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To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.

We have observed an excess heat capacity in liquid and bcc solid 3He at low temperatures. The heat capacity in the normal fluid is found to be the sum of the heat capacity of bulk normal fluid and a temperature-independent heat capacity ΔC due to amorphous solid layers on the silver sinter surface, where ΔC=7.3±6.8 μJK−1m−2 corresponds to 1.6±0.6 amorphous solid layers. The heat capacity for bcc solid 3He is the sum of the heat capacity originating from the multiple-exchange interaction and a temperature independent heat capacity. The excess heat capacity ΔC=12.1±3.1 μJK−1m−2 for bcc solid corresponds to 1.9±0.3 amorphous solid layers. Our result indicates that the amorphous solid layers on an amorphous substrate yield a universal ΔC in unit area throughout liquid, solid and adsorbed 3He.

In this study, we investigated the involvement of the interaction between sigma receptors and the nitric oxide/cyclic GMP pathway in short term memory in mice, assessed through spontaneous alternation behavior in a Y-maze. N(G)-Nitro-L-arginine methyl ester and 7-nitro indazole, both nitric oxide synthase inhibitors, impaired the spontaneous alternation behavior. These impairments were attenuated by (+) SKF 10,047 and (+) pentazocine, sigma(1) receptor agonists. Further, the sigma(1) receptor antagonist, NE-100, reversed the improvements made by sigma receptor agonists. Cyclic GMP levels and nitric oxide synthase activity in the hippocampus were reduced by treatment with N(G)-nitro-L-arginine methyl ester. The suppressive effects of N(G)-nitro-L-arginine methyl ester on the cyclic GMP levels were reversed by co-treatment with (+) SKF 10,047, but the decline in nitric oxide synthase activity was not. These results suggest that the nitric oxide/cyclic GMP pathway in the hippocampus is responsible for spontaneous alternation behavior in a Y-maze. Further, the ameliorating effects of (+) SKF 10,047 on the impairment of spontaneous alternation behavior may be mediated through activation of guanylate cyclase, but not nitric oxide synthase in the hippocampus of mice.

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (-)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT(2) receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT(2) receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.

Biochemical changes such as intracellular cAMP and Ca(2+) underlying morphine dependence and tolerance have been suggested. Therefore, we investigated the effects of nefiracetam (N-(2, 6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl) acetamide), which increases intracellular cAMP and Ca(2+) levels, on the development of morphine dependence and tolerance. Mice administered morphine (6 or 20 mg kg(-1)) twice daily for 5 days, showed withdrawal symptoms (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg kg(-1)), indicating morphine dependence. Furthermore, tolerance to the analgesic effect of morphine was observed in these mice. Co-administration of nefiracetam (5 or 10 mg kg(-1)) with morphine during the pretreatment period, significantly reduced the signs of withdrawal symptoms, moreover, the tolerance was significantly attenuated. Elevation of cAMP levels in the cortex was observed in morphine-dependent mice, but not in mice co-administered nefiracetam. Acute administration of nefiracetam shows no effect on the withdrawal symptoms and the analgesic effect in morphine-naive mice. Theophylline (3 or 10 mg kg(-1)) tended to attenuate and enprofylline (10 or 30 mg kg(-1)) significantly attenuated the development of morphine dependence and tolerance. These findings suggest that co-administration of nefiracetam or compounds, which increase the cAMP level, may be a useful strategy for attenuating the development of morphine dependence and tolerance in the clinic.

This article summarizes our recent finding that the nociceptin system is involved in the regulation of learning and memory. The nociceptin-knockout mice show greater learning ability in the water maze task, an enhanced latent learning in the water finding task, better memory in the passive avoidance task, and further, larger long-term potentiation in the hippocampal CA1 region than wild-type mice. Nociceptin itself induces an impairment of passive avoidance task in wild-type mice, which is reversed by naloxone benzoylhydrazone (NalBzoH). Thus, the nociceptin system seems to play negative roles in learning and memory, and NalBzoH may act as a potent antagonist for the nociceptin receptor.

