Performance on a modified signal detection task of attention is impaired in male and female rats following developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate.

Based on evidence that the developing mesocortical dopamine pathway is sensitive to progestins, in the present study we tested the hypothesis that attention, a fundamental component of successful cognitive behavior, is disrupted by developmental exposure to the synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC). To assess attentional impairments, a modified signal detection task was utilized with three stimulus modalities: compound (light and tone), light alone, and tone alone, for four stimulus durations (2, 0.5, 0.25, 0.125 s). Adult rats were trained to push one lever if they detected the stimulus, and another lever if the stimulus was not presented. 17-OHPC animals were able to attend to the task, as evidenced by similar correct responses as controls. However, as the task became increasingly difficult at shorter durations, 17-OHPC animals made significantly more omissions compared to controls, suggesting that 17-OHPC treatment may disrupt attentional processes and/or delay response time. These findings add to the current body of literature demonstrating that exposure to 17-OHPC during development produces deficits in cognitive behavior in adulthood. These results may inform potential risks associated with 17-OHPC treatment in pregnant women with a history of preterm delivery who are commonly recipients of such treatment.

Sex differences in dopamine innervation and microglia are altered by synthetic progestin in neonatal medial prefrontal cortex.

The synthetic progestin 17-α-hydroxyprogesterone caproate (17-OHPC) is commonly prescribed to pregnant women with a history of preterm delivery, despite little evidence of efficacy. The timing of 17-OHPC administration coincides with fetal mesocortical dopamine pathway development, yet the potential effects on cortical development and cognition are almost unknown. In rodent models, exposure to 17-OHPC significantly increased dopaminergic innervation of the medial prefrontal cortex (mPFC), an aberrant pattern of connectivity that may underlie deficits in cognitive flexibility observed in adulthood. In the present study, tyrosine hydroxylase (TH) immunoreactivity was used to determine whether 17-OHPC altered dopaminergic innervation of the mPFC during a neonatal period of synaptogenesis in males and females. Although there were no differences in the amount of TH-immunoreactive (-IR) fibres, there was a sex difference in TH-IR fibre distribution in deep layers of the prelimbic area (PL) mPFC; males had a narrower pattern of dopaminergic innervation than females. 17-OHPC exposure abolished these sex-specific patterns, such that 17-OHPC females had a narrower pattern in the PL than control females. In the infralimbic mPFC (IL), 17-OHPC males had a broader pattern of distribution of TH-immunoreactivity than control males with no differences in the amount of TH-IR fibres. 17-OHPC also created a sex difference in which males had a lower TH-IR fibre density than females. We also examined microglia, brain macrophages that play a key role in sculpting dopaminergic axon outgrowth in development, using phenotype as an indirect measure of microglial activity. Females had a greater number of reactive stout microglia compared to males in the PL, and males had more active round microglia than females in the IL. 17-OHPC treatment abolished the sex differences in both regions. These findings demonstrate that developmental exposure to 17-OHPC can exert differential effects in males and females and may diminish sex differences in cortical maturation.

NMDA receptor antagonism differentially reduces acquisition and expression of sucrose- and fructose-conditioned flavor preferences in BALB/c and SWR mice.

Conditioned flavor preferences (CFP) are elicited by sucrose and fructose relative to saccharin in rats and inbred mice. Whereas dopamine, but not opioid receptor antagonists interfere with the acquisition (learning) and expression (maintenance) of sugar-CFP in rats, these antagonists differentially affect acquisition and expression of sucrose- and fructose-CFP in BALB/c and SWR inbred mice. Given that NMDA receptor antagonism with MK-801 blocks acquisition, but not expression of fructose-CFP in rats, the present study examined whether MK-801 altered the expression and acquisition of sucrose- and fructose-CFP in BALB/c and SWR mice. In expression experiments, food-restricted mice alternately consumed a flavored (CS+, e.g., cherry, 5 sessions) 16% sucrose or 8% fructose+0.2% saccharin solution and a differently-flavored (CS-, e.g., grape, 5 sessions) 0.2% saccharin solution. 2-Bottle CS choice tests occurred following vehicle or MK-801 at doses of 100 or 200µg/kg. MK-801 mildly reduced the magnitude of the expression of sucrose- and fructose-CFP in BALB/c mice, and blocked the expression of fructose-, but not sucrose-CFP at the high dose in SWR mice. In acquisition experiments, groups of BALB/c (0, 100µg/kg) and SWR (0, 100, 200µg/kg) mice were treated prior to acquisition training sessions that was followed by 2-bottle CS choice tests without injections. MK-801 (100µg/kg) eliminated acquisition of sucrose- and fructose-CFP in BALB/c, but not SWR mice. The 200µg/kg MK-801 dose eliminated acquisition of sucrose- and fructose-CFP in SWR mice. Thus, NMDA receptor signaling is essential for the learning of both forms of sugar-CFP in both strains with BALB/c mice more sensitive to MK-801 dose effects.

