title: Estrogen Receptor-Selective Agonists Modulate Learning in Female Rats in a Dose- and Task-Specific Manner.
abstract: Estrogens are well known for their enhancing effects on hippocampus-sensitive cognition. However, estrogens can also impair learning and memory, particularly the acquisition of striatum-sensitive tasks. These cognitive shifts appear to be mediated through local estrogen receptor (ER) activation in each neural structure, but little information is known regarding which specific ER subtypes drive the opposing effects on learning. Elucidating the mnemonic roles of discrete ER subtypes is essential for predicting how treatments with distinct ER pharmacology such as drugs, hormone therapies, and phytoestrogen supplements affect cognitive abilities in and thus the daily lives of the women who take them. The present study examined the effects of the ERα-selective compound propyl pyrazole triol and the ERβ-selective compounds diarylpropionitrile and Br-ERb-041 on place and response learning in young adult female rats. Long-Evans rats were ovariectomized and maintained on phytoestrogen-free chow for 3 weeks before behavioral training, with treatments administered via subcutaneous injection 48 and 24 hours before testing. A dose-response paradigm was used, with each compound tested at 4 different doses in separate groups of rats. Propyl pyrazole triol, diarylpropionitrile, and Br-ERb-041 all enhanced place learning and impaired response learning, albeit with distinct dose-response patterns for each compound and task. These results are consistent with the detection of ERα and ERβ in the hippocampus and striatum and suggest that learning is modulated via activation of either ER subtype.
authors.affiliation: Neuroscience Program (S.L.P., S.L.N., S.L.S., D.L.K.) and Department of Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Comparative Biosciences (S.L.N., S.L.S.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Department of Psychology and Neuroscience (S.L.N.), Baldwin Wallace University, Berea, Ohio 44017; and Department of Biology (D.L.K.), Syracuse University, Syracuse, New York 13244.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Pisani
authors.affiliation: Neuroscience Program (S.L.P., S.L.N., S.L.S., D.L.K.) and Department of Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Comparative Biosciences (S.L.N., S.L.S.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Department of Psychology and Neuroscience (S.L.N.), Baldwin Wallace University, Berea, Ohio 44017; and Department of Biology (D.L.K.), Syracuse University, Syracuse, New York 13244.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Neese
authors.affiliation: Neuroscience Program (S.L.P., S.L.N., S.L.S., D.L.K.) and Department of Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Comparative Biosciences (S.L.N., S.L.S.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Department of Psychology and Neuroscience (S.L.N.), Baldwin Wallace University, Berea, Ohio 44017; and Department of Biology (D.L.K.), Syracuse University, Syracuse, New York 13244.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Neuroscience Program (S.L.P., S.L.N., S.L.S., D.L.K.) and Department of Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Comparative Biosciences (S.L.N., S.L.S.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Department of Psychology and Neuroscience (S.L.N.), Baldwin Wallace University, Berea, Ohio 44017; and Department of Biology (D.L.K.), Syracuse University, Syracuse, New York 13244.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Schantz
authors.affiliation: Neuroscience Program (S.L.P., S.L.N., S.L.S., D.L.K.) and Department of Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Comparative Biosciences (S.L.N., S.L.S.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Department of Psychology and Neuroscience (S.L.N.), Baldwin Wallace University, Berea, Ohio 44017; and Department of Biology (D.L.K.), Syracuse University, Syracuse, New York 13244.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Korol
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007859:Learning Disabilities / Q000209:etiology* / Q000517:prevention & control; D018782:Maze Learning / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects; D020258:Neurotoxicity Syndromes / Q000503:physiopathology* / Q000517:prevention & control; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D010052:Ovariectomy / Q000009:adverse effects; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects; D010636:Phenols / Q000008:administration & dosage / Q000009:adverse effects; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D020318:Rats, Long-Evans; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects*; D065853:Spatial Learning / Q000187:drug effects; D023382:Toxicity Tests, Acute
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009570:Nitriles; D010080:Oxazoles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D020845:Selective Estrogen Receptor Modulators; C502077:WAY 200070; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol