Alcohol administration blocks stress-induced impairments in memory and anxiety, and alters hippocampal neurotransmitter receptor expression in male rats.

Chronic exposure to stress has many deleterious effects on behavior, which can often lead to self-medication with anxiolytics, antidepressants, or alcohol. We determined the effects of alcohol administration following a stressor on established behavioral, physiological, and neural responses to stress. Male Sprague-Dawley rats received: No alcohol/No stress (CON), Alcohol alone (ALC), Stress alone (STR), or Stress plus Alcohol (STR+ALC). For seven consecutive days, two cohorts received an oral dose of 2.0 g/kg of either 20% ethanol or saline. In Cohort 1, behavioral testing began after the final treatment (day-8). Memory was tested using the object recognition (OR) and Y-maze, anxiety on the plus maze, and depression on the forced swim task. Memory on OR and Y-maze tasks was impaired in the ALC and STR groups. This deficit was reversed in the STR+ALC group, which performed not differently from the CON group. Stress alone was associated with increased anxiety, which was alleviated with alcohol treatment. No treatment effects were found in the forced swim task. In Cohort 2, hippocampal GABAα4 was upregulated in the STR+ALC group and GluN2B was upregulated in the ALC and STR+ALC groups. The STR+ALC group in Cohort 1 showed enhanced corticosterone levels after forced swim. The STR+ALC group in Cohort 2 showed increased corticosterone levels on day-1 of treatment and a habituation by day-7. In conclusion, this study found a reversal of stress-induced deficits in cognition and anxiety when alcohol was given post-stress, and changes in neurotransmitter receptor expression may contribute to these behavioral effects.

The gene encoding proline dehydrogenase modulates sensorimotor gating in mice.

Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.

Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas.

Acute effects of estrogens on mnemonic processes were examined at the behavioral and neurochemical levels. 17beta-estradiol and 17alpha-estradiol influences on memory consolidation were assessed using object placement (OP) and object recognition (OR) tasks. Subjects received treatment immediately after a sample trial (exploring two novel objects), and memory of objects (OR memory) or location of objects (OP memory) was tested 4h later. Both isomers of estradiol enhanced memory. For spatial memory, 15 and 20 microg/kg of 17beta-estradiol facilitated OP, while lower and higher doses were ineffective. 17alpha-estradiol had a similar pattern, but a lower dose was effective. When treatment was delayed until 45 min after a sample trial, memory was not enhanced. For non-spatial memory, OR was facilitated at 5 microg/kg of 17beta-estradiol and at 1 and 2 microg/kg of 17alpha-estradiol and, similar to OP, lower and higher doses were ineffective. These data demonstrate that beneficial effects of estrogens are dose, time and task dependent, and the dose-response pattern is an inverted U. Because monoamines are known to have contributions to memory, brains were removed 30 min after treatment for measurements of dopamine (DA), norepinephrine (NE), serotonin (5-HT), and metabolites. Estrogen elevated 5HT, NE metabolite MHPG, turnover ratio of NE to MHPG, and DA metabolite DOPAC levels in the prefrontal cortex, while NE and MHPG were decreased in the hippocampus. Thus, acute estrogens exert rapid effects on memory consolidation and neural function, which suggests that its mnemonic effects may involve activation of membrane associated estrogen receptors and subsequent signaling cascades, and that monoamines may contribute to this process.

Hippocampal dynorphin immunoreactivity increases in response to gonadal steroids and is positioned for direct modulation by ovarian steroid receptors.

