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 17 beta-estradiol (E-2)-mimetic therapies to women for treatment of menopausal symptoms. An important question is the nature of the trophic actions of E-2-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 E-2 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, E-2 (0.09 mg/kg) and/or raloxifene (1 mg/kg) subcutaneously 44-48 h before testing in a positive control, E-2-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. E-2 + raloxifene increased the number of tumors. Administration of E-2 or E-2 + raloxifene, but not raloxifene alone, increased pituitary and uterine weight, compared with vehicle administration. E-2 or E-2 + 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 E-2 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 E-2 and/or raloxifene can have some effects to alter the behavior of ovariectomized rodents, depending upon the task. As well, E-2, with or without raloxifene, can also have clear trophic actions in peripheral tissues, such as carcinogen-induced tumors, uterus, and pituitary glands. Behavioural Pharmacology 21: 231-240 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.