BALB/c and SWR inbred mice differ in post-oral fructose appetition as revealed by sugar versus non-nutritive sweetener tests.

Recent studies indicate that C57BL/6J (B6) and FVB inbred mouse strains differ in post-oral fructose conditioning. This was demonstrated by their differential flavor conditioning response to intragastric fructose and their preference for fructose versus a non-nutritive sweetener. The present study extended this analysis to SWR and BALB/c inbred strains which are of interest because they both show robust flavor conditioning responses to fructose. In the first experiment, ad-libitum fed mice were given a series of 2-day, two-bottle preference tests between 8% fructose and a more preferred, but non-nutritive 0.1% sucralose +0.1% saccharin (S+S) solution (tests 1 & 4), and fructose or S+S versus water (tests 2 and 3). In test 1, SWR mice preferred S+S to fructose, and in tests 2 and 3, they preferred both sweeteners to water. In test 4, SWR mice switched their preference and consumed more fructose than S+S. In contrast, ad-libitum fed BALB/c mice strongly preferred S+S to fructose in both tests 1 and 4, although they preferred both sweeteners to water in tests 2 and 3. Food-restricted BALB/c mice also preferred the non-nutritive S+S to fructose in tests 1 and 4. The experience-induced fructose preference reversal observed in SWR, but not BALB/c mice indicates that fructose has a post-oral reinforcing effect in SWR mice as in FVB mice. Because B6 and FVB mice prefer glucose to fructose based on the post-oral actions of the two sugars, the second experiment compared the preferences of SWR and BALB/c mice for 8% glucose and fructose solutions. Ad-libitum fed and food-restricted SWR mice strongly preferred glucose to fructose. In contrast, ad-libitum fed BALB/c mice were indifferent to the sugars, perhaps because of their overall low intakes. Food-restricted BALB/c mice, however, strongly preferred glucose. These findings indicate that SWR and BALB/c mice differ in their preference response to the post-oral actions of fructose.

Dopamine D1 and opioid receptor antagonist-induced reductions of fructose and saccharin intake in BALB/c and SWR inbred mice.

Sugar and fat intake in rodents are mediated in part by brain dopamine (DA) and opioid neurotransmitter systems although important strain differences exist. Thus, whereas sucrose intake of BALB/c and SWR mice was reduced by DA D1 (SCH23390: SCH) receptor antagonism, opioid (naltrexone: NTX) receptor antagonism reduced intake only in BALB/c mice. Both SCH and NTX reduced fat (Intralipid) intake in SWR, but not BALB/c mice. The present study extended this pharmacological analysis to caloric and non-caloric sweeteners by examining whether fructose (8%) or saccharin (0.2%) intakes were differentially suppressed in BALB/c and SWR mice by SCH (50-1600nmol/kg) or NTX (0.01-5mg/kg) over a 5- to 120-min time course. SCH significantly reduced fructose (200-1600nmol/kg) and saccharin (50-1600nmol/kg) intakes in both strains as did NTX (0.1-5mg/kg). Antagonist ID40 potencies were <50nmol/kg for SCH and 0.9mg/kg for NTX in inhibiting saccharin intake, and 1234nmol/kg for SCH and 5mg/kg for NTX in inhibiting fructose intake in BALB/c mice. For SWR mice, the ID40 potencies were <50nmol/kg for SCH and 0.02mg/kg for NTX in inhibiting saccharin intake, and 298nmol/kg for SCH and 2.6mg/kg for NTX in inhibiting fructose intake. Thus, saccharin intake was similarly reduced by SCH and NTX in BALB/c and SWR mice, but greater potencies of opioid (1.9-fold) and DA D1 (4-fold) receptor antagonism of fructose intake were observed in SWR relative to BALB/c mice, indicating strong strain differences.