We have measured the ac magnetic susceptibility in various fields and thermal expansion of single crystals of the heavy fermion compound ${\mathrm{CeCu}}_{6}$ at temperatures down to $250\ensuremath{\mu}\mathrm{K}$. The susceptibility of ${\mathrm{CeCu}}_{6}$ shows a peak at about 2 mK and has a large anisotropy. We also detected an anomaly of thermal expansion at the same temperature. The observed behaviors of the susceptibility and the thermal expansion in ${\mathrm{CeCu}}_{6}$ indicate the occurrence of an antiferromagnetic order.

To investigate an involvement of catecholamines and/or the cyclic adenosine monophosphate (cAMP) systems in the development of drug dependence, we examined whether phencyclidine (PCP) and morphine dependence were developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days) and increased the level of cAMP in the striatum, but not in the thalamus/hypothalamus. In TH+/- and CBP+/- mice, however, we could not find PCP-induced place preference. The increased level of cAMP in the striatum was observed in CBP+/-, but not TH+/- mice. When wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased jumping, rearing, and forepaw tremor counts as a sign of withdrawal and an increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. In TH+/- and CBP+/- mice, however, jumping and forepaw tremor counts were decreased compared to in wild-type mice. An increase in the level of cAMP in the thalamus/hypothalamus in CBP+/-, but not in TH+/- mice was observed. These results suggest that catecholamines and CBP are involved in the development of PCP and morphine dependence, and that changes in catecholaminergic and/or cAMP systems induced by repeated PCP and morphine treatments play an important role in the addiction to PCP and morphine.

The strain amplitude dependence of the energy dissipation and the shear modulus at several temperatures are measured in bcc solid 3 He and the results are compared with the model of a pinned dislocation loop of Granato and Lucke. In spite of the pure solid, the strong amplitude dependence of the dissipation is found in bcc solid 3 He by the high-Q torsional oscillator measurements, in contrast with the result of the ultrasonic and the torsional-oscillator measurements in hcp solid 4 He. In pure solids, the loop length of the dislocations cannot be limited by impurities. In order to clarify a pinning mechanism, the loop length and the network length are obtained from the experimental result by using the model of Granato and Lucke. Where, the loop length is determined by the pinning centers, and the network length is limited by the dislocation network nodes. It is found that the temperature dependence of the loop length is the same as that of the network length. This result shows that the pinning centers are the network nodes of the dislocation lines in ultra pure bcc solid 3 He.

We have observed an excess specific heat in bcc solid 3He at low temperatures and at pressures between the melting pressure and 46 bar. The excess specific heat is nearly independent of temperature. In the solid just above the melting pressure, the magnitude of the anomaly is about 2.5 times larger than that at high pressures. Except for the solid near the melting pressure, the magnitude is constant with pressure and is nearly the same as that in liquid 3He in Vycor. This anomaly of the specific heat in solid 3He is explained in terms of the amorphous surface solid on a disordered substrate.

We investigated the role of nociceptin system in learning and memory in mice. The deficiency of nociceptin receptors and nociceptin itself did not affect the alternation behavior in the Y-maze test. In the passive avoidance test, the step-through latencies of nociceptin receptor knockout mice were longer than those of wild-type mice. Nociceptin shortened the step-through latency in wild-type mice. This impairment on passive avoidance task was reversed by naloxone benzoylhydrazone (NalBzoH), indicating that the amnesic effects of nociceptin may be mediated through the NalBzoH recognition sites. These suggest that nociceptin system plays an important role in the memory retention of passive avoidance task, and NalBzoH-recognized sites are involved in nociceptin-induced impairment of the memory retention.

A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cyclic AMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) containing the CREB-binding domain (residues 462-661), showed clinical features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-negative inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP +/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.

We have measured the AC magnetic susceptibility and static magnetization of high-density bcc solid3He through the nuclear-ordering transition. The susceptibility in the paramagnetic state strongly depends on the frequency of the measuring field. Near the transition temperature a sharp peak in the real part of the AC susceptibility and an abrupt depression in the imaginary part are observed. The transition temperature indicated by the AC susceptibility is higher than that derived from static magnetization. We analyzed the new behavior in the susceptibility in terms of the spin relaxation between the Zeeman system and the exchange system. The relaxation time τ in the energy flow in the two systems is in the range of milliseconds in the paramagnetic state, and decreases drastically by two orders of magnitude in the ordered state. The relaxation time in the paramagnetic state is interpreted as due to exchange narrowing, while τ in the ordered state is explained to be the drift time of the spin wave limited by the size of the sample grown in the pores of the sintered silver. The ordering temperature is given as a function of molar volume in the entire range of the bcc phase.

