Abstract
BACKGROUND: Fear extinction, a laboratory model for exposure therapy, is modulated by endogenous levels of estradiol in adult female rodents and women, with extinction retention enhanced when extinction training occurs in a high-estradiol phase (e.g., proestrus) relative to a low-estradiol phase (e.g., metestrus). We recently demonstrated a similar effect of the estrous cycle in adolescent rats. However, the underlying mechanisms of this effect, especially in adolescence, remain unclear. A possible mechanism for enhanced extinction during proestrus is Brain-Derived Neurotrophic Factor (BDNF). Brain BDNF expression and activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB), co-vary with estradiol levels across the estrous cycle. AIMS & OBJECTIVES: Here, we investigated whether enhancing activation of TrkB during extinction rescues extinction retention deficits in adolescent female rats. It was hypothesised that females in low estradiol phases of the estrous cycle would have enhanced extinction retention when administered a TrkB agonist before extinction training relative to vehicle controls. METHOD: Adolescent female Sprague-Dawley rats received 3 noise-shock pairings, extinction training, and tests for extinction retention and renewal of fear on consecutive days. 7,8-Dihydroxyflavone (7,8-DHF), a potent TrkB agonist, or vehicle was administered at 5 mg/kg i.p. before extinction training. Estrous cycle was monitored daily using vaginal lavage. RESULTS: In rats undergoing extinction training during metestrus, relative to vehicle, those given 7,8-DHF had lower levels of freezing at the extinction retention test, comparable to rats extinguished during proestrus. However, the augmentation of extinction retention by 7,8-DHF was estrous cycle-dependent. That is, 7,8-DHF did not enhance extinction retention in rats receiving extinction during proestrus that had relatively high levels of freezing at the extinction retention test following a stronger fear conditioning (five noise-shock pairings) or weaker extinction procedures. Neither the estrous cycle nor 7,8-DHF influenced renewal of fear. DISCUSSION & CONCLUSIONS: These findings suggest a potential approach to augment fear extinction in adolescent females during low-estradiol phases of the estrous cycle.