Research report Response of tyrosine hydroxylase and GTP cyclohydrolase I gene expression to estrogen in brain catecholaminergic regions varies with mode of administration Lidia I. Serova a , Shreekrishna Maharjan a , An Huang b , Dong Sun b , Gabor Kaley b , Esther L. Sabban a, * a Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA b Department of Physiology, New York Medical College, Valhalla, NY 10595, USA Accepted 1 April 2004 Available online Abstract The effect of different dose, mode and duration of estradiol administration was examined in the different brain catecholaminergic areas in ovariectomized (OVX) female rats. We determined changes in mRNA levels of tyrosine hydroxylase (TH), rate-limiting enzyme in catecholamine (CA) biosynthesis, and of GTP cyclohydrolase I (GTPCH), rate-limiting enzyme in biosynthesis of tetrahydrobiopterin (BH4), as well as concentration of BH4, which is an essential cofactor for TH, tryptophan hydroxylase and nitric oxide synthase. Short-term administration of estradiol benzoate (EB) by five injections of 15 or 40 Ag/kg 12 h apart led to increase in TH and GTPCH mRNA levels in dopaminergic and noradrenergic cell bodies of the ventral tegmental area (VTA), substantia nigra (SN), locus coeruleus (LC) and the nucleus of solitary tract (NTS) depending on dose of administration. Estrogen-elicited alterations in BH4 concentrations were mostly correlated with changes in GTPCH mRNA levels, except in SN. Long-term administration of estradiol by injections (EB: 25 Ag/kg, 16 injections 24 h apart; 50 Ag/kg, 16 injections 48 h apart) or pellets (0.1 mg 17 h-estradiol, 14 days) were not very effective in modulating mRNA levels for both genes in most locations except the NTS. Long-term injections of EB elevated GTPCH mRNA levels throughout the NTS and in microvessels. Administration of estradiol by pellets led to decline of TH mRNA in rostral-medial and elevation in caudal parts of the NTS. Thus, estradiol has a complex and differential effect on TH and GTPCH gene expression in a tissue specific manner and depends on the mode of administration. D 2004 Elsevier B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters and receptors Topic: Catecholamines Keywords: Estradiol; Tyrosine hydroxylase; GTP cyclohydrolase I; mRNA; Tetrahydrobiopterin 1. Introduction The risk of cardiovascular disease displays gender specific differences with premenopausal women protected. Estrogens are likely at least partially responsible for this discrepancy (reviewed in Refs. [8,9,15]). Estrogen administration to experimental animals consistently showed neuroprotection, and improvements in microcirculation and reduction in blood pressure [3,16,31] indicating its potential benefit in alleviat- ing neurodegenerative and cardiovascular disorders. In fact, early studies suggested a reduction of cardiovascular events in women with hormone replacement therapy. However, recent double blind studies of the Woman’s Health Initiative suggesting an increase risk in coronary heart disease and perhaps dementia, led to cessation of Prempro (estrogen/ progesterone) administration. Discrepancies in the effects of estrogen therapy may be the result of methodological differ- ences between study designs or may relate to differences in the treatment regimens and/or in the subjects [10] . Conflicting results may also be due, in part, to the mode of hormone administration and their interaction with tissue specific effects of estrogens. Estrogen receptors (ERa and ERh) have been mapped not only to brain areas directly involved in the regulation 0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2004.04.002 * Corresponding author. Tel.: +1-914-594-4068; fax: +1-914-594- 4058. E-mail address: Sabban@nymc.edu (E.L. Sabban). www.elsevier.com/locate/brainres Brain Research 1015 (2004) 1 – 8