Pressure measurements have been made in a hcp solid3He at molar volumes from 18.90 to 19.45 cm3/mol, at temperatures down to 1 mK and in magnetic fields up to 0.16 Tesla. The results are analyzed by a high-temperature series expansion with multiple-exchange processes. The molar volume dependence of the multiple-exchange interactions has been determined by pressure measurements in magnetic fields. The results indicate that the exchange frequencies determined by the pressure measurements in a hcp solid3He are consistent with those obtained by magnetization measurements.

The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the brain, however, the physiological role of the modulation via the nociceptin receptor is still unclear. Administered nociceptin produces hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice show no significant abnormalities in nociceptive thresholds and locomotion. To clarify possible involvement of the nociceptin receptor in the regulation of nociception and locomotion, we made use of the knockout mice and naloxone benzoylhydrazone (NalBzoH) identified originally as a ligand for opioid receptors. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed with [3H]nociceptin binding and attenuated the nociceptin-induced inhibition of cAMP accumulation. Furthermore, behavioral studies demonstrated that NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion. It is therefore likely that NalBzoH can act as a potent antagonist for the nociceptin receptor in vivo. In wild-type mice, NalBzoH induced antinociception but did not affect locomotor activity. In contrast, in the knockout mice, no significant changes in nociception and locomotion were induced by NalBzoH. These results clearly suggest that the nociceptin system takes part in the physiological regulation of nociceptive thresholds but not in the basal modulation of locomotion.

We have measured the shear modulus of bcc solid 3 He at 827 Hz using the high- Q torsional oscillator technique. We observed a decrease in the shear modulus from the low-temperature value G0 to about 0.4G0 at a molar volume of 24.80 cm 3/mole and to 0.6G0 at 24.32 cm 3/mole near the melting point. The reduction of an effective shear modulus is explained by the dislocation theory of Granato and Lucke.

We have studied the origin of the excess specific heat (anomaly) above 10 mK in bcc solid3He near melting pressure. We applied strong magnetic fields to the sample to see whether the anomaly arises from spin polarons due to vacancies. The specific heat is the same before and after applying magnetic fields of 10-12 T. This result possibly indicates that the anomaly arises from the origin different from vacancies. Next, in order to check whether the anomaly comes from the surface magnetism, we measured the specific heat by coating the surface of sintered silver with three layers and two layers of4He. The results showed that unexpected large heat capacity due to phase separation of solid3He-4He surpassed and smeared the original specific heat anomaly. We are investigating the origin of the anomaly further.

We have measured the dissipation of dislocation motion in bcc solid3He using the high-Q torsional oscillator technique at 1079 Hz. We observed a broad maximum in the temperature dependence of the dissipation. The maximum of the dissipation can be explained by the theory of Granato and Lucke in which the dislocation mobility depends upon the interactions of dislocations with point defects.4He impurities tend to bind to the dislocation lines at low temperatures and pin this dislocation motion. The maximum of the dissipation corresponds to the depinning of the dislocation motion. From the amplitude dependence of the depinning temperature we first obtained the activation energy of 1.03 K of the impurity4He atom trapped on the dislocations in bcc solid3He at a molar volume of 24.30 cm3/mol. The activation energy of the impurity atom in bcc3He was found to be larger than the value of 0.7 Kin hcp4He.

We observed the excess specific heat (anomaly) other than nuclear origins above 10 mK in bcc solid 3 He of 24.21 cm 3/mole. We checked whether it arises from spin polarons due to vacancies out of equilibrium by applying a strong magnetic field, in which vacancies should diffuse and vanish due to high polarization. The specific heat is the same before and after applying a magnetic field of 10 T. This fact indicates that vacancies did not vanish even in a strong field or the anomaly arises from the origin different from vacancies.

