Katsumasa Muneoka

Nicotine exposure during pregnancy is a factor which influences serotonin transporter density in the rat brain

We examined the effects of nicotine exposure during pregnancy on serotonin transporter (SERT) expression in the brain. Nicotine (6 mg/kg/day) was administered to pregnant rats via subcutaneous injections or infusion pumps. Irrespective of the route of administration, nicotine increased SERT density in the forebrain on postnatal day 22, but not in the other brain regions. Our results suggest that nicotine use by pregnant women might be an environmental factor influencing SERT expression in their children.

Prenatal administration of nicotine results in dopaminergic alterations in the neocortex.

This study examined the effect of two high doses (3 or 6 mg/kg/day) of nicotine administrations via injections to pregnant rats on the dopaminergic, serotonergic, and noradrenergic systems in six brain regions in young adult male rats. The 3 mg/kg/day and 6 mg/kg/ day nicotine exposure resulted in significant decreases in dihydroxyphenylacetic acid (DOPAC) content in the neocortex and in both the neocortex and in the midbrain plus pons medulla, respectively, without any effects on the other brain regions such as the hypothalamus or striatum. No significant effects of prenatal nicotine were found on norepinephrine, serotonin, or 5-hydroxy-3-indolacetic acid levels. These data demonstrated that prenatal nicotine induced disturbances in the dopaminergic system in the young adult period. Furthermore, the region-specific reductions in the DOPAC content suggests that the exposure to a high dose of nicotine in utero might cause a predisposition to diseases related to a dopaminergic dysfunction in the frontal cortex.

5-Hydroxytryptamine7 (5-HT7) receptor immunoreactivity-positive 'stigmoid body'-like structure in developing rat brains.

We examined the expression of 5‐hydroxytryptamine7 (5‐HT7) receptor protein in developing and adult rats with immunohistochemical technique. In adult male rats, 5‐HT7 receptor immunoreactivity was detected in the septum, striatum, indusium griseum, tenia tecta, thalamus, hippocampus and hypothalamus in the forebrain as well as the pons and cerebellum. In brains of 1, 7, 15 and 21 days old male rats but not of adult ones, 5‐HT7 receptor immunoreactivity‐positive dot‐like structures were detected. The dot‐like structures were visualized in hypothalamus, hippocampus, frontal cortex, brainstem and cerebellum at 1 day old male rats. In 7 days old male rats, the dot‐like structures were found in the hypothalamus, medial preoptic area (MPA), bed nucleus of the stria terminalis (BST), amygdaloid nucleus and brainstem reticular formation. In 15 and 21 days old male and female rats, 5‐HT7 receptor immunoreactive dots were most clearly detected in MPA, hypothalamus, raphe pallidus, raphe magnus and brainstem reticular formation. The 5‐HT7 receptor immunoreactivity‐positive dot‐like structures were shown in the cytoplasm and they were less than 1 μm in diameter in 1 and 7 days old rats and became larger to 1–3 μm in 15 and 21 days old rats. From the distribution and morphologic features, the 5‐HT7 receptor immunoreactivity‐positive dot‐like structure found in developing rat brains is considered to be identical to a cytoplasmic inclusion named ‘stigmoid body’.

A study of a dendritic marker, microtubule-associated protein 2 (MAP-2), in rats neonatally treated neurosteroids, pregnenolone and dehydroepiandrosterone (DHEA)

Neurosteroids administered during the neonatal period affect the development of several brain systems. We examined the effects of neonatal treatment with pregnenolone and dehydroepiandrosterone (DHEA) on a marker of neuronal dendrites, microtubule-associated protein 2 (MAP-2), in rat brain. Neonatal treatment with pregnenolone and DHEA increased the expression of MAP-2 in the hippocampus and nucleus accumbens but not in the prefrontal cortex, striatum or amygdala in adulthood.

A Neuroactive Steroid, Pregnenolone, Alters the Striatal Dopaminergic Tone before and after Puberty

Neuroactive steroids are known to modulate excitability in neurons. Neuronal activity during early development is critical to normal development of the brain. A neuroactive steroid, pregnenolone, was administered (10 µg/g) to rats from postnatal day 3 (PD 3) through PD 7. Dopamine (DA), serotonin (5-HT) and their metabolites were measured in the striatum. The results showed that neonatal treatment with pregnenolone increases DA and 5-HT turnover in the striatum at 3 weeks of age. The increased 5-HT turnover in the pregnenolone-treated animals was normalized at 14 weeks of age whereas the DA turnover in the pregnenolone-treated group was lower than in the control group. The present study indicated that pregnenolone treatment during the neonatal period induced abnormal development of the striatal dopaminergic function in adulthood.