The hippocampal formation (HF) is involved in modulating learning related to drug abuse. While HF-dependent learning is regulated by both endogenous opioids and estrogen, the interaction between these two systems is not well understood. The mossy fiber (MF) pathway formed by dentate gyrus (DG) granule cell axons is involved in some aspects of learning and contains abundant amounts of the endogenous opioid peptide dynorphin (DYN). To examine the influence of ovarian steroids on DYN expression, we used quantitative light microscopic immunocytochemistry to measure DYN levels in normal cycling rats as well as in two established models of hormone-treated ovariectomized (OVX) rats. Rats in estrus had increased levels of DYN-immunoreactivity (ir) in the DG and certain CA3 lamina compared with rats in proestrus or diestrus. OVX rats exposed to estradiol for 24 h showed increased DYN-ir in the DG and CA3, while those with 72 h estradiol exposure showed increases only in the DG. Six hours of estradiol exposure produced no change in DYN-ir. OVX rats chronically implanted with medroxyprogesterone also showed increased DYN-ir in the DG and CA3. Next, dual-labeling electron microscopy (EM) was used to evaluate the subcellular relationships of estrogen receptor (ER) alpha-, ERbeta and progestin receptor (PR) with DYN-labeled MFs. ERbeta-ir was in some DYN-labeled MF terminals and smaller terminals, and had a subcellular association with the plasmalemma and small synaptic vesicles. In contrast, ERalpha-ir was not in DYN-labeled terminals, although some DYN-labeled small terminals synapsed on ERalpha-labeled dendritic spines. PR labeling was mostly in CA3 axons, some of which were continuous with DYN-labeled terminals. These studies indicate that ovarian hormones can modulate DYN in the MF pathway in a time-dependent manner, and suggest that hormonal effects on the DYN-containing MF pathway may be directly mediated by ERbeta and/or PR activation.

Facilitated sexual behavior reversed and serotonin restored by raphe nuclei transplanted into denervated hypothalamus.

Fetal raphe cells transplanted into the hypothalamus reversed facilitation of feminine sexual behavior in rats with brain lesions induced by 5,7-dihydroxytryptamine. Immunocytochemical and chemical analyses of serotonin indicate that reinnervation of the ventromedial nucleus of the hypothalamus by the transplants is associated with behavioral recovery. The findings suggest that transplanted fetal tissue can exert functional regulation over an innate, complex, hormone-dependent behavior in adult rats.

Sex-dependent changes in anxiety, memory, and monoamines following one week of stress.

Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.

Chronic stress and neural function: accounting for sex and age.

Cognitive responses to stress follow the temporally dependent pattern originally established by Selye (1) wherein short-term stressors elicit adaptive responses whereas continued stress (chronic) results in maladaptive changes--deleterious effects on physiological systems and impaired cognition. However, this pattern for cognitive effects appears to apply to only half the population (males) and, more specifically, to young, adult males. Females show different cognitive responses to stress. In contrast to impaired cognition in males after chronic stress, female rodents show enhanced performance on the same memory tasks after the same stress. Not only cognition, but anxiety, shows sex-dependent changes following chronic stress--stress is anxiolytic in males and anxiogenic in females. Moreover, behavioral responses to chronic stress are different in developing as well as aging subjects (both sexes) as compared to adults. In aged rats, chronic stress enhances recognition memory in both sexes, does not alter spatial memory, and anxiety effects are opposite to young adults. When pregnant dams are exposed to chronic stress, at adulthood the offspring display yet different consequences of stress on anxiety and cognition, and, in contrast to adulthood when the behavioral effects of stress are reversible, prenatal stress effects appear enduring. Changing levels of estradiol in the sexes over the lifespan appear to contribute to the differences in response to stress. Thus, theories of stress dependent modulations in CNS function--developed solely in male models, focused on peripheral physiological processes and tested in adults--may require revision when applied to a more diverse population (age- and sex-wise) at least in relation to the neural functions of cognition and anxiety. Moreover, these results suggest that other stressors and neural functions should be investigated to determine whether age, sex and gonadal hormones also have an impact.

Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex.