In this study, we gave the soybean powder-added food pellets (soybean pellets) to investigate anti-anxious effects of soybean in male mice. Twenty eight days after feeding control pellets or soybean pellets, we observed the behavioral changes in the elevated plus maze. There was no significant difference on the time spent in the open arms (%) between mice fed the control and soybean pellets. When we administered m-chlorophenylpiperazine (m-CPP, 2.5 mg/kg, i.p.) to mice, the mice fed control pellets showed the decrease in the time spent in the open arms, suggesting that anxiety-like behavior was induced by m-CPP. On the other hand, we could not observe the m-CPP-induced anxiety-like behavior in mice fed soybean pellets in this test. These results suggest that soybean pellets may attenuate anxiety-like behavior in mice.

We previously reported that the continuous feeding of mice with pellets of pregerminated brown rice (PGBR; Hatsuga genmai in Japanese) enhances their spatial learning. Here, we show the possible relationships of the enhancement of learning and memory with the glutamatergic system in the brain of PGBR-pellet-fed mice. The enhancement of learning and memory in the novel object recognition and Y-maze tests after 28-day-feeding of PGBR pellets was inhibited by dizocilpine (10 μg/kg s.c.), an N-methyl-D-aspartate (NMDA) receptor antagonist, whereas the extracellular glutamate level and the glutamate content were not affected in the frontal cortex and hippocampus. In the frontal cortex of mice fed PGBR pellets, the phosphorylation of calcium calmodulin kinase IIα (CaMKIIα), one of the important events after NMDA receptor activation, was facilitated compared with that of mice fed control pellets. This facilitation was inhibited by dizocilpine (10 μg/kg s.c.), whereas the phosphorylation of extracellular signal-regulated protein kinases (ERKs), another index of memory formation was not affected by PGBR pellets. On the other hand, in the hippocampus, there was no significant difference in the phosphorylation of CaMKIIα and ERKs between the control and PGBR pellets-fed mice. Taken together, these results suggest that PGBR enhances the NMDA receptor/CaMKIIα signaling in the frontal cortex, leading to enhanced learning and memory in mice.

Temperature dependences of the third-order nonlinear dielectric constant in the mixed crystals of Rb 1- x (NH 4 ) x H 2 PO 4 with x =0.25, 0.3, 0.4, 0.5, 0.6 and 0.7 were measured in the temperature range between 4 and 50 K. It was observed that the nonlinear dielectric constant in these crystals increases near the glass transition point and it is strongly dispersive at low frequencies. It was found that the third-order nonlinear dielectric constant is proportional to the imaginary part of the linear dielectric constant when measured under changing temperature at a fixed frequency.

In the G-protein-coupled receptor superfamily, the opioid receptor subfamily is constituted of the three distinct opioid receptors (namely delta-, mu- and kappa-subtypes) and the receptor for nociceptin (also designated orphaninFQ). The members of the opioid receptor subfamily were known to mediate a variety of cellular inhibitory effects. The three opioid receptors are known to play central roles in mediating analgesia and many other physiological activities; however, the nociceptin receptor was identified recently and less is known about its physiological roles. Here we report the generation and characterization of mice lacking the nociceptin receptor. The knockout mice showed no significant differences in nociceptive threshold and locomotor activity compared with control mice, but they lost nociceptin-induced behavioral responses. These results indicate that the nociceptin system is not essential for regulation of nociception or locomotor activity. On the other hand, we found insufficient recovery of hearing ability from the adaptation to sound exposure in the mutant mice. Thus, the nociceptin system appears to participate in the regulation of the auditory system.

In a previous report, we identified a novel molecule, SHATI/NAT8L, having an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). SHATI/NAT8L attenuates the METH-induced increase in dopamine overflow in the nucleus accumbens (NAc) by promoting plasmalemmal and vesicular dopamine uptake. However, the biological functions of the protein remain unclear. In this study, we explored NAT8L-binding proteins using pull-down assays and identified a number of components of the adaptor protein (AP)-2 complex, which is a multimeric protein localized to the plasma membrane that functions to internalize cargo during clathrin-mediated endocytosis. To investigate whether NAT8L regulates the receptor localization to the cell surface, cell-surface dopamine D1 receptor in the NAc of Nat8l knockout (KO) mice was quantified. We found that dopamine D1 receptor on the cell surface was increased in the NAc of Nat8l KO mice compared with the wild type (WT) animals. Consistent with this finding, Nat8l KO mice showed higher basal locomotor activity and heightened sensitivity to D1 agonist compared with WT mice. In addition, METH-induced sensitization and CPP were enhanced in Nat8l KO mice. These results suggest that NAT8L might regulate the localization of cell-surface dopamine D1 receptor, thereby controlling basal behaviour and sensitivity to METH. Furthermore, we observed a single nucleotide polymorphism (SNP) in the human NAT8L gene related to reward dependence, a personality trait, and grey matter volume in the caudate nucleus in healthy subjects, suggesting that NAT8L might also affect human personality.

