Androgens Enhance Recognition Memory and Dendritic Spine Density in the Hippocampus and Prefrontal Cortex of Ovariectomized Female Rats.

Estrogen replacement has been repeatedly shown to enhance memory and increase dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized (OVX) female rats. Given the potential deleterious effects of chronic estrogen administration, the present study assessed cognitive function using recognition memory tasks and measured dendritic spine density in the CA1 region of the hippocampus and medial prefrontal cortex after subchronic androgen replacement to adult OVX female rats. All androgens enhanced recognition memory in OVX rats, but object placement (OP) and object recognition (OR) results differed. Only testosterone enhanced OR. Testosterone had no effect on OP while dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and androstenedione (AD) enhanced OP. Dendritic spine density was increased by both TP and DHEA in both brain areas (DHT and AD were not tested). Lastly, we used the aromatase inhibitor, letrozole, to discriminate between potential androgenic and estrogenic effects of androgens on behavior. Letrozole alone did not alter recognition memory in OVX rats and did not block the effects of either TP or DHEA on recognition memory suggesting that effects were mediated via androgenic mechanisms. The present results expand previous information on gonadal hormone actions and show that, in addition to estrogens, androgens also improve memory and increase spine density in brains of OVX female rats. While requiring further investigation, these observations provide a basis for therapeutic interventions in the treatment of menopausal, age or disease related memory loss.

Estradiol and ERß agonists enhance recognition memory, and DPN, an ERß agonist, alters brain monoamines.

Effects of estradiol benzoate (EB), ERα-selective agonist, propyl pyrazole triol (PPT) and ERß-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2-4h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ERß contribute to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60-130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40-80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ERß mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus.

Non-intromissive mating stimuli are sufficient to enhance sexual behaviors in ovariectomized female rats.

When ovariectomized/adrenalectomized female rats, injected with subthreshold doses of estradiol are given copulatory stimulation by a male rat at half hour intervals, the level of lordosis gradually increases over the course of a few hours. We tested the hypothesis that paracopulatory behaviors (behaviors that occur repetitively prior to and between mounts), also generally considered to be heavily dependent on progesterone, are enhanced by this stimulation as well. We have reported previously that the enhancement of copulatory behavior is dependent to a large extent on intromissive stimulation by the male. In the present study, mating stimulation induced high levels of paracopulatory behaviors, as well as lordosis. Surprisingly, though, and in contrast to previous findings, this increase was seen not only in rats receiving intromissive stimulation, but in those receiving non-intromissive stimulation as well. Furthermore, intromissive stimulation induced high levels of rejection behavior. In a subsequent experiment, experimenter-induced, mechanical stimulation increased only rejection behaviors, not copulatory behavior. The results collectively demonstrate that, under the conditions used in these experiments, non-intromissive stimulation is sufficient for inducing both copulatory and paracopulatory behaviors in estradiol-primed rats. However, under the conditions used in these studies, intromissive stimulation increases rejection behaviors.