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. 2011 Nov;218(2):405-18.
doi: 10.1007/s00213-011-2322-4. Epub 2011 May 12.

Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time

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Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time

B Blair Braden et al. Psychopharmacology (Berl). 2011 Nov.

Abstract

Rationale: The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system.

Objectives: Using rats, we evaluated the long-lasting cognitive and GABAergic effects of MPA administered in young adulthood (Early-MPA), modeling contraception, and how this early exposure interacts with later MPA treatment (Late-MPA), modeling HT.

Methods: Early-MPA treatment involved weekly anti-ovulatory MPA injections (3.5 mg) from 4 to 8 months of age in ovary-intact rats. At 10 months old, rats were Ovx and weekly MPA injections were re-initiated and continued throughout testing for Late-MPA treatment.

Results: On the water radial-arm maze, all MPA-treated groups showed working memory impairment compared to Controls (p < 0.05); Early + Late-MPA rats were impaired on multiple dimensions of working memory (p < 0.05). On the Morris maze, Late-MPA rats showed greater overnight forgetting compared to Controls (p < 0.05). At study conclusion, MPA was detected in serum in all MPA-treated groups except Early-MPA, confirming treatment and clearance from serum in Early-MPA rats. In animals with detectable serum MPA, higher MPA levels were associated with less dorsal-hippocampal glutamic acid decarboxylase, the synthesizing enzyme for GABA (p = 0.0059).

Conclusions: Findings suggest that MPA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system. Further research defining the parameters of the negative impact of this widely used progestin on brain and cognition is warranted.

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Figures

Fig. 1
Fig. 1
A time line summarizing injections, ovariectomy, and behavioral testing for each group
Fig. 2
Fig. 2
Mean error scores (±SE) on the water radial-arm maze by treatment group [Control (white circle); Early-MPA (gray down-pointing triangle); Late-MPA (gray triangle); Early+Late-MPA (black square)]. a WMC errors across all days of testing. b WMI errors across all days of testing. c WMC errors across all trials, and at the highest working memory load (inset graph) during the latter portion of testing (days 5–11). d WMI errors across all trials, and at the highest working memory load (inset graph) during the latter portion of testing (days 5–11). *p<0.05
Fig. 3
Fig. 3
Mean distance scores in centimeters (±SE) on Morris maze Initial Testing days 1–4 by treatment group [Control (white circle); Early-MPA (down-pointing gray triangle); Late-MPA (gray triangle); Early+Late-MPA (black square)]. a Distance scores across all days and trials of initial testing (days 1–4). b Distance scores across the overnight interval. c Percent distance in the target NE quadrant as compared to the opposite SW quadrant during the probe trial day 4. *p<0.05
Fig. 4
Fig. 4
Mean distance scores in centimeters (±SE) on Morris maze Platform Switch testing day 5. a Distance across all eight trials by new (white circle) vs. original (black circle) platform location. b Percent distance in the target SW quadrant as compared to the opposite NE quadrant during the probe trial day 5 by treatment group [Control (white square); Early-MPA (gray square); Late-MPA (dark gray square); Early+Late-MPA (black square)]. *p<0.05
Fig. 5
Fig. 5
Mean latency scores in seconds (±SE) on the visible platform maze by treatment group [Control (white circle); Early-MPA (down-pointing gray triangle); Late-MPA (gray triangle); Early+Late-MPA (black square)]
Fig. 6
Fig. 6
Mean serum concentrations (±SE) by treatment group [Control (white square); Early-MPA (gray square); Late-MPA (dark gray square); Early+Late-MPA (black square)]. a MPA concentrations. b Progesterone concentrations. c Allopregnanolone concentrations. *p<0.05 vs. Control; ^p<0.05 vs. Early-MPA
Fig. 7
Fig. 7
Relation between MPA serum concentrations and GAD protein in the dorsal hippocampus in animals that had detectable levels of MPA at sacrifice (Late-MPA and Early+Late-MPA)

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