We report the results of a search for a spontaneous magnetization in the superconducting B-phase of UPt3 which is predicted to exist because of broken time-reversal symmetry. We have measured the change of magnetic flux upon the superconducting transition in a field very close to zero by using a SQUID magnetometer. Our result gives the upper limit of 2 mG for the spontaneous internal field, one order of magnitude smaller than obtained by a recent μSR measurement. The small value favors the theory of orbital degeneracy of the pair wave function over the theory of spin degeneracy.

We previously identified a new molecule, "SHATI/NAT8L," which has an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference. Nevertheless, the extent of SHATI localization and its functions are only partially understood. In this study, we used the FLAG-tag method to investigate SHATI localization. We found that SHATI was localized to microtubules when expressed in COS7 cells and cortical primary neurons. This distribution of SHATI was less apparent after cells were treated with colchicine, a tubulin polymerization inhibitor that disrupts the microtubule structure. This finding suggests that SHATI is associated with microtubule structure. Interestingly, overexpression of SHATI in COS7 cells could attenuate the colchicine-induced decrease in acetylated microtubules, indicating that SHATI plays a role in stabilizing microtubules. Furthermore, we showed that Shati deletion impaired neurite elongation. In cortical primary neurons, neurite length and complexity in Shati-knockout (KO) mice were significantly decreased. In pyramidal neurons in the prefrontal cortex, dendrite length and complexity were also significantly decreased in Shati-KO mice compared with wild-type mice. These results suggest a novel function for SHATI, which may be a new member of the microtubule-associated protein family.

In this study, we investigated whether the food pellets containing pre-germinated brown rice (PGBR; hatsuga genmai in Japanese) were effective on the impairments of cognitive function induced by s-amyloid peptide25-35 (As25-35) in mice. To evaluate the effects of PGBR, mice were received AIN-93G (as control pellets) or PGBR-added food pellets (PGBR pellets) during this study. As25-35 (3 nmol/3 smol i.c.v.) was injected to mice on the day 22. On the days 30 and 31, we assessed the tasks related to visible cognition using novel object recognition tests. By the injection of As25-35 in the control pellets-fed mice impairments were observed, but the mice fed PGBR-added food pellets did not show the deficits. After the behavioral tests, we found As25-35 increased lipid peroxidation in the hippocampus of control pellets-fed mice but not PGBR pellets-fed mice. Taken together, these results suggest that continuous feeding of food pellets containing PGBR (i) attenuates the As25-35-induced impairments of cognitive function, and (ii) inhibited increases in lipid peroxidation in the hippocampus.

We have measured AC susceptibility of bcc solid3 He in a two orders of magnitude with a wider range than in the previous study. For the sample of 23.0 cm3/mol, the relaxation time between the Zeeman and exchange reservoirs in the paramagnetic state is on the order of 10 ms, while the relaxation time in the ordered state decreases down to one hundredth of the value in the paramagnetic state. This small relaxation time is related to the process of spin wave relaxation in the ordered state.

We report AC susceptibility of b.c.c. solid 3He in both the paramagnetic and ordered states. The frequency range in which the measurements were done was from 16 Hz to 2 kHz, being much wider than in the previous study. The results of the measurements revealed that the relaxation time between the Zeeman energy and exchange energy in the paramagnetic state is on the order of ms, being in agreement with the previous work, while that in the ordered state decreases drastically. This fact is discussed in relation to the process of spin wave relaxation.