Effects of ovariectomy (OVX) on performance of the memory tasks, Object Recognition (OR) and Object Placement (OP), and on dendritic spine density in pyramidal neurons in layer II/III of the prefrontal cortex and the CA1 and CA3 regions of the hippocampus were determined. OVX was associated with a significant decline in performance of the memory tasks as compared to intact rats beginning at 1 week post OVX for OR and 4 weeks post OVX for OP. Golgi impregnation at 7 weeks post OVX showed significantly lower spine densities (17-53%) in the pyramidal neurons of the medial prefrontal cortex and the CA1, but not the CA3, region of the hippocampus in OVX compared to intact rats. These results suggest that cognitive impairments observed in OVX rats may be associated with morphological changes in brain areas mediating memory.

Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats.

Long-term maintenance of ovariectomized rats (9 weeks) on chow containing high phytoestrogen levels (Purina LabDiet 5001) as compared to chow with minimal phytoestrogens (Harlan 2016 Teklad) was associated with better performance of the spatial memory task, object placement, increased dendritic spine density in CA1 and prefrontal cortex pyramidal neurons, and higher uterine weights. Object recognition memory, anxiety on an elevated plus maze and body weight were unaffected by phytoestrogen levels in the diet.

Effects of an estrogen antagonist on enzyme activities and [3H]estradiol nuclear binding in uterus, pituitary and brain.

The estrogenic and anti-estrogenic properties of CI-628 on these specific biochemical markers of estrogen action was not identical in the different target tissues. The CI-628 dependent changes in protein content and enzyme activities in the uterus were less than half of the EB changes. In the preoptic area and CM-amygdala, CI-628 resulted in approximately the same changes in CAT and MAO activity as EB. 3) In the pituitary and uterus, CI-628 antagonized the EB-dependent increase in G6PDH activity. In the CM-amygdala and preoptic area, CI-628 pretreatment did not anatagonize the EB dependent changes in CAT and MAO. 4) CI-628 reduced nuclear binding of[3H]estradiol to approximately 5% of control in the uterus and pituitary and this effect lasted for at least 96 h. In contrast, CI-628 reduced nuclear binding in the preoptic area-hypothalamus-amygdala to 13% of control at 18 h after CI-628, but at 96 h nuclear binding of [3H]estradiol had recovered to 70% of control. Thus, the effect of CI-628 ON THESE SPECIFIC BIOCHEMICAL MARKERS OF ESTROGEN ACTION WAS NOT IDENTICAL IN THE DIFFERENT TARGET TISSUES. The possibility is discussed that the basis for the heterogeneity of responses may reside in the different time course of CI-628 interaction with cellular estrogen receptors in the target tissues.or the heterogeneity of responses may reside in the different time course of CI-628 interaction with cellular estrogen receptors in the target tissues.

Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments.

We investigated whether estrogenic actions of testosterone during development which mediate the suppression of feminine reproductive behavior and cyclic gonadotropin secretion also contribute to reported sex differences in the induction of choline acetyltransferase (ChAT) after estrogen priming in the diagonal band region of the preoptic area. Newborn female rats received estradiol (E2 females); newborn males received 1,4,6-androstatrien-3,17-dione (ATD), an inhibitor of aromatase (ATD males); and some of both sexes received vehicle treatment (control). In adulthood, feminine sexual behavior (lordosis) was tested after E2 plus progesterone priming. The neonatal treatments reversed the sex-specific response pattern; E2 females were defeminized and displayed minimal lordosis, as did control males, while ATD males showed maximal lordosis, as did control females. E2 was then administered, and ChAT activity was measured in the horizontal and vertical nuclei of the diagonal bands (hDB and vDB, respectively). Controls exhibited the normal sex-specific response to E2. Females showed increased ChAT activity in the hDB and unaltered activity in the vDB: males had unaltered ChAT activity in the hDB and decreased activity in the vDB. In neonatally treated males and females, ChAT activity after E2 administration was not altered from the normal sex-specific pattern in the hDB, i.e. all females showed increased hDB ChAT after E2, and no male responded. In the vDB, groups defeminized in terms of lordosis (E2 females and control males) showed higher ChAT activity in the absence of E2 priming, and E2 treatment decreased vDB ChAT in these groups. In addition, ATD males showed a unique response to E2 in the vDB, namely increased ChAT activity. Although neonatal E2 and ATD treatments did not completely reverse the sex-specific pattern of E2 priming on ChAT activity, the results obtained suggest that a net increase in diagonal band cholinergic function, as indexed by increased ChAT activity after E2 priming, may contribute to the ability of hormones to induce lordosis and/or LH surges.