Effects of a neurosteroid, pregnenolone, during the neonatal period on adenosine A1 receptor, dopamine metabolites in the fronto-parietal cortex and behavioral response in the open field

Neuronal dysfunction in the frontal cortex has been reported in the etiology of mental disorders, including schizophrenia. The adenosine A(1) receptor system, as well as the dopaminergic system, are important in the control of cortical neuronal activity. We hypothesize that neuroexcitability in early life is critical to the normal development of the brain, and neurosteroids are factors that modulate neuroexcitability during the development period. In this study, we treated neonatal rats with a neurosteroid, pregnenolone (10 microg/g) from postnatal day (PD) 3 until PD 7. In pregnenolone-treated male and female rats, adenosine A(1) receptor density, the amount of dopamine (DA), serotonin (5-HT) and their metabolites in the fronto-parietal cortex and behavioral responses in the open field were examined pre- and post-puberty. A decrease in K(d) values for the adenosine A(1) receptor binding assay using [(3)H]1,3-dipropyl-8-cyclopentylxanthine (DPCPX), increased formation of DA metabolites and hyper-locomotor activity in the open field were found in pregnenolone-treated rats compared with controls in pre- and post-puberty. An increase in 5-HT metabolites was found in the pregnenolone-treated rats in pre-puberty, but not post-puberty. These effects of pregnenolone were not different between males and females. However, correlations between horizontal and vertical activities in the open field were disrupted only in pregnenolone-treated females. The present results indicate that pregnenolone treatment during the neonatal period influences the cortical dopaminergic and adenosinergic systems as well as behavioral responses in the open field.

Serotonin-induced platelet intracellular Ca2+ responses in untreated depressed patients and imipramine responders in remission

BACKGROUND Intracellular Ca2+ metabolism in platelets has been investigated as a peripheral marker of affective disorders. METHODS We investigated the intracellular free Ca2+ concentration in platelets in both untreated depressed patients with no medications and patients in remission who were treated by imipramine (IMI) (IMI responders) using a Ca(2+)-sensitive fluorescent probe fura-2. RESULTS The increases in intracellular free Ca2+ concentration in platelets induced by stimulation with serotonin (5-HT) ([Ca2+] delta) were significantly higher in both the untreated patients and the IMI responders compared with healthy controls; however, there were no significant differences in the basal Ca2+ levels in the platelets ([Ca2+]B) among the three groups. On the other hand, in the IMI responders, we observed positive correlations between the duration of the remission and [Ca2+]B, but not [Ca2+] delta. CONCLUSIONS Our present data suggest that the enhancement of 5-HT2A-induced Ca2+ responses persisted after remission in depressed patients, and that the duration of the remission is a factor varying the intracellular basal Ca2+ levels.

Periodic maternal deprivation-induced potentiation of the negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response persists throughout the animal's life-span

In this study, it was clearly demonstrated that the enhanced negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response, which was produced by periodic maternal deprivation (PMD) treatment for the first 3 weeks of life, did persist in rats tested at 66 and 92 weeks of life, suggesting that some stressful experience during early life permanently alters the adrenocortical response to stressful stimuli. This effect of PMD was not accompanied by an increased density of glucocorticoid receptor binding sites in the hippocampus from 93-week-old rats.

Pregnenolone and dehydroepiandrosterone administration in neonatal rats alters the immunoreactivity of hippocampal synapsin I, neuropeptide Y and glial fibrillary acidic protein at post-puberty

It is well documented that neurosteroids administered during the neonatal period influence the development of several brain systems. In our previous study, pregnenolone administered to rats during the neonatal period altered adenosinergic and dopaminergic functions in the striatum and cerebral cortex. The present study examined the effects of the treatment with pregnenolone and dehydroepiandrosterone (DHEA) from the postnatal day (P) 3-P7 on synapsin I (a marker for presynaptic terminals) and glial fibrillary acidic protein (GFAP: a marker for astroglia) levels in the hippocampus of Sprague-Dawley rats at 3 and 7 weeks of age. In addition, neuropeptide Y and dynorphin A immunoreactivity was measured. The administration of pregnenolone and DHEA to neonatal rats significantly altered the expression of synapsin I in the dentate gyrus and CA3 region at post-puberty but not at pre-puberty. A significantly greater expression of GFAP-immunoreactive astrocytes or processes was demonstrated in the pregnenolone- and DHEA-treated groups at both pre-puberty and post-puberty. A significant increase in the number and size of GFAP-immunoreactive astrocytes and in the extension of arborization was seen in the overall hippocampus. The number of neuropeptide Y-positive cells in the hilus region was also significantly increased in the neurosteroid-treated group at post-puberty. No differences were detected in dynorphin A immunoreactivity among the experimental groups. These results of this study suggest that pregnenolone and DHEA play an important role in the development of hippocampus.

Electrolytes in erythrocytes of patients with depressive disorders

The concentrations of calcium, sodium, potassium and magnesium in the erythrocytes of patients were measured in the active and remission phases of depressive disorders. Twelve patients in the active phase and 19 patients in remission with major depression were studied and compared with 20 age‐matched healthy controls. Patients with major depression in both active and remission phases showed significantly lower calcium concentrations in the erythrocytes compared with controls, although no significant differences in sodium, potassium or magnesium concentrations were found among the three groups. In addition, no differences were found in the electrolyte concentrations between the active and remission phases in the same patients. This calcium concentration had no relationship to the age, gender, or medication drugs of the subjects. Low calcium concentrations were found in the erythrocytes of depressed patients, which may be a relevant marker for depression.