title: Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats.
abstract: The mesocortical dopaminergic pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) contributes to the processing of reward signals. This pathway is regulated by gonadal steroids including estradiol. To address the putative role of estradiol and isotype-selective estrogen receptor (ER) agonists in the regulation of the rodent mesocortical system, we combined fMRI, HPLC-MS and qRT-PCR techniques. In fMRI experiments adult, chronically ovariectomized rats, treated with either vehicle, estradiol, ERα agonist 16α-lactone-estradiol (LE2) or ERβ agonist diarylpropionitrile (DPN), received a single dose of d-amphetamine-sulphate (10mg/kg, i.p.) and BOLD responses were monitored in the VTA and the PFC. Ovariectomized rats showed no significant response to amphetamine. In contrast, the VTA of ER agonist-substituted ovariectomized rats showed robust amphetamine-evoked BOLD increases. The PFC of estradiol-replaced animals was also responsive to amphetamine. Mass spectroscopic analysis of dopamine and its metabolites revealed a two-fold increase in both dopamine and 3,4-dihydroxyphenylacetic acid content of the PFC in estradiol-replaced animals compared to ovariectomized controls. qRT-PCR studies revealed upregulation of dopamine transporter and dopamine receptor in the VTA and PFC, respectively, of ER agonist-treated ovariectomized animals. Collectively, the results indicate that E2 and isotype-selective ER agonists can powerfully modulate the responsiveness of the mesocortical dopaminergic system, increase the expression of key genes related to dopaminergic neurotransmission and augment the dopamine content of the PFC. In a broader sense, the findings support the concept that the manifestation of reward signals in the PFC is dependent on the actual estrogen milieu of the brain.
authors: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary. Electronic address: sarvari@koki.hu.
authors: Miklós
authors: M
authors: Sárvári
authors: Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői út 19-21, 1103 Budapest, Hungary.
authors: Levente
authors: L
authors: Deli
authors: Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői út 19-21, 1103 Budapest, Hungary.
authors: Pál
authors: P
authors: Kocsis
authors: Institute of Biochemistry and Medical Chemistry, School of Medicine, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság út 20, 7624 Pécs, Hungary; Imaging Center for Life and Material Sciences, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
authors: László
authors: L
authors: Márk
authors: Institute of Biochemistry and Medical Chemistry, School of Medicine, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság út 20, 7624 Pécs, Hungary; Imaging Center for Life and Material Sciences, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
authors: Gábor
authors: G
authors: Maász
authors: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary.
authors: Erik
authors: E
authors: Hrabovszky
authors: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary; Faculty of Information Technology, Pázmány Péter Catholic University, Práter utca 50/A, 1083 Budapest, Hungary.
authors: Imre
authors: I
authors: Kalló
authors: Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői út 19-21, 1103 Budapest, Hungary.
authors: Dávid
authors: D
authors: Gajári
authors: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary.
authors: Csaba
authors: C
authors: Vastagh
authors: Institute of Biochemistry and Medical Chemistry, School of Medicine, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság út 20, 7624 Pécs, Hungary.
authors: Balázs
authors: B
authors: Sümegi
authors: Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői út 19-21, 1103 Budapest, Hungary.
authors: Károly
authors: K
authors: Tihanyi
authors: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary; Faculty of Information Technology, Pázmány Péter Catholic University, Práter utca 50/A, 1083 Budapest, Hungary.
authors: Zsolt
authors: Z
authors: Liposits
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007783:Lactones / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007783:Lactones; D009570:Nitriles; D011422:Propionates; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D004958:Estradiol; D010100:Oxygen; D003913:Dextroamphetamine; D004298:Dopamine
keywords: Dopamine; Estradiol; Estrogen receptor alpha; Estrogen receptor beta; Mesocortical pathway; Rat