Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood

Abstract

The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery.

Figure 1.

Set shift task procedure. Habituation trials were conducted for 3 days prior to testing in which all arms were baited with a food reward. Set 1, Rats were trained to a criterion of eight consecutive correct trials in which one arm was barricaded and another arm was baited in a forced-choice paradigm. Barricaded and start arms were counterbalanced and the maze was rotated to eliminate use of spatial cues. Rats were placed into the start arm and were trained to learn a rule (ie, an association between a specific maze arm dimension [ie, color: light/dark or texture: rough/smooth] and the food reward [eg, food reward in light arms]). Set 2, Twenty-four hours after set 1, rats underwent 80 trials (10 trials per trial block), regardless of performance, in which a new rule using a different sensory domain was imposed (eg, food reward switched from light arm to rough arm). This extradimensional shift (from one sensory domain to another) is dependent on dopaminergic activity in the mPFC (10, 12). Again, the maze was rotated and start arms were counterbalanced across trials. Entry into an arm using the new rule was a correct trial. Entry into an arm using the rule from set 1 was considered a perseveration error. Entry into an arm that uses neither the new rule nor the old rule was considered an omission error.

Figure 2.

17-OHPC exposure during development did not affect learning of the initial rule in set 1 in adulthood. A and C, The number of trials required to reach criterion (ie, eight consecutive correct trials). B and D, The mean time required to complete each trial in set 1 of the set shift task in females (A and B) and males (C and D) treated neonatally with either 17-OHPC or the vehicle control. There were no significant effects of 17-OHPC treatment on either measure.

Figure 3.

17-OHPC exposure during development impaired cognitive flexibility and increased perseveration in adulthood. The percentage correct responses per trial block (each block is eight trials) in set 2 in females (A) and males (B) treated neonatally with either 17-OHPC or the vehicle control are shown. Dashed line indicates the point at which the shift to the new rule occurs in controls (see Materials and Methods). The number of perseveration errors (C and D) and omission errors (E and F) in set 2 for trial blocks 1–5 and trial blocks 6–10 in females and males treated neonatally with either 17-OHPC or the vehicle control is shown. *, Significant difference between control and 17-OHPC treated (P < .05); #, Significant difference between trial blocks 1–5 and 6–10 (P < .001). There were no significant effects of treatment or trial blocks on omission errors.*, Significantly different from control; *, P < .05) **, P < .01.

Figure 4.

17-OHPC exposure during development increased dopaminergic innervation in the prelimbic mPFC in preadolescence. Digital photomicrographs (×20 magnification) depicting PL mPFC layers I/II (A) and V/VI (B) are shown. The relative density of THir fibers in layers I/II (C and E) and layers V/VI (D and F) of the PL mPFC (C and D) or AC (E and F) in P25 males and females treated neonatally with either 17-OHPC or the vehicle control. *, Significantly different from control (P < .05). There were no significant effects of treatment in layers V/VI of the PL mPFC and no significant effects in either layer of the AC.