Post-Training Administration of Estrogen and/or Androgens with Actions at ERα and/or ERβ to Male Rats Can Improve Performance in the Object Recognition Task

ABSTRACT

A decline in androgen and/or estrogen levels with aging can be associated with cognitive deficits in men. Androgen replacement to rodents with reduced androgen levels due to extirpation of the testes can reverse these deficits. However, there are multiple routes of metabolism and multiple substrates through which androgens may act to produce beneficial cognitive effects. Testosterone (T), which has a high affinity for androgen receptors (ARs), can be aromatized to 17β-estradiol, which may have actions at estrogen receptor β–(ERα) to produce beneficial cognitive effects. Alternatively, T can be 5-reduced to dihydrotesterone (DHT), which also has actions at ARs, or further reduced to 5-- androstane,17α-diolβ 3-diol (3-diol), which may have actions at GABA/benzodiazepine (GBRs) or ERβ. The present studies examined whether administration of estrogens and androgens that may have actions at ERs can enhance cognitive performance of male rats. Adult male rats were sham-surgerized and administered vehicle, or gonadectomized 3-6 weeks prior to testing. Gonadectomized rats were administered 3-diol, selective estrogen receptor modulators (SERMs) that had similar affinity for ERand ER (17α-estradiol), greater affinity for ER than ER (3-diol, diarylpropionitrile (DPN), coumestrol), or greater affinity for ERα than ERβ (17α-estradiol, propyl pyrazole triol (PPT), or vehicle control. Compounds were administered via 1 mg/kg subcutaneous injections immediately following training in the object recognition task. Four hours later, rats were tested in the task. Rats administered 17-estradiol, 3-diol, 17estradiol, or DPN had enhanced performance in the object recognition task compared to vehicle-administered rats. Thus, actions at ERs may underlie some of estrogens’ or androgens’ cognitive-enhancing effects. Keywords: Cognitio

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