Blockade of multiple monoamines receptors reduce insulin secretion from pancreatic ß-cells.

Clinical use of olanzapine frequently causes severe hyperglycemia as an adverse effect. In this study, we elucidated mechanisms by which olanzapine reduced insulin secretion using the hamster pancreatic ß-cell line HIT-T15. Reverse transcriptional-PCR analysis revealed expression of dopamine (D2, D3 and D4), serotonin (5-HT2A, 5-HT2B, 5-HT2C, and 5-HT6), and histamine (H1 and H2) receptors in HIT-T15 cells. Olanzapine decreased insulin secretion from HIT-T15 cells at clinically relevant concentrations (64-160 nM). A dopamine D2 agonist, D3 antagonist, and D4 antagonist suppressed insulin secretion, whereas a D2 antagonist and D3 agonist increased it. A serotonin 5-HT2B agonist slightly increased insulin secretion, while a 5-HT2C antagonist slightly decreased it. Other agonists and antagonists for serotonin receptors did not affect insulin secretion. A histamine H1 agonist increased insulin secretion, whereas an H1 antagonist and H2 agonist suppressed it. Our results suggest that dopamine (D2, D3 and D4), serotonin (5-HT2B and 5-HT2C), and histamine (H1 and H2) receptors, which are expressed on pancreatic ß-cells, directly modulate insulin secretion from pancreatic ß-cells. Thus, olanzapine may induce hyperglycemia in clinical settings by suppressing insulin secretion from pancreatic ß-cells through inhibition of dopamine D3, serotonin 5-HT2B and 5-HT2C, and histamine H1 receptors.

Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor.

The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and sertraline show a high affinity for sigma-1 receptors. Fluvoxamine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells via a sigma-1 receptor-mediated mechanism, which suggests that neurogenesis may be involved in the antidepressant action of fluvoxamine. However, the effects of sertraline on neurite outgrowth remain unclear. Here, we report the effects of sertraline on NGF-induced neurite outgrowth in PC12 cells. At concentrations above 0.3 µM, sertraline inhibited neurite outgrowth induced by NGF (50 ng/mL) in PC12 cells in a concentration-dependent manner. At 0.3-3 µM, sertraline inhibited NGF-induced neurite outgrowth; however, had no effect on cell viability. This suggests that at these concentrations, sertraline inhibits NGF-induced neurite outgrowth without causing cell toxicity. Because sertraline has a high affinity for the sigma-1 receptor, we investigated whether this receptor is involved in sertraline's inhibitory effect on NGF-induced neurite outgrowth. The effect was reversed by both the sigma-1 receptor agonist PRE-084 and the sigma-1 receptor antagonist NE-100. These results suggest that sertraline inhibits NGF-induced neurite outgrowth in PC12 cells by acting as an inverse agonist of the sigma-1 receptor in this system.

Effects of fluvoxamine on nerve growth factor-induced neurite outgrowth inhibition by dexamethasone in PC12 cells.

In the present study, we examined the effects of fluvoxamine on nerve growth factor (NGF)-induced neurite outgrowth inhibition by dexamethasone (DEX) in PC12 cells. Fluvoxamine increased NGF-induced neurite outgrowth. Compared with co-treatment with NGF and fluvoxamine, p-Akt levels were higher than the values without fluvoxamine. The phosphorylated extracellular regulated kinase 1/2 levels were slightly increased by co-treatment with NGF and fluvoxamine. Fluvoxamine concentration-dependently improved NGF-induced neurite outgrowth inhibition by DEX. Fluvoxamine also improved the decrease in the NGF-induced p-Akt level caused by DEX. Interestingly, the sigma-1 receptor antagonist NE-100 blocked the improvement effects of fluvoxamine on NGF-induced neurite outgrowth inhibition by DEX. The selective sigma-1 receptor agonist PRE-084 also improved NGF-induced neurite outgrowth inhibition by DEX, which is blocked by NE-100. These results indicate that the improvement effects of fluvoxamine on NGF-induced neurite outgrowth inhibition by DEX may be attributable to the phosphorylation of Akt and the sigma-1 receptor.

Cholinesterase inhibitor rivastigmine enhances nerve growth factor-induced neurite outgrowth in PC12 cells via sigma-1 and sigma-2 receptors.

Rivastigmine (Riv) is a potent and selective cholinesterase (acetylcholinesterase, AChE and butyrylcholinesterase, BuChE) inhibitor developed for the treatment of Alzheimer's disease (AD). To elucidate whether Riv causes neuronal differentiation, we examined its effect on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. At concentrations of 0-100 µM, Riv was non-toxic in PC12 cells. Riv caused dose-dependent (10-100 µM) enhancement of NGF-induced neurite outgrowth, which was completely inhibited by the TrkA antagonist GW-441756. By contrast, Riv-mediated enhancement of neurite outgrowth was not blocked by the acetylcholine receptor antagonists, scopolamine and hexamethonium. However, the sigma-1 receptor (Sig-1R) antagonist NE-100 and sigma-2 receptor (Sig-2R) antagonist SM-21 each blocked about half of the Riv-mediated enhancement of NGF-induced neurite outgrowth. Interestingly, the simultaneous application of NE-100 and SM-21 completely blocked the enhancement of NGF-induced neurite outgrowth by Riv. These findings suggest that both Sig-1R and Sig-2R play important roles in NGF-induced neurite outgrowth through TrkA and that Riv may contribute to neuronal repair via Sig-1R and Sig-2R in AD therapy.

Effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by a κ-opioid antagonist, nor-BNI, in ICR mice.

OBJECTIVE: In this study, we aimed to study the effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by intradermal injection of a ?-opioid antagonist, nor-binaltorphimine (nor-BNI), into the rostral back of ICR mice were investigated. MATERIALS AND METHODS: Male ICR mice weighing 30?35 g were used. The number of scratching episodes were counted for 60 min after i.d. injection of nor-BNI. RESULTS: nor-BNI dose dependently increased in the number of scratching episodes in ICR mice. nor-BNI-induced scratching behavior was inhibited by not only nalfurafine but also ICI204,448, a peripherally selective ?-opioid agonist. Naloxone and naloxone methiodide, a peripherally restricted ?-opioid antagonist, also inhibited nor-BNI-induced scratching behavior. Scratching behavior induced by nor-BNI was inhibited by chlorpheniramine as well as levocetirizine, a third-generation H1 antagonist that does not cross into the CNS. CONCLUSION: These results suggest that scratching behavior induced by this ?-opioid antagonist, nor-BNI, is related to not only central but also peripheral opioid and H1 receptors.

The interaction between histamine H1 receptor and µ- opioid receptor in scratching behavior in ICR mice.

In this study, we examined the interaction between histamine H1 receptor and µ-opioid receptor in scratching behavior in ICR mice. Both histamine and morphine caused scratching and simultaneous injection of histamine and morphine had an additive effect. Chlorpheniramine and naloxone inhibited histamine-induced scratching behavior. These two drugs also inhibited morphine-induced scratching behavior. Simultaneous injection of chlorpheniramine and naloxone caused a significant inhibition of histamine-induced scratching compared with separate injections. The same findings were also noted for morphine-induced scratching. These results strongly indicate a close relationship between histamine H1 receptor and µ-opioid receptor in scratching behavior in ICR mice.

Serotonergic mechanisms are involved in antidepressant-like effects of bisbenzylisoquinolines liensinine and its analogs isolated from the embryo of Nelumbo nucifera†Gaertner seeds in mice.

OBJECTIVES: We attempted to ascertain if bisbenzylisoquinoline alkaloids, liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and compare the effects with those previously obtained by their analogue neferine. METHODS: Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine. KEY FINDINGS: Liensinine and isoliensinine elicited antidepressant-like effects in mice after the FST. Anti-immobility effects of liensinine and isoliensinine were antagonized by the 5-hydroxytryptamine1 A (5-HT1 A ) receptor antagonist WAY 100635, but not by the α1 -adrenoceptor antagonist prazosin. The anti-immobility effects of liensinine, isoliensinine and neferine were blocked by pretreatment with p-chlorophenylalanine (PCPA), which depletes serotonin (5-HT). CONCLUSIONS: These data suggest that liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and that antidepressant-like effects of liensinine and its analogues are closely related to serotonergic mechanisms.

Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.

Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts.

Synthesis and pharmacological activity of alkaloids from embryo of lotus, Nelumbo nucifera.

Bisbenzylisoquinoline alkaloid, nelumboferine which was recently isolated from the embryo of Nelumbo nucifera, and stereoisomers of neferine, which is a major alkaloid of the embryo of N. nucifera, were stereoselectively synthesized. Pharmacological activity of nelumboferine, stereoisomers of neferine, liensinine, isoliensinine, and O-methylneferine were evaluated.

