, Volume 218, Issue 2, pp 405–418

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


  • B. Blair Braden
    • Department of PsychologyArizona State University
    • Arizona Alzheimer’s Consortium
  • Alexandra N. Garcia
    • Department of PsychologyArizona State University
  • Sarah E. Mennenga
    • Department of PsychologyArizona State University
    • Arizona Alzheimer’s Consortium
  • Laszlo Prokai
    • University of North Texas Health Science Center
  • Stephanie R. Villa
    • Department of PsychologyArizona State University
  • Jazmin I. Acosta
    • Department of PsychologyArizona State University
    • Arizona Alzheimer’s Consortium
  • Natalie Lefort
    • Center for Metabolic BiologyArizona State University
  • Alain R. Simard
    • Barrow Neurological Institute
    • Department of PsychologyArizona State University
    • Arizona Alzheimer’s Consortium
Original Investigation

DOI: 10.1007/s00213-011-2322-4

Cite this article as:
Braden, B.B., Garcia, A.N., Mennenga, S.E. et al. Psychopharmacology (2011) 218: 405. doi:10.1007/s00213-011-2322-4



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.


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.


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.


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).


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.


Hormone therapyContraceptiveCognitionProgestinsMenopauseAgingLearning and memory

Copyright information

© Springer-Verlag 2011