Abstract
In women, high levels of natural progesterone have been associated with detrimental cognitive effects via the “maternal amnesia” phenomenon as well as in controlled experiments. In aged ovariectomized (Ovx) rats, progesterone has been shown to impair cognition and impact the GABAergic system in cognitive brain regions. Here, we tested whether the GABAergic system is a mechanism of progesterone’s detrimental cognitive effects in the Ovx rat by attempting to reverse progesterone-induced impairments via concomitant treatment with the GABAA antagonist, bicuculline. Thirteen month old rats received Ovx plus daily vehicle, progesterone, bicuculline, or progesterone+bicuculline injections beginning 2 weeks prior to testing. The water radial-arm maze was used to evaluate spatial working and reference memory. During learning, rats administered progesterone made more working memory errors than those administered vehicle, and this impairment was reversed by the addition of bicuculline. The progesterone impairment was transient and all animals performed similarly by the end of regular testing. On the last day of testing, a 6 hour delay was administered to evaluate memory retention. Progesterone-treated rats were the only group to increase working memory errors with the delay relative to baseline performance; again, the addition of bicuculline prevented the progesterone-induced impairment. The vehicle, bicuculline, and progesterone+bicuculline groups were not impaired by the delay. The current rodent findings corroborate prior research reporting progesterone-induced detriments on cognition in women and in the aging Ovx rat. Moreover, the data suggest that the progesterone-induced cognitive impairment is, in part, related to the GABAergic system. Given that progesterone is included in numerous clinically-prescribed hormone therapies and contraceptives (e.g., micronized), and as synthetic analogs, further research is warranted to better understand the parameters and mechanism(s) of progesterone-induced cognitive impairments.
Highlights
Within their lifetime, women will have to make the decision of whether to take exogenous hormones, either for contraception or for hormone therapy (HT) associated with menopause
Water Radial-Arm Maze For the omnibus ANOVA, across all testing days (Days 1–14) and including all treatment groups, there was a main effect of Day for each error type (WMC: F(13,429) = 5.828; p < 0.0001; Working Memory Incorrect (WMI): F(13,429) = 11.638; p < 0.0001; Reference Memory (RM): F(13,429) = 12.839; p < 0.0001), with errors decreasing across days, demonstrating learning
The results add to a growing body of literature implicating both medroxyprogesterone acetate (MPA) and natural progesterone as detrimental to cognition in the middle-aged to aged surgically menopausal rat (Bimonte-Nelson et al, 2004b, 2006; Braden et al, 2010, 2011; Lowry et al, 2010; but see Chisholm and Juraska, 2012)
Summary
Women will have to make the decision of whether to take exogenous hormones, either for contraception or for hormone therapy (HT) associated with menopause. Administration of allopregnanolone, a progesterone metabolite, has been shown to impair cognition in healthy women (Kask et al, 2008) and young rats (Frye and Sturgis, 1995; Ladurelle et al, 2000; Johansson et al, 2002; Rabinowitz et al, 2014) These findings are salient since the use of progesterone (natural progesterone in its micronized form to be orally bioavailable) as the progestogen component of HT has become an option for women in the United States as recently as 1999 (Langer, 1999) and is a promising new candidate to replace MPA (Sturdee et al, 2011; The Writing Group for the PEPI Trial, 1995; Langer, 1999)
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