Nicotine replacement treatments are being alternatively applied as an aid to smoking cessation during pregnancy. However, the effects of nicotine exposed at the prenatal stage on the emotional behaviors in offspring are not well understood due to the lack of systematic investigations. The current study has therefore initially aimed to evaluate emotional behaviors in young mouse offspring (postnatal day 28-36) which experienced gestational and/or perinatal nicotine exposure (GPNE) in six different time-windows. Pregnant C57BL/6J mice were exposed to nicotine via sweetened (2% sucrose) drinking water during 6 different time-windows including gestational day 0-day 13 (G0-G13), G14-perinatal day 0 (P0), G0-P0, G14-P7, G0-P7, and P0-P7. During P28-P36 days, both male and female offspring were given a battery of behavioral tests including light and dark box test, marble burying behavior test, novelty-suppressed feeding test, sociability and social novelty preference test, social avoidance tube test, and elevated plus maze test. GPNE during G0-P0, G14-P0, G14-P7, and G0-P7 induced abnormal behaviors in male and female offspring to different extent. Results indicated that nicotine at any time points of gestational and/or perinatal period impairs emotional behaviors in offspring, and suggested certain time-windows for further neurochemical or molecular studies in relation with GPNE-induced emotional abnormalities.

The ubiquitin–proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.

Methamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. We investigated the effect of galantamine on the reinstatement of cue-induced METH-seeking behavior using a self-administration experiment. Treatment with galantamine (1 mg/kg, p.o.) 30 minutes before exposure to the cues suppressed the reinstatement of METH-seeking behavior. However, galantamine did not affect the cue-induced reinstatement of food-seeking behavior or locomotor activity. These results suggest that galantamine may be a candidate drug for treating relapses of METH-seeking behavior.

The tail suspension test (TST) is widely recognized as a useful experimental paradigm for assessing antidepressant activity and depression-like behavior. We have previously identified ubiquitin-specific peptidase 46 (Usp46) as a quantitative trait gene responsible for decreasing immobility time in the TST in mice. This Usp46 mutation has a 3-bp deletion coding for lysine in the open reading frame, and we indicated that Usp46 is implicated in the regulation of the GABAergic system. However, it is not known precisely how the immobile behavior is regulated by the GABAergic system. Therefore, in the present study, we examined whether the immobility time is influenced by drugs affecting the action mediated by GABA(A) receptor using both 3-bp deleted (the Usp46 mutant) and null Usp46 (Usp46 KO) mice. Nitrazepam, an agonist at the benzodiazepine-binding site of the GABA(A) receptor, which potentiates the action of GABA, produced a dose-dependent increase in TST immobility time in the Usp46 mutant mice without affecting general behaviors. The Usp46 KO mice exhibited short immobility times comparable to the Usp46 mutant mice, which was also increased by nitrazepam administration. The effects of nitrazepam in the Usp46 mutant and KO mice were antagonized by flumazenil. These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABA(A) receptor might participate in the regulation of TST immobility time.

In the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane on: (i) neurosteroid and monoamine levels in the brain, and (ii) the antidepressant activity of steroids and antidepressants in the forced swimming test (FST). 3β-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehydroepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, γ-aminobutyric acid (GABA) and serotonin (5-HT), with consequences on mood and depression. We previously reported that trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocorticotropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamus-pituitary-adrenal (HPA) axis activation. We here observed that adrenalectomy/castration blocked the trilostane effect, outlining the importance of peripheral steroid levels. Trilostane (25 mg/kg) decreased hippocampus PROG contents and paradoxically increased circulating PROG levels. It also increased PREG levels in the hippocampus and frontal cortex. In the FST, a co-treatment with trilostane facilitated DHEAS (5-20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10-40 mg/kg), PROG (10-40 mg/kg) or allopregnanolone (ALLO, 1-8 mg/kg). Trilostane (25 mg/kg) treatment significantly increased 5-HT and (-)-norepinephrine (NE) turnovers in the hippocampus, an effect likely related to its antidepressant action. In co-administration studies, trilostane further decreased immobility following fluoxetine (30-60 mg/kg), sertraline (20-40 mg/kg) and imipramine (20-40 mg/kg), but not desipramine (20-40 mg/kg), treatments. A significant additive effect was observed for the selective 5-HT reuptake inhibitors (SSRI) at their highest dose. This study confirmed that a systemic administration of trilostane directly affected peripheral and brain levels in neuroactive steroids and monoamine turnover, resulting in antidepressant activity. The drug could be proposed as a co-treatment with SSRI. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder, great efforts have been made to generate genetic animal models for major mental illnesses. As these disorders are multifactorial, comparisons among drug-induced (non-genetic) and genetic models are becoming an important issue in biological psychiatry. A major barrier is that the standard mouse strain used in the generation of genetic models is C57BL/6, whereas almost all studies with PCP-induced models have utilized other strains. To fill this technical gap, we systematically compared the behavioural changes upon PCP administration in different mouse strains, including C57BL/6N, C57BL/6J, ddY, and ICR. We observed strain differences in PCP-induced hyperlocomotion and enhanced immobility in the forced swim test (ddY>>C57BL/6N and 6J>ICR). In contrast, there was no strain difference in the impairment of recognition memory in the novel object recognition memory test after withdrawal of chronic PCP administration. This study provides practical guidance for comparing genetic with PCP-induced models of psychosis in C57BL/6. Furthermore, such strain differences may provide a clue to the biological mechanisms underlying PCP-induced endophenotypes possibly relevant to major mental illnesses.

