coumestrol and 2-3-bis(4-hydroxyphenyl)-propionitrile

Estradiol (E(2)) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the beta isoform of estrogen receptor (ER) are important for E(2)'s effects for anxiety and/or depressive behavior. Whether ERbeta in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERbeta in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERbeta than ERalpha to the hippocampus, but not a control region/missed sites (i.e. the ventral tegmental area), should decrease anxiety and depressive behavior, compared to vehicle and that ERalpha-specific SERMs should not have the same effect. To investigate this, ovariectomized (ovx) rats were surgically-implanted with guide cannulae aimed at the hippocampus (target site) or ventral tegmental area (control site). Rats were administered vehicle, or 17beta-E(2) (equal affinity for ERalpha and ERbeta), SERMs with greater affinity for ERalpha vs. ERbeta (17alpha-E(2) or propyl pyrazole triol), or SERMs with greater affinity for ERbeta vs. ERalpha (coumestrol or diarylpropionitrile) to these sites (2 microg/microl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERbeta-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17beta-E(2) or ERbeta SERMs entered more central squares in an open field, spent more time on the open arms of the plus maze, and spent less time immobile compared to rats administered vehicle. Administration of ERalpha-specific SERMs produced similar effects as vehicle administration. Thus, E(2)'s anti-anxiety and anti-depressive effects may involve ERbeta in the hippocampus.

Topics: Animals; Anxiety; Coumestrol; Depression; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Hippocampus; Injections; Motor Activity; Nitriles; Ovariectomy; Propionates; Rats; Rats, Long-Evans; Selective Estrogen Receptor Modulators; Swimming

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.

Topics: Animals; Arousal; Avoidance Learning; Brain; Coumestrol; Dose-Response Relationship, Drug; Emotions; Escape Reaction; Estradiol; Estrogen Receptor alpha; Estrogen Receptor Modulators; Fear; Female; Inhibition, Psychological; Maze Learning; Mental Recall; Nitriles; Orientation; Phenols; Propionates; Pyrazoles; Rats; Rats, Long-Evans; Reaction Time; Receptors, Estrogen; Sexual Behavior, Animal