Raloxifene and/or estradiol decrease anxiety-like and  depressive-like behavior, whereas only estradiol increases  carcinogen-induced tumorigenesis and uterine proliferation  among ovariectomized rats.
Controversy surrounds the efficacy and safety of 17beta-estradiol (E2)-mimetic therapies to women for treatment of menopausal symptoms. An important question is the nature of the trophic actions of E2-mimetics in the brain for behavioral processes versus in the periphery for beneficial effects related to osteoporosis, or unwanted proliferative effects in the reproductive tissues, such as mammary glands and uterus. Of recent interest are the effects of selective estrogen receptor modulators, which can have tissue specific actions, for these processes. In the present study, the effects were determined of E2 alone, or co-administered with a selective estrogen receptor modulator, raloxifene, for anxiety-like, depression-like, and trophic peripheral effects in ovariectomized rats that were exposed to a chemical carcinogen (7,12-dimethylbenz(a)anthracene), or not. Once per week, rats were administered vehicle, E2 (0.09 mg/kg) and/or raloxifene (1 mg/kg) subcutaneously 44-48 h before testing in a positive control, E2-dependent behavior (lordosis), depression (forced swim test), and anxiety (elevated plus maze) behavioral assays. In addition to behavioral endpoints, incidence and number of tumors, and tumor, pituitary gland, and uterine weight 14 weeks after carcinogen-exposure, and weekly hormone treatments, were analyzed. Rats administered 7,12-dimethylbenz(a)anthracene had an increased number and size of tumors, compared with vehicle treatment. E2 + raloxifene increased the number of tumors. Administration of E2 or E2 +raloxifene, but not raloxifene alone, increased pituitary and uterine weight, compared with vehicle administration. E2 or E2 + raloxifene, but not raloxifene alone, also increased the incidence of lordosis and reduced the depression-like behavior in the forced swim test (i.e. decreased time spent immobile) compared with vehicle administration. However, administration of E2 or raloxifene reduced anxiety behavior in the elevated plus maze (i.e. increased time spent on the open arms of the maze), compared with vehicle treatment. Together these data show that E2 and/or raloxifene can have some effects to alter the behavior of ovariectomized rodents, depending upon the task. As well, E2, with or without raloxifene, can also have clear trophic actions in peripheral tissues, such as carcinogen-induced tumors, uterus, and pituitary glands.
Walf
Alicia A
AA
Department of Psychology, The University at Albany, State University of New York, Albany, NY 12222, USA.
Frye
Cheryl Anne
CA
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D009369:Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D012044:Regression Analysis; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D014599:Uterus / Q000473:pathology
D002273:Carcinogens; D004967:Estrogens; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene