assess the involvement of corticosterone in the expression and extinction of the conditioned freezing response in both male and female rats, considering different phases of the estrous cycle. It was anticipated that blocking corticosterone synthesis through metyrapone administration would reduce the expression of conditioned freezing in both males and females, without affecting motor activity, with more robust results during proestrus/estrus. To achieve this, we evaluated the effects of metyrapone (30 and 60 mg/kg) in contextual aversive conditioning in adult Wistar rats (45 males and 93 females; CEUA protocol 9367190422). The female rats designated for experiments were grouped based on the estrous cycle phase on the day of testing, into proestrus/estrus and metestrus/diestrus. Animals underwent a contextual aversive conditioning protocol, involving the presentation of electric footshocks during the training session. After 24 hours, metyrapone or vehicle was administered, followed by a test session to assess the freezing response. Retention of extinction was evaluated in a retest session conducted 24 hours after the test. Catalepsy and motor activity in the open field were assessed in animals 48 hours after retesting. Overall, blocking corticosterone synthesis with metyrapone impaired the extinction of conditioned contextual freezing response in both males and females. On the other hand, metyrapone reduced the expression of conditioned fear only in males. Additionally, metyrapone did not produce motor impairment in males, as assessed by catalepsy and open field tests. In females, however, metyrapone increased horizontal exploration in the open field. These results suggest the importance of corticosterone in contextual aversive conditioning, with sex-dependent involvement in conditioned fear expression, while its role in extinction appears to be independent of sex and estrous cycle phase, but more robust for males and metaestrus/diestrus females.