Sodium selenite supplementation during pregnancy and lactation promotes anxiolysis and improves mnemonic performance in wistar rats' offspring.

Selenium is a micronutrient which is part of selenoprotein molecules and participates in a vast number of physiological roles and, among them,we have fetal and neonatal development. Therefore, the aimof this studywas to evaluate possible behavioral changes in offspring of female rats supplemented during pregnancy and lactation with sodium selenite. To address that, we treated two groups of female rats by saline or sodium selenite at a dose of 1mg/kg through oral route and performed neurochemical and behavioral tests. In the offspring, the thyroid profile and hippocampal neurochemistrywere evaluated. Behavioral testswere performed in pups both during childhood and adulthood. We found out that selenium (Se) supplementation increased serum levels of triiodothyronine (25%, p b 0.001) and thyroxine (18%, p b 0.05) and promoted a tryptophan hydroxylase 2 (TPH 2) expression decrease (17%, p b 0.01) and tyrosine hydroxylase (TH) expression increase (202%, p b 0.01) in the hippocampus. The cholinesterase activity was decreased (28%, p b 0.01) in Se supplemented rats, suggesting a neurochemical modulation in the hippocampal activity. During childhood, the Sesupplemented offspring had a reduction in anxiety-like behavior both in elevated plus maze test and in light­dark box test. In adulthood, Se-treated pups had an increase in the locomotor activity (36%, p b 0.05) and in rearing episodes (77%, p b 0.001) in the open field test, while in the elevated plus maze test they also exhibited an increase in the time spent in the open arms (243%, p b 0.01). For the object recognition test, Se-treated offspring showed increase in the absolute (230.16%, p b 0.05) and relative index discrimination (234%, p b 0.05). These results demonstrate that maternal supplementation by sodium selenite promoted psychobiological changes both during childhood and adulthood. Therefore, the behavioral profile observed possibly can be explained by neurochemical changes induced by thyroid hormones during the critical period of the central nervous system ontogeny.

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.

Behavioral coping strategies in response to social stress are associated with distinct neuroendocrine, monoaminergic and immune response profiles in mice.

Individual variation in behavioral coping strategies to stress implies that animals may have a distinct physiological adaptation to stress; these differences may underlie differences in vulnerability to stress-related diseases. This study was designed to test the hypothesis that different behavioral coping strategies (active vs. passive) are stable over time and that they would be associated with differences in hypothalamic-pituitary-adrenal (HPA) and sympathetic-adreno-medular (SAM) axes, and monoaminergic and immune activity. Male mice were subjected to social stress. Twelve days after the first social interaction, mice were subjected to a second identical social stress interaction. Behavior was videotaped and assessed during both sessions. One hour after the final social interaction, serum was collected for corticosterone and adrenaline concentrations and brains were collected for hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression. Monoaminergic system activity was determined by mRNA expression of serotonin, dopamine and noradrenaline synthetic enzymes in the brain stem. Immune system activity was determined by mRNA expression of hypothalamic interleukin-1ß (IL-1ß) and splenic IL-1ß and interleukin-2 (IL-2). Mice engaging in a passive strategy had higher serum corticosterone and lower serum adrenaline concentrations than the active group. The passive group showed lower hypothalamic mRNA expression of IL-1ß and CRH and lower splenic mRNA expression of IL-2 and IL-1ß relative to mice in the active group. An active strategy was associated with higher expression of the dopaminergic synthetic enzyme, while a passive strategy was associated with decreased expression of the serotonergic synthetic enzyme. These findings indicate that individual coping strategies are stable over time and are related to differences in the physiological stress response and immune activity.

Progesterone receptor isoforms differentially regulate the expression of tryptophan and tyrosine hydroxylase and glutamic acid decarboxylase in the rat hypothalamus.