Involvement of the sigma1 receptor in the antidepressant-like effects of fluvoxamine in the forced swimming test in comparison with the effects elicited by paroxetine.

We studied the involvement of the sigma(1) receptor in the antidepressant-like effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in DBA/2 mice using the forced swimming test. The effects of the selective sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) at 1mg/kg significantly antagonized the anti-immobility elicited by fluvoxamine (10mg/kg). However, the anti-immobility effects elicited by another SSRI, paroxetine (5m/kg), were not altered by BD1047. The selective sigma(1) receptor agonist 2S-(2α,6α,11R(*))-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol ((+)SKF-10047) elicited dose-dependent anti-immobility effects in DBA/2 mice. BD1047 significantly blocked the anti-immobility effects induced by (+)SKF-10047 at 10mg/kg. These results suggested that the sigma(1) receptor was associated with fluvoxamine-induced antidepressant-like effects but not with paroxetine-induced antidepressant-like effects.

Differences between mice strains in response to paroxetine in the forced swimming test: involvement of serotonergic or noradrenergic systems.

We studied the effect of the selective serotonin reuptake inhibitor (SSRI) paroxetine on the immobility time in the forced swimming test using different strains of mice (ICR, ddY, C57BL/6, BALB/c and DBA/2). There was a difference between strains in the response to paroxetine (although it induced anti-immobility effects in all strains of mice used). The mouse strain most sensitive to paroxetine was DBA/2; the ICR strain showed the lowest sensitivity. We previously demonstrated variations in the responses to another SSRI, fluvoxamine, in different strains of mice, which was in agreement with the present findings. In DBA/2 and ICR mice, the anti-immobility effects of paroxetine were significantly antagonized by the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). The noradrenergic α(1)-adrenoceptor antagonist prazosin significantly reduced the anti-immobility effects elicited by a high dose (5mg/kg) of paroxetine in DBA/2 and ICR mice. However, prazosin did not affect the anti-immobility effects of a lower dose of paroxetine (1mg/kg) in DBA/2 mice. This suggests that the anti-immobility effects of a higher dose of paroxetine in mice are associated with serotonergic and noradrenergic neurons. Prazosin did not the affect anti-immobility effects of fluvoxamine. These results suggest that there are differences between mice strains in the antidepressant-like effects of paroxetine (which are similar to those elicited by fluvoxamine). Moreover, involvement of the noradrenergic system was partly related to the anti-immobility effects of paroxetine (which are different to those elicited by fluvoxamine).

Bisbenzylisoquinoline Alkaloids from Nelumbo nucifera.

From the embryos of the seeds of Nelumbo nucifera, three bisbenzylisoquinoline alkaloids, nelumboferine and nelumborines A and B, were isolated along with four known compounds, neferine, liensinine, isoliensinine and anisic acid. The structures of the new alkaloids were determined mainly by spectroscopic methods.

Protective effects of cyclo(L-Leu-L-Tyr) against postischemic myocardial dysfunction in guinea-pig hearts.

The protective effects of cyclic dipeptides in alcoholic beverages were investigated in the perfused guinea-pig hearts subjected to ischemia and reperfusion. Subsequently, in order to determine the importance of cyclic dipeptide structure, the effects of cyclo(L-Leu-L-Tyr) (cLY) were compared with those of the newly synthesized non-cyclic dipeptides, L-Leu-L-Tyr (LY) and L-Tyr-L-Leu (YL). After reperfusion, pressure recovery (%) in the left ventricle reached a peak of over 90% in the presence of cLY (10(-6) M and 10(-5) M) (control: 22.9%). The recovery by LY and YL was significantly lower than that by cLY, and ATP levels simultaneously monitored using (31)P-NMR were already lower during the ischemic end period than those observed with cLY treatment. In perfused mitochondrial preparations, cLY significantly inhibited mitochondrial Ca(2+) ([Ca(2+)](m)) elevation in a similar way to that of the mitochondrial permeability transition pore (MPTP) inhibitor cyclosporin A. In vitro electron paramagnetic resonance (EPR) revealed that the active oxygen radicals quenching activity of cLY was greater than those of non-cyclic dipeptides. cLY inhibited caspase-3-induced apoptosis. The cyclic dipeptide structure inhibits opening of the MPTP by preventing [Ca(2+)](m) overload-induced apoptosis related to mitochondrial active oxygen radical accumulation in ischemia-reperfusion hearts.

