The synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC), is prescribed during gestation with the intent of reducing preterm delivery in individuals at risk for premature birth following a previous early delivery (Meis et al., 2003). Administered from gestational weeks 16–20 until week 37, in singleton pregnancies (Berghella, 2012), 17-OHPC is detectable within cord plasma of neonates up to 44 days after the termination of treatment (Caritis et al., 2012). This suggests that the fetus may be exposed to the synthetic progestin from maternal circulation. Recent research has raised concern regarding the efficacy of 17-OHPC. In a confirmatory trial required by the FDA in 2019, the Progestin's Role in Optimizing Neonatal Gestation trial demonstrated that 17-OHPC failed to reduce the incidence of preterm birth at gestational week 35 in individuals at risk when compared to a control group that received placebo treatment (Blackwell et al., 2020). Subsequently, the FDA has withdrawn its approval of 17-OHPC, and the manufacturer is set to voluntarily remove 17-OHPC from the market. Despite evidence that the developing fetus is exposed to 17-OHPC in utero and growing concern for the safety and efficacy of the use of 17-OHPC, little is known regarding the potential long-term effects of 17-OHPC on neural and behavioral development in children who may have been exposed.

The timing of 17-OHPC administration during pregnancy coincides with a critical period of development for the mesocorticolimbic dopaminergic pathway in the human fetal brain (Verney et al., 1993​). In rats, the mesocorticolimbic dopamine pathways develop during the late embryonic and early postnatal period (Kalsbeek et al., 1988; Niederkofler et al., 2015; Verney et al., 1982). In the neonatal rat, progesterone receptor (PR) is expressed within dopaminergic neurons of the ventral tegmental area (VTA) for the first two weeks of life and within pyramidal neurons in layers 2/3 of the medial prefrontal cortex (mPFC) from postnatal day 6 (P6) until at least P25 (Willing and Wagner, 2016b). Further, PR is expressed in the dopaminergic cells of the VTA that project to the mPFC (Willing and Wagner, 2016b). These findings suggest that both the source of dopaminergic projections (VTA) and the cortical target of those projections (mPFC) are sensitive to progestins during critical periods of maturation. Therefore, exposure to the exogenous synthetic progestin 17-OHPC may alter the development of this behaviorally important pathway.

Administration of 17-OHPC to rats during the first two postnatal weeks increased dopaminergic fiber density within the prelimbic (PL) mPFC at P25 (Willing and Wagner, 2016a) and altered the distribution pattern of dopaminergic fibers in females in PL at P7 (Lolier and Wagner, 2021). Considerable evidence demonstrates that the dopaminergic system within the mPFC regulates the expression of complex cognitive behaviors, such as attention, decision-making, cognitive flexibility, and behavioral impulsivity (Granon et al., 2000; St. Onge et al., 2011). Collectively, these data support the hypothesis that disruption of dopaminergic innervation to mPFC following developmental 17-OHPC exposure may have profound effects on adult cognitive behaviors mediated by the mesocorticolimbic dopamine pathway.

Indeed, previous research in rats has demonstrated that neonatal exposure to 17-OHPC disrupts complex cognitive behavior. Following 17-OHPC administration during the first two postnatal weeks, adult rats were significantly delayed in switching to a new rule in an extra-dimensional set-shifting task and committed significantly more preservative errors compared to controls (Willing and Wagner, 2016a). Likewise, in a reversal-learning task, 17-OHPC-exposed rats required more time to adjust to the inversion of a previously-acquired rule, compared to controls (Serpa et al., 2020). These deficits in changing strategy in response to changing contingencies suggest that developmental exposure to 17-OHPC impairs cognitive flexibility.

Decision-making deficits have also been observed in rodents exposed to 17-OHPC during development. In a modified signal detection task (mSDT) of attention, 17-OHPC exposure significantly increased response omissions across stimulus modalities in males and females, particularly at shorter stimulus durations, even though the accuracy of their responses was unaffected (Lolier et al., 2021). These results suggest that 17-OHPC treatment does not disrupt the ability to attend to stimuli per se. Increased omissions were also observed in 17-OHPC-exposed male rats in a delay discounting task as the delay lengthened. Remarkably, 17-OHPC-exposed males demonstrated greater inhibitory control compared to controls, consistent with a decrease in impulsive responding (Fahrenkopf et al., 2021). Collectively, developmental exposure to 17-OHPC increases response omissions across different cognitive tasks suggesting a deficit in fundamental aspects of decision making as the task became more difficult. While the underlying mechanism of omissions remains unclear, 17-OHPC may slow decision making, so that exposed rats may not respond on a lever within the 10-s response interval for delay discounting. Another alternative is that omissions may be an indicator of deficits in attention as resulting from disrupted dopaminergic innervation of mPFC. In addition, the effects of neonatal 17-OHPC on decision-making and omissions in females have not yet been investigated.

In humans, response omissions are thought to indicate lapses in attention and deficits in the ability to respond to a stimulus (Perri et al., 2017). Response omissions have been observed in studies involving humans with attention-deficit/hyperactivity disorder (ADHD) (De La Peña et al., 2020) with Methylphenidate (MPH), a common treatment for ADHD, significantly reduced omissions in children diagnosed with ADHD (Losier et al., 1996; Tucha et al., 2006). MPH exerts its effect by binding to norepinephrine (NET) and dopamine transporters (DAT), blocking the reuptake of norepinephrine and dopamine thereby increasing norepinephrine and dopamine availability at the synaptic cleft. The effect of MPH on omissions in measures of attention in children suggests that omissions are mediated by dopaminergic and noradrenergic activity. In rodents, systemic administration of MPH in rodents increased extracellular DA in mPFC and anterior cingulate cortex (ACC) when compared to controls and to baseline (Berridge et al., 2006). Therefore, dopaminergic activity mediated by MPH may play a role in regulating omissions committed by rodents as well.

The present study tested the hypothesis that developmental 17-OHPC exposure in female rats increases omissions in the Delay Discounting task, similar to males. Furthermore, we predict that omissions are not the result of prolonged response time but are altered by a clinically-relevant dopaminergic drug. Our previous study of delay discounting in males required a response within 10 s (Fahrenkopf et al., 2021). Therefore, in the current experiment, the response time was increased to 20 s, and response latencies were recorded. Additionally, we examined the effects of MPH on 17-OHPC-exposed females during delay discounting. We hypothesized that the increase in omissions following 17-OHPC administration may reflect an ADHD-like trait. Therefore, it was predicted that MPH, a common prescription to treat ADHD in humans, would decrease omissions in 17-OHPC-exposed rats.