title: WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent.
abstract: Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ER beta agonist, WAY-200070, to examine the role of ER beta activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. WAY-200070 also increased c-fos activation 4h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ER beta KO mice confirms that WAY-200070 was targeting ER beta. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed approximately 50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ER beta KO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient approximately 100% increase in 5-HT. To further investigate the role of ER beta receptors on serotonergic function, 5-HTP accumulation was measured. ER beta KO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3-30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response). The effects of the selective ER beta agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ER beta function may provide a novel treatment for affective disorders.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. hughesz@wyeth.com
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Platt
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Claudine M
authors.initials: CM
authors.lastname: Pulicicchio
authors.forename: Guoming
authors.initials: G
authors.lastname: Zhang
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Mark
authors.initials: M
authors.lastname: Day
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism; D019417:Hindlimb Suspension / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D010080:Oxazoles / Q000627:therapeutic use*; D010636:Phenols / Q000627:therapeutic use*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010080:Oxazoles; D010636:Phenols; C502077:WAY 200070; D006916:5-Hydroxytryptophan; D051076:Proto-Oncogene Proteins c-fyn