1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei.

To better understand the role of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in brain function, the level of calcium-binding protein (CaBP) and the activities of choline acetyltransferase (CAT) and monoamine oxidase were measured in discrete brain nuclei of vitamin D-deficient and -replete male rats. The nuclei sampled were those in which receptors for 1,25-(OH)2D3 and/or vitamin D-dependent CaBP have been localized. Significant elevations in CAT activity were found in the arcuatemedian eminence and in the bed nucleus of the stria terminalis of rats made vitamin D replete by eight daily ip injections of 100 or 200 ng 1,25-(OH)2D3 as well as by constant intraventricular (ivi) infusion of 25 ng 1,25-(OH)2D3 for 7 days. The percent increase ranged from 12-45% and was related to the ip dose administered. Constant ivi of 2 mM CA2+ or 125 ng 25-hydroxyvitamin D3/day for 7 days did not alter CAT activity. No significant changes in monoamine oxidase or CaBP in discrete brain nuclei were observed with vitamin D repletion. Since the arcuate-median eminence of the hypothalamus is an important regulatory site in the neuroendocrine control of reproduction, serum testosterone was measured. Serum testosterone levels were abnormally low in the vitamin D-deficient animals, but increased 2- to 5-fold to normal values in those rats made vitamin D replete by constant ivi of 25 ng 1,25-(OH)2D3 or by ip injection of 100 or 200 ng 1,25-(OH)2D3. Patterns of serum LH paralleled those for testosterone. Our results suggest that 1,25-(OH)2D3 effects cholinergic activity in several discrete brain regions and may play a role in the neuroendocrine regulation of certain aspects of anterior pituitary gland function.

Age and sex-dependent decreases in ChAT in basal forebrain nuclei.

Microdissection techniques were utilized to measure the activity of choline acetyltransferase (ChAT) (enzyme responsible for synthesis of acetylcholine) in individual basal forebrain nuclei of aged (24 month) and young (4 month) male and female rats. Small but consistent decreases in the activity of ChAT in aged rats were found, and the location of the changes was dependent on the sex of the rat. Aged female rats showed approximately 30% lower ChAT and 40% lower acetylcholinesterase (AChE) activity in the ventral globus pallidus (vGP). Aged males did not show decreased ChAT in the vGP but activity in the medial aspect of the horizontal diagonal band nucleus was 50% lower than in the young males. ChAT activity in four other closely aligned basal forebrain nuclei was not different between the young and aged rats. Analysis of cell number, density and area in the vGP by AChE histochemistry showed no significant differences between aged and young females. In addition, age and sex-dependent changes were measured in pituitary glucose-6-phosphate dehydrogenase activity. The relationship of the changes to age-dependent decrements in memory, the possible influence of gonadal hormones on aging, and the mechanisms responsible for age-related declines in ChAT activity are discussed.

Effects of chronic restraint stress and estradiol on open field activity, spatial memory, and monoaminergic neurotransmitters in ovariectomized rats.

