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.

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.

Gonadal hormones alter hypothalamic GABA and glutamate levels.

GABA and glutamate levels were measured in brain sites important for lordotic responding and in other hypothalamic sites after gonadal hormone treatments sufficient to activate lordosis. Estradiol increased GABA and glutamate in the ventromedial nucleus and the vertical diagonal bands. Progesterone administration to estradiol primed females led to a rapid decline of the transmitters in these areas. Results are discussed in relation to neuroendocrine regulation.

Serotonergic lesions decrease mu- and delta-opiate receptor binding in discrete areas of the hypothalamus and in the midbrain central gray.

Serotonergic nerve terminals in the brain were lesioned by intraventricular infusion of the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) and levels of mu- and delta-opiate binding were measured in brain areas implicated in reproductive behavior and gonadotropin secretion. The lesion decreased mu-receptor binding in the preoptic area (mPOA) and the midbrain central gray, while delta-receptor binding was decreased in the mPOA and the dorsomedial nucleus of the hypothalamus. Hypothalamic serotonergic lesions also attenuated morphine inhibition of female sexual behavior. These results indicate the existence of serotonergic-opiate interactions in select regions of the brain and suggest that these interactions may be important in the regulation of lordosis behavior.

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.

GABAergic-serotonergic interactions in regulating lordosis.

The GABAB agonist, baclofen, causes a dose-dependent decrease in lordosis, and this effect is attenuated following hypothalamic serotonin, (5-HT) lesions. Baclofen administration is associated with decreased 5-HT activity in the medial preoptic (mPOA) and ventromedial nuclei and enhanced 5-HT activity in the midbrain central gray, and with enhanced norepinephrine activity in the mPOA. Interactions between gamma-aminobutyric acid (GABA) and 5-HT may, therefore, be important for the activation of lordosis.

Testosterone locally increases vasopressin content but fails to restore choline acetyltransferase activity in other regions in the senescent male rat brain.

Age-related decreases have been reported in both vasopressinergic and cholinergic innervation in the rat brain. Since both systems are also sensitive to sex steroids, the effect of testosterone supplementation on vasopressin (AVP) levels and on choline acetyltransferase (ChAT) activity was investigated in the brains of young, middle-aged and aged male rats. Although no age-related changes in AVP levels were observed in the lateral septum or the medial amygdala (MA), peripheral testosterone administration raised AVP levels in the MA in all age groups. ChAT activity decreased with age in the medial preoptic area and was not restored by testosterone.

Hypothalamic serotonin lesions unmask hormone responsiveness of lordosis behavior in adult male rats.

Hypothalamic lesions of serotoninergic afferents following bilateral stereotoxic injections of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the region of the ventromedial hypothalamus enhanced the effects of hormonally induced lordosis responding in both male and female rats. However, similarities and differences in the enhanced responsiveness to ovarian hormones were observed between the sexes. Compared with sham-lesioned controls, lesioned males displayed elevated lordosis responding to estradiol (E) priming alone, as well as to priming with E followed by progresterone (P). On the other hand, lesioned females displayed elevated lordosis in response to E priming alone, but were not different from controls in a synergistic facilitation of lordosis by P after E priming. With respect to receptivity, neither lesioned nor control males displayed ear-wiggling and hop-darting in response to E + P, whereas both lesioned and control females were proceptive following this treatment. Therefore, hypothalamic lesions following 5,7-DHT increase lordosis, but fail to unmask in males the responsiveness to E + P priming proceptive behaviours by females. Further, the levels of lordosis responding displayed by lesioned males are lower than those of either lesioned or control females after E + P priming, as well as those of lesioned females after E priming alone, thus indicating that other inhibitory mechanisms continue to operate in the lesioned males.

Effects of hypothalamic serotonin depletion on lordosis behavior and gonadal hormone receptors.

The effects of chronic depletion of serotonin on feminine sexual behavior (lordosis), cytosolic progestin receptors and estradiol nuclear receptors were investigated. Intrahypothalamic administration of 5,7-dihydroxytryptamine (5,7-DHT) markedly enhanced lordotic responding in estradiol benzoate (EB)-primed, 5,7-DHT-treated female rats and in EB-progesterone primed, 5,7-DHT-treated male rats. Cytosolic progestin receptors were measured in preoptic-hypothalamic nuclei related to reproductive function in sham and 5,7-DHT-treated rats after EB priming. In both sexes, no differences between sham and 5,7-DHT-treated subjects were noted for progestin binding in the medial preoptic nucleus, ventromedial nucleus or arcuate-median eminence area. Estrogen-nuclear complexes were measured in the same brain nuclei of female rats following EB priming, and no differences between sham and 5,7-DHT-treated rats were found. Under the conditions employed, it would appear that, despite marked elevations in lordotic responsivity, the accumulation of estrogen nuclear receptors and the levels of estrogen inducible progestin receptors remain unaltered after chronic depletion of serotonin. Thus, serotonergic influences on lordosis do not appear to involve changes in the expression of steroid receptor levels in preoptic-hypothalamic nuclei known to mediate hormone-dependent neuroendocrine processes.

