Developmental exposure to the synthetic progestin, 17α‐hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision‐making in rats

Abstract

The synthetic progestin, 17α‐hydroxyprogesterone caproate (17‐OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17‐OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17‐OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17‐OHPC from postnatal days 1–14 decreased the density of SERT‐ir fibers within superficial and deep layers and decreased the density of synaptophysin‐ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17‐OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17‐OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision‐making. These results suggest that further investigation is warranted in the clinical use of 17‐OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

Sex differences in cognitive flexibility are driven by the estrous cycle and stress-dependent

“…It is equally important to consider how progesterone levels during the proestrus phase may affect set shifting. Other studies found that administration of progestin during development increases omissions and perseverative errors in cognitive tasks in adulthood (Willing and Wagner, 2016 ; Fahrenkopf et al, 2021 ). The observed omissions and perseverative errors made by the proestrus female rats during the light discrimination task indicate both slower cortical processing and cognitive rigidity (Uddo et al, 1993 ; Vasterling et al, 1998 ; Van Laethem et al, 2016 ; Miles et al, 2021 ).…”

Pharmacovigilance study of the association between progestogen and depression based on the FDA Adverse Event Reporting System (FAERS)

“…Levonorgestrel entering the blood circulation can affect the hypothalamic/pituitary axis, which can adversely affect mood [31]. A basic study in rats has shown that 17α-hydroxyprogesterone caproate inserted into progesterone receptors in the medial prefrontal cortex during development in rats caused damage to the medial prefrontal cortex serotonergic nerve, thereby affecting 5-HT nervemediated behavior [32]. Since the decline of 5-HT function is considered to be one of the important mechanisms of depression, this report suggests that progesterone may have a certain correlation with the occurrence of depression.…”