Effects of the phytoestrogen coumestrol on locomotor and fear-related behaviors in female mice.

Effects of the estrogenic plant isoflavonoid coumestrol (COUM) on locomotor activity and fear-related behaviors in both the absence and the presence of estradiol benzoate (EB) were examined in adult ovariectomized Swiss-Webster mice. In a running wheel paradigm conducted over 10 days, with treatment beginning 12 days prior to testing, daily subcutaneous (sc) injections of 10 microg of COUM did not influence locomotor activity, whereas even the low dose of EB supplied by sc Silastic implant (2.5 microg lasting 5 weeks) produced a significant increase in locomotor activity over animals receiving vehicle alone. In animals receiving both COUM and EB, locomotor activity was significantly diminished compared to the activity observed in animals receiving EB alone. The same animals were also tested in three behavioral paradigms having known activity and fear components (open field, dark/light transition, elevated plus-maze). COUM did not produce significant effects in these assays. However, in an associative fear learning paradigm (fear conditioning), COUM produced significantly less freezing ("fearfulness") in the conditioned fear task than with animals receiving vehicle or a low dose of EB, which did not differ from each other. Unlike EB, which has comparable affinities for estrogen receptor (ER) alpha and ER beta, COUM has a higher affinity for ER beta than for ER alpha. COUM might disrupt estrogen-enhanced locomotor activity by altering the dynamic by which EB acts on the brain through these two ER isoforms. The conditioned fear result suggests that COUM may produce additional effects through alternative pathways. Copyright 2001 Academic Press.