In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Xanthoceraside has anti-inflammatory and antioxidative activities. However, it remains unclear whether xanthoceraside improves amyloid β (Aβ)-induced neurotoxicity.The purpose of this study was to examine the effect of xanthoceraside on behavioral impairments, inflammatory responses, and oxidative stress induced by Aβ peptide(25-35) (Aβ(25-35)) in mice.The mice were treated orally with xanthoceraside (0.02, 0.08, or 0.32 mg/kg, once daily) after the intracerebroventricular injection of Aβ(25-35) (day 0). Cognitive functions were evaluated in Y-maze (day 6) and novel object recognition tests (days 7 and 8). Inducible nitric oxide synthase (iNOS) and nitrotyrosine levels in the hippocampus were examined (day 9). The mRNA expressions of iNOS and interleukin-4 (IL-4) in the hippocampus were measured 2 h and 3 days after the Aβ(25-35) injection by real-time reverse transcription-polymerase chain reaction.Xanthoceraside significantly attenuated behavioral impairments induced by Aβ(25-35) in the Y-maze and novel object recognition tests. Repeated treatment with xanthoceraside significantly inhibited the increase in the expression of iNOS and nitrotyrosine in the hippocampus induced by Aβ(25-35), which is associated with an enhanced expression of the IL-4 mRNA.These findings suggest that xanthoceraside attenuates memory impairments through amelioration of oxidative stress and inflammatory responses induced by Aβ(25-35) and is a potential candidate for an AD treatment.

Altered glutamatergic neurotransmission in the prefrontal cortex (PFC) has been implicated in a myriad of neuropsychiatric disorders. We previously reported that prenatal exposure to PCP produced long-lasting behavioral deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors. In addition, these behavioral changes were attenuated by clozapine treatment. However, whether the prenatal exposure adversely affects pre-synaptic glutamatergic neurotransmission in postpubertal mice remains unknown. In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the impairment of cognitive and emotional behavior after prenatal PCP treatment (5mg/kg/day) from E6 to E18 in mice. The PCP-treated mice showed an impairment of recognition memory in a novel object recognition test and enhancement of immobility in a forced swimming test at 8 weeks of age. Moreover, the prenatal treatment reduced the extracellular glutamate level, but increased the expression of a glial glutamate transporter (GLAST) in the PFC. The microinjection of DL-threo-β-benzyloxyaspartate (DL-TBOA, 10 nmol/site/bilaterally), a potent blocker of glutamate transporters, reversed these behavioral deficits by enhancing the prefrontal glutamatergic neurotransmission. Taken together, prenatal exposure to PCP produced impairments of long-term memory and emotional function which are associated with abnormalities of pre-synaptic glutamate transmission in the PFC of postpubertal mice. These findings suggest the prenatal inhibition of NMDA receptor function to contribute partly to the pathophysiology of neurodevelopment-related disorders, such as schizophrenia.

The deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which are suitable for the large scale preclinical screening of attention-improving compounds or drugs are few in the field. In this study, we have developed object-based attention task as a simple and wherever-practical method that suitable for quick drug screening in mice. Treatment with p-chlorophenylalanine (pCPA) (200mg/kg/day, i.p.) for three consecutive days reduced the prefrontal cortical content of serotonin and dopamine, and increased turn-over of dopamine while decreasing turn-over of norepinephrine in the prefrontal cortex on day 7. Auditory attention and working memory, but not long-term object memory after a long (10 min) object (two objects)-exposure period, were impaired on day 7 after the same treatment paradigm with pCPA. Novel object recognition ability immediately (

Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5-2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an "ongoing" protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain.