Antidepressant-like effects of neferine in the forced swimming test involve the serotonin1A (5-HT1A) receptor in mice.

The effects of neferine, an alkaloid of Nelumbo nucifera Gaertner embryos, on immobility in the forced swimming test, which is used to evaluate antidepressants, were investigated in mice. The administration of neferine from 25 to 100 mg/kg i.p. elicited anti-immobility effects in mice. The molecular dose effects of neferine in the forced swimming test were almost equal to those of the typical antidepressants maprotiline and imipramine. The involvement of the 5-HT receptor subtypes was also studied using 5-HT receptor antagonists. Anti-immobility effects of neferine are antagonized by the serotonin1A (5-HT1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT1B receptor antagonist, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide dihydrochloride (GR 55562), the 5-HT2 receptor antagonist, 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT3 receptor antagonist, ondansetron and the 5-HT4 receptor antagonist, 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not affect the anti-immobility effects of neferine. The anti-immobility effect of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetaralin (8-OH-DPAT) was also antagonized by WAY 100635. Furthermore, co-administration of subactive doses of neferine (10 mg/kg) and 8-OH-DPAT (0.1 mg/kg) produced synergistic antidepressant-like effects. These results suggest that neferine shows antidepressant-like effects in mice similar to typical antidepressants and that these effects are mediated by the 5-HT1A receptor. Therefore, the central effects of neferine are likely to be linked to serotonergic neurotransmission.

Involvement of the 5-HT(1A) receptor in the anti-immobility effects of fluvoxamine in the forced swimming test and mouse strain differences in 5-HT(1A) receptor binding.

We previously demonstrated the presence of strain differences in baseline immobility time and sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in five strains of mice (ICR, ddY, C57BL, DBA/2 and BALB/c mice). Furthermore, variations in serotonin (5-HT) transporter binding in the brain were strongly related to strain differences in baseline immobility and sensitivity to fluvoxamine. In the present study, we examined the involvement of the 5-HT(1A) receptor in anti-immobility effects in DBA/2 mice, which show high sensitivity to fluvoxamine. The anti-immobility effects of fluvoxamine in DBA/2 mice were inhibited by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT(1B) receptor antagonist 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide (GR55562), the 5-HT(2) receptor antagonist 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT(3) receptor antagonist ondansetron and the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not influence the anti-immobility effects of fluvoxamine in DBA/2 mice. These results suggest that fluvoxamine-induced antidepressant-like effects in DBA/2 mice are mediated by the 5-HT(1A) receptor. We analyzed 5-HT(1A) receptor binding in the brains of five strains of mice. Strain differences in 5-HT(1A) receptor binding were observed. 5-HT(1A) receptor binding in brain was not correlated with baseline immobility time in the five strains of mice examined. These results suggest that, although the anti-immobility effects of fluvoxamine in DBA/2 mice are mediated by the 5-HT(1A) receptor, strain differences in 5-HT(1A) receptor binding are not related to variation in immobility time and responses to fluvoxamine.

[A case of conversion disorder (hysteria) after spinal anesthesia].

We report a case of conversion disorder after spinal anesthesia. A 16-year-old healthy woman underwent arthroscopic surgery under spinal anesthesia. She showed tremor all over and it did not stop. We sedated her with propofol during the operation. After the operation, her involuntary tremble continued. We consulted with a pediatrician who diagnosed her as conversion disorder. Magnetic resonance imaging and computed tomography were performed to rule out some pathological changes and abnormality in her head. As a result, Rathke cleft cyst was suspected but it could not explain this episode. We consider that her stress for the operation under spinal anesthesia caused this episode. In a case of a younger patient, it is necessary to consider mental support. And we need to suspect conversion disorder when we see tremor during operation under regional anesthesia.

Effects of extracts and neferine from the embryo of Nelumbo nucifera seeds on the central nervous system.