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [3H]serotonin binding.

The relationship between serotonin (5-HT) levels and [3H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [3H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [3H]5-HT binding. Fifty days postlesion, no significant differences in [3H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [3H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.

Serotonin and 5-hydroxyindoleacetic acid levels in discrete hypothalamic areas of the rat brain: relation to circulating corticosterone.

We examined the influence of adrenalectomy (ADX), and chronic corticosterone (CORT) replacement, on serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in discrete hypothalamic areas of the rat brain. A significant decrease in 5-HT (-25%) and 5-HIAA (-28%) content was observed in the paraventricular nucleus (PVN) 7 days following ADX. A similar decrease in 5-HT levels (-27%) was observed in the preoptic area (POM) following ADX. In contrast, 5-HT and 5-HIAA levels in the supraoptic nucleus (SON) were significantly elevated by 82% and 54%, respectively. Replacement therapy with subcutaneous CORT implants (200 mg) was effective in preventing these effects of ADX in some cases. These findings suggest that the pituitary-adrenal endocrine system may influence various physiological and behavioral functions via its action on serotonergic neurons within specific hypothalamic sites.

Noradrenergic regulation of alpha 1-receptors during the postnatal development of the guinea pig.

In guinea pig brain, alpha 1-noradrenergic receptor concentrations undergo region-specific fluctuations during the first weeks of postnatal life. However, the factors involved in the regulation of these receptors have yet to be identified. In this study, the ontogeny of one possible regulatory factor, norepinephrine, was examined in relation to postnatal changes in alpha 1-receptor levels in several different regions of guinea pig brain. Results from these studies showed that while the activity of the noradrenergic system increased throughout the first weeks of postnatal development in each brain area examined, the concentration of alpha 1-receptors decreased in preoptic area and hypothalamus and increased in cortex. In subsequent experiments, the effects of noradrenergic lesions with 6-hydroxydopamine on alpha 1-receptor levels were assessed to examine the possibility that alpha 1-receptors are differentially sensitive to noradrenergic stimulation in cortex and preoptic area/hypothalamus in immature guinea pigs. Noradrenergic lesions which reduced norepinephrine levels by 87-94% resulted in significant elevations in alpha 1-receptors in all regions examined. These results are discussed with reference to the anatomical distribution of alpha 1-receptors and their regulation by norepinephrine.

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)

Intrahypothalamic 5,7-dihydroxytryptamine: temporal analysis of effects on 5-hydroxytryptamine content in brain nuclei and on facilitated lordosis behavior.

The long-term relationship between serotonin (5-HT) levels in discrete hypothalamic nuclei and female rat sexual behavior, the lordosis response, was examined following intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). One week following 5,7-DHT injection, 5-HT levels in the ventromedial hypothalamic nucleus, dorsomedial nucleus, anterior hypothalamic nucleus and the medial preoptic nucleus were approximately 90% depleted as compared to sham animals. Other hypothalamic and preoptic areas including the arcuate-median eminence, vertical nucleus of diagonal band and lateral septal nucleus showed smaller reductions in 5-HT, from 40 to 70% of sham values. At this time estrogen-dependent lordosis behavior in the lesioned group was facilitated. Behavioral facilitation was greatest at 4 weeks post lesion when depletion of 5-HT in the VMN was maximal. 5-HT levels increased at 57 days after 5,7-DHT treatment in most areas, and by 71 days post lesion, no significant differences in 5-HT levels were found between sham and 5,7-DHT-treated groups. Concomitant with the increases in 5-HT, facilitated lordosis behavior gradually decreased. Loss of behavioral facilitation appeared to be most closely related to increases in content of 5-HT in the ventromedial nucleus. These results further support the hypothesis that 5-HT endings in the hypothalamus exert tonic inhibitory regulation over hormone-dependent lordosis in the female rat. They also indicate that regenerating 5-HT fibers in the hypothalamus can reinstate a normal pattern of hormone-dependent behavioral function.

Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats.

Administration of estradiol to gonadectomized female, but not male rats, is associated with increased activity of choline acetyltransferase in the medial aspect of the horizontal diagonal band nucleus, the frontal cortex, and CA1 of the dorsal hippocampus. Four other basal forebrain cholinergic nuclei did not show changes in choline acetyltransferase activity after estradiol. These data have implications for possible benefits of estradiol administration to patients with senile dementia of the Alzheimer's type.