Progesterone exerts a variety of actions in the brain through the interaction with its receptors (PR) which have two isoforms with different function and regulation: PR-A and PR-B. Progesterone may modulate neurotransmission by regulating the expression of neurotransmitters synthesizing enzymes or their receptors in several brain regions. The role of PR isoforms in this modulation is unknown. We explored the role of PR isoforms in the regulation of tryptophan (TPH) and tyrosine (TH) hydroxylase, and glutamic acid decarboxylase (GAD) expression in the hypothalamus of ovariectomized rats. Two weeks after ovariectomy, animals were subcutaneously injected with 5 µg of estradiol benzoate (EB), and 40 h later, progesterone (P) was intracerebroventricularly (ICV) injected. Each animal received two ICV injections of 1 µg/µl (4 nmol) of PR-B and total PR (PR-A+PR-B) sense or antisense (As) oligonucleotides (ODNs). First injection was made immediately before sc EB injection, and 24h later animals received the second one. Twenty-four hours after P administration, rats were euthanized and brains removed to measure the expression of PR-A and PR-B, TPH, TH and GAD by Western blot. We observed that sense ODNs modified neither PR isoforms nor enzymes expression in the hypothalamus, whereas PR A+B antisense (PR A+B As) clearly decreased the expression of both PR isoforms in this region. ICV administration of PR-B As only decreased PR-B isoform expression with no significant effects on PR-A expression. A differential protein expression of TPH, TH and GAD was observed after PR isoforms antisense administration. PR-B As administration decreased the expression of TPH (65% with respect to control). In contrast, PR A+B As and PR-B As administration increased (51.6% and 34.4%, respectively) TH expression. The administration of PR A+B As and PR-B As diminished GAD expression (33.4% and 41.6%, respectively). Our findings indicate that PR isoforms play a differential role in the regulation of the content of TPH, TH and GAD in the rat hypothalamus.

Red ginseng inhibits exercise-induced increase in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in dorsal raphe of rats.

Red ginseng has been used as an ergogenic aid for endurance exercise. In this study, the effect of aqueous extract of Red ginseng on the endurance in treadmill exercise and 5-hydroxytryptamine (serotonin) synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats were studied. Rats receiving Red ginseng showed increased time to exhaustion for treadmill running, and Red ginseng treatment inhibited exercise-induced increases in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe. These results suggest that the suppressive effect of Red ginseng on serotonin level during exercise is a possible ergogenic mechanism of Red ginseng.

Effects of Paeonia radix on 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats.

Paeonia radix is the root of Paeonia japonica MIYABE, a perennial plant classified in the family Paeoniaceae. In the present study, the effects of Paeonia radix on performance in treadmill exercise, and 5-hydroxytryptamine (5-HT) synthesis and tryptophan hydroxylase (TPH) expression in the dorsal raphe were investigated. Time to exhaustion in treadmill exercise was increased and exercise-induced increases in 5-HT synthesis and TPH expression in the dorsal raphe were shown to be suppressed by Paeonia radix treatment; 5-HT synthesis and TPH expression were inhibited by Paeonia radix treatment under resting conditions as well. In sum, treatment with Paeonia radix, inhibiting 5-HT synthesis and TPH expression, may bring about reduced fatigue, both during exercise and the resting state.

Effects of acupuncture on the 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats.

In the present study, the effects of acupuncture on the endurance treadmill exercise, serotonin (5-hydroxytryptamine, 5-HT) synthesis, and tryptophan hydroxylase (TPH) expression in the dorsal raphe nuclei were investigated. Acupunctural stimulation were bilaterally inserted into the locus of Zusanli in each hind leg for 20 min. Onset of exhaustion time on the treadmill running was increased significantly by acupunctural stimulation and exercise-induced increments of the 5-HT synthesis and TPH expression in the dorsal raphe were suppressed by acupunctural stimulation. Based on the results, it can be suggested that the suppressive effects of acupunctural stimulation on the 5-HT synthesis and TPH expression in the dorsal raphe during exercise is one of ergogenic mechanisms of acupuncture.

Inducible expression of tryptophan hydroxylase without serotonin synthesis in hypothalamic dopaminergic neurons.