Twenty-one days of chronic restraint stress impairs male rat performance on the radial arm maze [Luine et al. (1994) Brain Res. 639, 167-170], but enhances female rat performance [Bowman et al. (2001) Brain Res. 904, 279-289]. To assess possible ovarian hormone mechanisms underlying this sexually dimorphic response to stress, we examined chronic stress effects in ovariectomized rats. Ovariectomized rats received Silastic capsule implants containing cholesterol or estradiol and were assigned to a daily restraint stress (21 days, 6 h/day) or non-stress group. Following the stress period, subjects were tested for open field activity and radial arm maze performance. Stress and estradiol treatment affected open field activity. All stressed animals, with or without estradiol treatment, made fewer total outer sector crossings. In contrast, estradiol-treated animals, with or without stress, made more inner sector visits, an indication that estradiol decreased anxious behavior on the open field across time. As measured by the total number of visits required to complete the task, stress did not affect radial arm maze performance in ovariectomized rats, but estradiol-treated animals, with or without stress, performed better than non-treated animals on the radial arm maze. Stressed subjects receiving estradiol showed the best radial arm maze performance. Following killing, tissue samples were obtained from various brain regions known to contribute to learning and memory, and monoamine and metabolite levels were measured. Several changes were observed in response to both stress and estradiol. Most noteworthy, stress treatment decreased homovanillic acid levels in the prefrontal cortex, an effect not previously observed in stressed intact females. Estradiol treatment increased norepinephrine levels in CA3 region of the hippocampus, mitigating stress-dependent changes. Both stress and estradiol decreased dentate gyrus levels of 5-hydroxyindole acetic acid. In summary, the current study provides novel information showing that estradiol alters behavioral and neurochemical responses to stress in ovariectomized rats. Estradiol treatment decreased anxious behavior on the open field and stressed animals receiving estradiol had enhanced radial arm maze performance. In relation to interactions between stress and estradiol on cognition and anxiety, changes in the prefrontal cortex dopaminergic system, dentate gyrus serotonergic system, and norepinephrine levels in the CA3 region appear important. Results show that estradiol may moderate stress effects on cognition and anxiety through both organizational and activation effects.

Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type.

Previous studies have suggested that estrogen may have an effect on cognitive and emotional function in women. Studies in rodents and non-human primates have demonstrated the presence of estrogen receptors in brain, and that estrogen can affect behavior in animals. Estrogen administration to ovariectomized rats increases choline acetyltransferase activity in certain regions of brain. Choline acetyltransferase activity is known to be significantly decreased in senile dementia-Alzheimer's type (SDAT). Based on these observations, we treated seven women with SDAT with low dosages of estradiol over a six week period. A battery of assessments was performed throughout the study period. Significant improvements in three women were noted on measures of attention, orientation, mood and social interaction. These estrogen-responsive women were characterized by dementia associated with an affective disorder, older age at onset, and evidence of osteoporosis. Side effects of estradiol therapy included withdrawal bleeding in one woman and transient breast tenderness in another. Estradiol therapy thus may benefit some postmenopausal women with SDAT. The occurrence of osteoporosis in the estrogen-responsive group suggests that SDAT in some women may be associated with or related to a systemic estrogen deficiency state. However, considering the potential for serious side effects as a result of estrogen therapy, the current risk to benefit ratio precludes the routine clinical use of estrogen for dementia until careful clinical research trials have been performed.

Relationship of gonadal hormone administration, sex, reproductive status and age to monoamine oxidase activity within the hypothalamus.

