Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle.
Smokers often report an anxiolytic effect of cigarettes. In addition, stress-related disorders such as anxiety, post-traumatic stress syndrome and depression are often associated with chronic nicotine use. To study the role of the alpha5 nicotinic acetylcholine receptor subunit in anxiety-related responses, control and alpha5 subunit null mice (alpha5(-/-)) were subjected to the open field activity (OFA), light-dark box (LDB) and elevated plus maze (EPM) tests. In the OFA and LDB, alpha5(-/-) behaved like wild-type controls. In the EPM, female alpha5(-/-) mice displayed an anxiolytic-like phenotype, while male alpha5(-/-) mice were undistinguishable from littermate controls. We studied the hypothalamus-pituitary-adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin-releasing factor. Consistent with an anxiolytic-like phenotype, female alpha5(-/-) mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of alpha5, we treated cultured NTera 2 cells with progesterone and found that alpha5 protein levels were upregulated. In addition, brain levels of alpha5 mRNA increased upon progesterone injection into ovariectomized wild-type females. Finally, we tested anxiety levels in the EPM during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolytic-like in wild-type mice, but no cycle-dependent fluctuations in anxiety levels were found in alpha5(-/-) females. Thus, alpha5-containing neuronal nicotinic acetylcholine receptors may be mediators of anxiogenic responses, and progesterone-dependent modulation of alpha5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.
Gangitano
D
D
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Salas
R
R
Teng
Y
Y
Perez
E
E
De Biasi
M
M
D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000523:psychology; D004031:Diestrus; D030762:Estrous Cycle / Q000187:drug effects*; D005260:Female; D005838:Genotype; D019417:Hindlimb Suspension; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003345:Corticosterone; D003346:Corticotropin-Releasing Hormone; D011374:Progesterone; D011978:Receptors, Nicotinic; C523972:CHRNA5 protein, mouse