Ethinyl estradiol and levonorgestrel alter cognition and anxiety in rats concurrent with a decrease in tyrosine hydroxylase expression in the locus coeruleus and brain-derived neurotrophic factor expression in the hippocampus.
In the United States, more than ten million women use contraceptive hormones. Ethinyl estradiol and levonorgestrel have been mainstay contraceptive hormones for the last four decades. Surprisingly, there is scant information regarding their action on the central nervous system and behavior. Intact female rats received three weeks of subcutaneous ethinyl estradiol (10 or 30μg/rat/day), levonorgestrel (20 or 60μg/rat/day), a combination of both (10/20μg/rat/day and 30/60μg/rat/day), or vehicle. Subsequently, the rats were tested in three versions of the novel object recognition test to assess learning and memory, and a battery of tests for anxiety-like behavior. Serum estradiol and ovarian weights were measured. All treatment groups exhibited low endogenous 17β-estradiol levels at the time of testing. Dose-dependent effects of drug treatment manifested in both cognitive and anxiety tests. All low dose drugs decreased anxiety-like behavior and impaired performance on novel object recognition. In contrast, the high dose ethinyl estradiol increased anxiety-like behavior and improved performance in cognitive testing. In the cell molecular analyses, low doses of all drugs induced a decrease in tyrosine hydroxylase mRNA and protein in the locus coeruleus. At the same time, low doses of ethinyl estradiol and ethinyl estradiol/levonorgestrel increased galanin protein in this structure. Consistent with the findings above, the low dose treatments of ethinyl estradiol and combination ethinyl estradiol/levonorgestrel reduced brain-derived neurotrophic factor mRNA in the hippocampus. These effects of ethinyl estradiol 10μg alone and in combination with levonorgestrel 20μg suggest a diminution of norepinephrine input into the hippocampus resulting in a decline in learning and memory.
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: jsimone@uga.edu.
Jean
J
Simone
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: eabogue@uga.edu.
Elizabeth A
EA
Bogue
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: dionnetb@uga.edu.
Dionnet L
DL
Bhatti
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: leday86@gmail.com.
Laura E
LE
Day
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: drwfarr@uga.edu.
Nathan A
NA
Farr
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA. Electronic address: anna.mary.grossman@gmail.com.
Anna M
AM
Grossman
Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, 150 Paul D. Coverdell Center, Athens, GA 30602, USA; Psychology, University of Georgia, 125 Baldwin Street, Athens, GA 30602, USA. Electronic address: pvholmes@uga.edu.
Philip V
PV
Holmes
D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D016912:Levonorgestrel / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D014446:Tyrosine 3-Monooxygenase
Anxiety; Brain-derived neurotrophic factor (BDNF); Contraceptive hormones; Learning/memory; Novel object recognition tests; Tyrosine hydroxylase