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  • These findings further extend our knowledge of how

    2021-04-08

    These findings further extend our knowledge of how P4 and/or E2 can mediate anxiety and fear responses. Female rats in behavioral estrous and ovx rats administered systemic P4 and/or E2 demonstrated significantly less anxiety in the open field and/or elevated plus maze, compared to diestrous rats, and those administered vehicle, respectively (Frye et al., 2000, Frye and Walf, 2004, Mora et al., 1996, Walf and Frye, 2005). Previous work demonstrated that rats in behavioral estrous, or ovx rats administered P4, show significantly less burying and freezing after touching a electrified prod, than do diestrous rats or ovx rats administered vehicle (Frye et al., 2000, Frye and Walf, 2004). The present findings extend these results to the marble burying and conditioned fear paradigms, in which rats in behavioral estrous or ovx rats administered P4 and/or E2, exhibited significantly less freezing than did those in diestrous or vehicle-administered rats, respectively. These findings suggest high progestogens and/or Dequalinium Chloride levels among intact and/or ovx rats may contribute to immediate responses to novel (marbles) and/or later response to contextual settings that had been paired with aversive (shock) stimuli. The present findings provide insight into how progestogens and/or estrogens may influence response to novel and/or aversive stimuli. Rats in behavioral estrous spent less time burying than did diestrous rats. Typically, rats in behavioral estrous exhibit more motor, and less anxiety, behavior than do diestrous rats (Frye et al., 2000). Administration of P4 or E2 alone to ovx rats does not increase motor activity in the open field, but co-administration does increase motor activity (Frye and Walf, 2004). Whether endogenous increases in progestogens and/or estrogens, or other hormones, that are elevated during behavioral estrous, may have contributed to differences in burying behavior were unclear. Given that ovx rats administered P4 or both P4 and E2 spent less time burying than did their E2-only or vehicle-administered counterparts, this implies that increases in progestogens and/or estrogens may underlie differences in burying responses to novel stimuli (marbles). However, in the conditioned fear task, progestogen- and estrogen-attributable differences in the flinch/jump responses of intact rats were not observed. Exposure to marbles and shock are very different. Shock is more aversive and cannot be avoided or ignored. As such, differences in aversive response to shock during training likely did not contribute to the freezing that was later observed during testing. Progestogen- or estrogen-related decreases in freezing associated with re-experiencing the contextual setting associated with aversive shock, may be in part due to effects of progestogens and/or estrogens to attenuate anxiety and/or fear. As well, pre-and/or post-training exposure to progestogens or estrogens did not produce amnestic effects in the conditioned fear paradigm. Indeed, progestogens and estrogens can enhance learning and/or memory when present after training in cognitive tasks (Frye et al., 2007, Walf et al., 2006). However, most cognitive tasks examined have assessed willingness to approach novel stimuli, rather than assessing avoidance of aversive stimuli. Performance in the conditioned fear task does not dissociate cognitive effects, from avoidance and/or coping response to aversive stimuli. Lower anxiety behavior generally observed when progestogen and estrogen levels are high may positively influence consolidation of aversive stimuli and later responses. Thus, physiological increases in progestogens and estrogens may enhance approach to novel stimuli, as well as decrease avoidance of aversive stimuli, while consolidating and/or engendering adaptive coping responses. Progesterone may play a role in mediating anxiety, impulsivity, fear and motor responses, and can produce other non-behavioral effects that are important when considering treatment options in a clinical population. As well, estrogen may be mediating effects on burying and aversive responses to novel and/or aversive stimuli. In intact naturally cycling female rats, progestogen and estrogen levels are high in behavioral estrous, and low in diestrous. Our lab has demonstrated systemic administration of estrogen to ovariectomized rats reduces anxiety in the open field and freezing in response to shock in the defensive freezing task compared to vehicle counterparts (Frye and Walf, 2004). In addition, administration of E2 at 10 µg or coumestrol at 10 µg, an ERβ selective estrogen receptor modulator (SERM), and post-training in the inhibitory avoidance task result in increased latencies to cross-over to the shock-associated side of the chamber (Rhodes and Frye, 2006). Co-administration of E2 and P4 to ovx rats decreases anxiety in the open field and freezing in response to shock in the defensive freezing task (Frye and Walf, 2004). Results from this research extend this to progestogen and/or estrogen's effects on impulsive burying and fear responses, such that administration of P4 alone or in combination with E2 to ovx rats reduces impulsive burying in the marble burying task, but estrogen alone does not. Additionally, administration of P4 and/or E2 reduces fear responding in the conditioned fear task. This suggests high levels of P4 and/or E2 may have actions to reduce impulsivity and fear responding. However, administration of RU38486, a progesterone receptor antagonist, to ovx female rats prior to P4 injection does not alter P4 elicited anxiolytic behavior in the elevated plus maze task (Bitran et al., 1995). This suggests P4 may not be altering burying behaviors or fear responding directly through progesterone receptors.