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.

Intrahypothalamic 5,7-dihydroxytryptamine facilitates feminine sexual behavior and decreases [3H]imipramine binding and 5-HT uptake.

5,7-Dihydroxytryptamine (5,7-DHT) injected into the hypothalamus facilitated feminine sexual behavior in ovariectomized, estrogen-treated female rats beginning 9 days post-lesion. 5,7-DHT treatment was associated with decreased [3H]5-HT but not [3H]NE uptake in the whole hypothalamus and with decreased [3H]-imipramine binding in some hypothalamic nuclei. These data provide the first demonstration using chemical lesions that 5-HT neurons may exert tonic inhibition on hormone-mediated feminine sexual behavior.

Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas.

Activities of type A monoamine oxidase (MAO), acetylcholine esterase (AChE), and glucose-6-phosphate dehydrogenase (G6PDH) were differentially altered in hormone-sensitive areas of the preoptic-hypothalamic continuum after administration of estrogen and progesterone. Estrogen increased activity of AChE in the bed nucleus of the stria terminalis and activity of G6PDH in the periventricular area (PVE) of the preoptic area, arcuate-median eminence (Ar-ME) and pituitary. Estrogen decreased activity of MAO in the PVE of the anterior hypothalamus, pars lateralis of the ventromedial nucleus and in the Ar-ME. Acute administration of progesterone (1 h) to estrogen-treated females did not further alter estrogen-dependent changes in AChE or G6PDH; however, MAO activity in the ventromedial nucleus and Ar-ME was rapidly increased after progesterone. Without prior estrogen administration, progesterone did not affect MAO activity. Administration of the protein synthesis inhibitor anisomycin prior to progesterone did not antagonize progesterone-dependent increases in MAO. Progesterone added in vitro to homogenates from estrogen-treated but not from untreated females increased MAO activity. The hormonal specificity, time course of effects and anatomical location of the enzymatic changes suggest that some of them may participate in the mediation of gonadal hormone action in the CNS. In particular, changes in MAO activity in the ventromedial nucleus and Ar-ME are consistent with reported effects of these hormones on monoamine turnover which in turn have been suggested to contribute to hormonal regulation of feminine sexual behavior and gonadotropin secretion.

Inhibition of lordosis behavior by intrahypothalamic implants of pargyline.

Hypothalamic sites responsible for monoaminergic of gonadal hormone-facilitated female sexual behavior (the lordosis response) were investigated. Pargyline, an irreversible inhibitor of monoamine oxidase, was applied stereotaxically to the hypothalamus of ovariectomized, estrogen-primed females 2 h prior to progesterone administration. Application of pargyline dorsal to or within the lateral aspect of the ventromedial nucleus led to a reduction in lordosis quotients and quality scores 5-7 and 29-31 h later. Implantation dorsal to or within the dorsomedial nucleus did not inhibit lordosis responding 5-7 h later but did inhibit the response 29-31 h later. In both implant sites, lordosis responding returned to prepargyline levels within 55 h after drug placement. The effects of the pargyline cannulae were verified biochemically by measuring activity of monoamine oxidase in preoptic-hypothalamic nuclei. Enzyme activity was inhibited to some extent in all nuclei sampled. The ability of the implants to antagonize lordosis responding was related to the extent to which they inhibited monoamine oxidase activity in the hypothalamus. Results suggest that localized perturbations in hypothalamic cells whose monoamine metabolism is known to be affected by gonadal hormones is sufficient to affect female sexual behavior.

Effects of monoamine oxidase inhibition on female sexual behavior, serotonin levels and type A and B monoamine oxidase activity.

Administration of various monoamine oxidase (MAO) inhibitors to ovariectomized-adrenalectomized, estrogen and progesterone-treated female rats was utilized to study possible relationships between the lordosis response and levels of preoptic-hypothalamic MAO and serotonin (5HT). Depending on the drug and dose, behavioral changes ranged from no effect to complete abolition of the lordosis response. Surprisingly, only those treatments which substantially inhibited both the A and B forms of MAO affected lordosis. However, behavioral deficits were related to increases in 5HT levels in a graded manner. In fact, a sigmoid-shaped dose-response curve was generated by plotting either the lordosis quotient or quality score versus the percent increase in preoptic-hypothalamic 5HT. Proceptivity was reduced by some treatments but not abolished, suggesting that different neurotransmitters may mediate receptive and proceptive components of female sexual behavior. In general, these results support the hypothesis that 5HT may exert inhibitory control over hormone dependent female sexual behavior and suggest that previously reported changes in MAO activity and 5HT levels following gonadal steroid treatment could pay a role in hormonal facilitation of female sexual behavior.