In the present study we have further studied the previous findings that rat hypothalamic dopaminergic neuronal cell groups may express tryptophan hydroxylase (TpH), the serotonin synthesizing enzyme, without a detectable serotonin synthesis. Chemical and mechanical neuronal injuries, namely colchicine treatment and axonal transection, respectively, were performed, and distributions of neurons exhibiting immunoreactivity for TpH and/or tyrosine hydroxylase (TH), the dopamine synthesizing enzyme, were analyzed throughout the hypothalamic periventricular and arcuate nuclei. After colchicine treatment there was a statistically significant 87% (P = 0,01) increase in the number of TpH expressing neurons, while TH expression remained essentially similar. Axonal transection resulted also in a statistically significant 131% (P < 0,01) increase in the number of TpH expressing neurons, while TH expression was not significantly altered. All TpH expression coexisted with TH expression, and the induction of TpH expression by neuronal injuries occurred evenly throughout the rostrocaudal length of the territory studied. A possible serotonin synthesis by TpH was examined by giving drugs that increase brain serotonin synthesis, but no immunohistochemically detectable serotonin synthesis could be found in any of the TpH expressing neurons. Finally the possibility was studied that the relative shortage of the cofactor tetrahydrobiopterin would limit serotonin synthesis. However, an administration of tetrahydrobiopterin did not result in detectable serotonin synthesis in these neurons. Taken together these results suggest that dopaminergic neurons in the hypothalamic periventricular and arcuate nuclei are able to express TpH, this expression is induced after neuronal injury, and this induction occurs similarly throughout the territories studied. TpH expression occurs independently of TH expression, and the newly expressed TpH appears not to synthesize serotonin, regardless of pharmacological pretreatments. Thus, our findings (i) support the idea that neurons may possess inducible expression of nonfunctional transmitter-synthesizing enzymes, in this case TpH, and (ii) suggest that expression of an enzyme synthesizing a certain transmitter may not necessarily imply the corresponding transmitter phenotype.

Changes in activity and mRNA for rat tryptophan hydroxylase and aromatic L-amino acid decarboxylase of brain serotonergic cell bodies and terminals following neonatal 5,7-dihydroxytryptamine.

In the present study, we examined time-dependent changes in activity, mRNA and immunoreactivity of the serotonin biosynthetic enzymes, tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC) in dorsal raphe nucleus (DRN), caudal brainstem and hypothalamus, following intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT) in neonatal rats. TPH activity in central serotonergic cell bodies and terminals was reduced to 20-30% of control levels at 1-8 weeks after neonatal, low-dose 5,7-DHT injection (24 micrograms free base). In contrast, AADC activity was either not changed or decreased to 40% of control levels, depending on the region. In situ hybridization and immunocytochemical staining indicated that 5,7-DHT caused a marked reduction in TPH and AADC message levels as well as the number of 5-HT and AADC-immunoreactive cells within the DRN as early as 1 week after 5,7-DHT. Even 15 weeks after drug administration recovery did not occur. This apparent neuronal loss was region-specific suggesting that some serotonergic neurons are more resistant to neonatal 5,7-DHT treatment than others. Taken together, these studies indicate that neonatal treatment with 5,7-DHT produces a marked and permanent (up to 15 weeks) reduction in the number of central serotonergic neurons.

Effect of flunarizine and nimodipine on the decrease in tryptophan hydroxylase activity induced by methamphetamine and 3,4-methylenedioxymethamphetamine.

The effect of calcium channel blockers on the decrease in central tryptophan hydroxylase (TPH) activity and serotonin (5-HT) concentration induced by repeated large doses of methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received four or five injections of METH (10 or 15 mg/kg) or MDMA (10 mg/kg) at 6-h intervals, and were sacrificed 18 to 20 h or 1 week after the last administration. Flunarizine (30 mg/kg) prevented the decline in cortical and neostriatal TPH activity induced by MDMA, but failed to alter the effect of METH. The effect of flunarizine on the METH- and MDMA-induced changes in cortical 5-HT and 5-hydroxyindoleacetic acid concentrations paralleled the changes in enzyme activity. Nimodipine, diltiazem or TA-3090 failed to prevent the MDMA- and the METH-induced decline in TPH activity or in 5-HT and 5-hydroxyindoleacetic acid content. Because haloperidol failed to mimic the protective action of flunarizine, it is unlikely that flunarizine exerts its action by blocking the dopamine D-2 receptors. This study suggests that calcium influx may participate in the MDMA-induced decline in central TPH activity, and that the mechanism by which MDMA and METH decreases TPH activity differs.