The effects of embryos of the seeds of Nelumbo nucifera on the central nervous system were studied in mice. MeOH extracts of embryos of Nelumbo nucifera seeds significantly inhibited locomotor activity in mice. The MeOH extract was successively partitioned between H(2)O and n-hexane, between H(2)O and CHCl(3), and between H(2)O and n-BuOH. CHCl(3) extracts strongly inhibited locomotor activity in mice, although other extracts had no effect on locomotor activity. The main alkaloid of CHCl(3) extracts, neferine, dose-dependently inhibited locomotor activity in mice. Neferine induced hypothermia in mice and apparently potentiated thiopental-induced sleeping time. An anxiolytic, diazepam, decreased locomotor activity, rectal temperature and enhanced sleep elicited by thiopental, similar to neferine. In addition, neferine and diazepam showed anti-anxiety effects in the elevated plus maze test. Neferine did not affect muscle coordination by the rota-rod test. Neferine did not affect strychnine- nor picrotoxin-induced seizure. In contrast, diazepam had apparent muscle relaxant and anti-convulsant effects. These results suggest that neferine has several central effects and that neferine may participate in the efficacy of the sedative effects of embryos of the seeds of Nelumbo nucifera. The mechanisms of the sedative effects of neferine are not similar to those of diazepam.

Mouse strain differences in immobility and sensitivity to fluvoxamine and desipramine in the forced swimming test: analysis of serotonin and noradrenaline transporter binding.

Strain differences in immobility time in the forced swimming test were investigated in five strains of mice, namely, ICR, ddY, C57BL/6, DBA/2 and BALB/c mice. There were significant strain differences. The immobility times of ICR, ddY and C57BL/6 mice were longer than those of DBA/2 and BALB/c mice. Immobility times were not significantly related to locomotor activity in these strains. There were also differences in sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine. In ICR, ddY and C57BL/6 mice, fluvoxamine did not affect immobility time, while it reduced the immobility time of DBA/2 and BALB/c mice dose-dependently. The noradrenaline reuptake inhibitor desipramine decreased immobility time in all strains of mice. Serotonin (5-HT) transporter binding in the brains of all five strains of mice was also investigated. Analysis of 5-HT transporter binding revealed significant strain differences, being lower in DBA/2 and BALB/c mice than in other strains of mice. The amount of 5-HT transporter binding was correlated to baseline immobility time. However, there was no significant relation between noradrenaline transporter binding and immobility time. These results suggest that the duration of baseline immobility depends on the levels of 5-HT transporter binding, leading to apparent strain differences in immobility time in the forced swimming test. Furthermore, differences in 5-HT transporter binding may cause variations in responses to fluvoxamine.

Effects of the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran on marble burying behavior in mice.

The effects of milnacipran, a serotonin and noradrenaline reuptake inhibitor (SNRI) on the obsessive compulsive disorder (OCD) model, marble burying behavior, were investigated in mice. Milnacipran above the dosage of 10 mg/kg inhibited marble burying behavior significantly in mice as similar to fluvoxamine. Milnacipran inhibiting marble burying behavior did not affect locomotor activity. These results suggest that milnacipran can inhibit marble burying behavior and that milacipran may be useful for OCD therapy.

Strain differences of neurosteroid levels in mouse brain.

Neurosteroids, pregnenolone (Preg), dehydroepiandrosterone (DHEA) and their sulfates (PregS and DHEAS) are reported to exert their modulatory effects of neuronal excitability and synaptic plasticity via amino acid receptors, which affect and regulate the learning and memory process, mood, and depression. Although the brain levels of these steroids have been reported in rodents, the strain differences of the levels of these steroids have not been demonstrated. We examined the concentrations of Preg, 17-OH-Preg, DHEA, androstenediol (ADIOL) and their sulfates in whole brains from DBA/2, C57BL/6, BALB/c, ddY and ICR mice, the genetic backgrounds of which are different. No differences in the brain levels of Preg and DHEA were found among the strains. In contrast, PregS levels in DBA/2 were significantly lower than in the others, while DHEAS concentrations in DBA/2 were significantly higher than those in other strains. Strain differences were found in 17-OH-Preg, ADIOL and 17-OH-PregS but not in ADIOLS levels. The ranges of Preg and PregS levels were the highest among the steroids studied. Further, we measured serum these steroid levels. Although strain differences were also found in serum steroids, correlation study between brain and serum levels revealed that brain neurosteroids studied may not come from peripheral circulation. In conclusion, this is the first report of demonstrating mammalian brain levels of 17-OH-Preg, ADIOL, 17-OH-PregS and ADIOLS and the strain differences in neurosteroid levels in mice brains. The differences in levels may involve the strain differences in their behavior, e.g. aggression, adaptation to stress or learning, in mice.