title: Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ 85287, USA.
authors.forename: B Blair
authors.initials: BB
authors.lastname: Braden
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Garcia
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mennenga
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Villa
authors.forename: Jazmin I
authors.initials: JI
authors.lastname: Acosta
authors.forename: Natalie
authors.initials: N
authors.lastname: Lefort
authors.forename: Alain R
authors.initials: AR
authors.lastname: Simard
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bimonte-Nelson
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced*; D003271:Contraceptive Agents, Female / Q000009:adverse effects* / Q000097:blood; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects* / Q000097:blood; D008570:Memory, Short-Term / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D003271:Contraceptive Agents, Female; D005680:gamma-Aminobutyric Acid; D017258:Medroxyprogesterone Acetate; D005968:Glutamate Decarboxylase