Abstract Activity of Type A monoamine oxidase (MAO) was measured in microdissected samples from preoptic-hypothalamic and hindbrain areas of young male and female rats, and aged female rats. Administration of estradiol and progesterone, in doses sufficient to facilitate lordosis behavior and induce a luteinizing hormone surge in ovariectomized, but not castrated rats, was associated with sexually dimorphic changes of MAO activity within the hypothalamus. Forty-two h following estradiol benzoate administration, increased MAO activity was measured in the ventromedial nucleus (VML) and midbrain central gray of females, while decreased MAO activity was measured in the VML and arcuate-median eminence (ArME) of males. Progesterone administration to estradiol benzoate-primed rats was associated with decreased MAO activity in the VML and medial preoptic nucleus (mPOA) of females and decreased activity in the dorsal raphe nucleus of males. Activity of MAO on diestrus, proestrus and estrus was assessed in ten preoptic-hypothalamic and hindbrain sites. Differences between days of the cycle were limited to the mPOA, ArME and VML. While activities were generally lowest at estrus, these areas exhibited different patterns of activity across the cycle. Activity was highest at proestrus in the mPOA and highest at diestrus in the VML and ArME. Activity of MAO in some areas of 25-month old, diestrus rats was altered as compared to young, cycling rats; however, ageing was not associated with widespread changes in MAO activity. In the suprachiasmatic nucleus, aged rats showed approximately 30% less activity than young rats. In the mPOA, VML and ArME, activity in aged females was different from some, but not all, days of the estrous cycle. These results show that MAO activity changes within specific hypothalamic sites when the neuroendocrine axis is altered. Since the changes are present in areas where activity of rnonoaminergic systems is critical for initiating gonadotrophin surges and inducing lordosis behavior, these results provide initial evidence that catabolism of monoamines by MAO may contribute to rnonoaminergic regulation of reproductive function.

Steroid hormone influences on spatial memory.

Our studies have shown that both stress-induced, enhanced secretion of corticosterone and adrenalectomy-induced, reduced secretion of corticosterone are associated with impaired spatial memory performance. On the other hand, estradiol administration is associated with enhancements in spatial memory performance. Although these changes in performance are small, they are consistent with structural changes induced by these hormones (or their lack) on specific cells within the hippocampus which form the tri-synaptic loop (a summary of the behavioral and morphological effects is shown in Figs. 1 and 2). Thus, these results suggest that the morphological changes induced by the hormones have an impact on hippocampal function. Important goals of future studies are to seek ways to maximize gonadal hormone-dependent enhancements in memory function and to minimize adrenal steroid-dependent impairments in memory function as well as to understand the mechanisms behind these behavioral and morphological changes.

5,7-DHT facilitated lordosis: effects of 5-HT agonists.

The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.

Analysis of temporal and dose-dependent effects of estrogen on monoamines in brain nuclei.

Levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were measured in hypothalamic and limbic nuclei of ovariectomized rats after various doses of estradiol and at various intervals after estradiol administration. Of 13 areas examined, time- and dose-dependent effects of estrogen on monoamine content were restricted to only a few, discrete areas which concentrate estradiol. Subcutaneous administration of 1-50 micrograms of estradiol benzoate (EB) and measurement of monoamines 24 h later was associated with dose-dependent increases of NE in the medial preoptic nucleus, diagonal band nucleus and periventricular area of the anterior hypothalamus, and increased levels of DA in the periventricular area of the preoptic area. No changes were found in 5-HT levels, but dose-dependent increases in the level of the 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), were measured in the lateral portion of the ventromedial nucleus. Effects of 5 micrograms of EB were evaluated at 1.5, 6, 12 and 45 h after administration. No changes were noted at 1.5 h, but 5-HIAA in the ventromedial nucleus was elevated at 6 and 12 h. NE levels were elevated at 12 and 45 h in the diagonal band and preoptic nuclei and at 45 h in the lateral septum and periventricular area of the hypothalamus. DA levels decreased in the arcuate-median eminence area 45 h after estrogen. Intravenous administration of 10 micrograms of estrogen and measurement of monoamines 1 h later was not associated with altered levels of any monoamine suggesting that the estrogen-dependent changes are consistent with the genomic model for steroid hormone action.(ABSTRACT TRUNCATED AT 250 WORDS)

Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT.

Activity of choline acetylase (ChAT) was measured in basal forebrain cholinergic nuclei and in projection sites of these cells in the hippocampus and cortex of young rats and of aged rats who showed impaired performance on the radial arm maze. Decreased ChAT activity was found in the vertical diagonal band nucleus, the dentate gyrus and striatum of aged rats.