In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (Abeta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of Abeta peptide(25-35) (Abeta(25-35)) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the Abeta(25-35) injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 h after the Abeta(25-35) injection. We found that silibinin significantly attenuated memory deficits caused by Abeta(25-35) in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Abeta(25-35). Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by Abeta(25-35). These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Abeta(25-35) and (ii) may be a potential candidate for an AD medication.

The Zeeman-exchange relaxation time τ of h.c.p. solid 3He was obtained from the a.c. susceptibility measured in a molar volume of 19.29 cm3/mole at temperatures down to 34 μK. In the lowest-temperature region τ increased with decreasing temperature, which indicates the nature of the second-order phase transition. Below 100 μK, τ is found to obey the power law τ - τ0 ∝ (T - Tc)-1.37±0.07 under the assumption that the ordering temperature Tc is equal to 12 μK, where τ0 is the relaxation time at the high-temperature limit.

Early-life stress during the postnatal period could precipitate long-lasting alterations in the functional properties underlying emotional expression in humans, but how the psychological stress of cross-fostering affects emotional behavior during adulthood in mice remains primarily unknown. The purpose of the present study was to examine the long-term effects of cross-fostering on the emotional behavior and cognitive functions of ICR offspring in adulthood. Cross-fostering was performed from postnatal day 7 for 3 weeks. Mice were divided into three groups: (1) biological group: pups born from ICR dams fostered by their original mothers; (2) in-foster group: pups born from ICR dams but adopted by other ICR dams and (3) cross-foster group: ICR pups adopted by C57 dams. ICR mice were subjected to behavioral experiments at the age of 8 weeks. Emotional behaviors in the cross-fostered mice were significantly altered in the open-field, elevated plus maze and forced swimming tests, as well as social interaction tests. However, the cross-fostered mice showed normal memory function in the Y-maze and novel object recognition tests. The contents of serotonin metabolisms were decreased in the prefrontal cortex and hippocampus indicated the deficit of serotoninergic neuronal function by cross-fostering. These findings suggested that the early-life stress of cross-fostering induced long-lasting emotional abnormalities, which might be possibly related to alterations of serotonin metabolisms.

最近は一時に比べ，健康食品ブームもようやく落ち着いてきた．しかし充分な検証もないまま効能だけが一人歩きし，あたかも医薬品以上の効果があるかのように謳う商品が未だに存在することは由々しきことである．そうした商品が世の中にあふれるのは，マスコミなどメディアの過剰な報道によることと同時に，充分な検証がされていないことにも問題があると思われる．大雑把に言えば，ヒトや動物が口に入れるもののうち医薬品（医薬部外品）でないものが健康食品で，そのうち特定保健用食品と栄養機能食品については国が基準を定めている．医薬品（医薬部外品）が発売されるまでには動物やヒトを用いた基礎および臨床研究によって十分な効果を実証し（その上で毒性試験など）厳しい審査基準をクリアしなければならないが，そのほかのものは医薬品と比べると厳しくない．我々は食品についても十分な基礎薬理学的な検討が必要と考え，いくつかの食材や食品について行動薬理学的に検討してきた．ここでは日本人の主食であるコメおよびコメに含まれる成分に着目しマウスにおける効果を薬理学的に検証したのでその一部を報告したい．

An ac mutual inductance bridge for magnetic susceptibility measurements of solid3He in a metallic cell at ultralow temperatures is described. A null detector for the bridge was composed of an rf-biased superconducting quantum interference device (rf-SQUID) system and a lock-in amplifier that avoided strong fields of the nuclear demagnetization magnets. A design of a sample cell to reduce eddy currents and allow large skin depths associated with the ac measurements while securing high-thermal conductance is also described. The magnetic susceptibility of solid3He with a hexagonal close-packed structure was measured with this system down to 90 µK. The signal-to-noise ratio was 300 at 300 µK and 1 at 90 mK. The quantity of heat evolved in the susceptibility measurements was less than 3 pW.

We fed mice food granules containing fermented soybean (natto in Japanese) powder (hereafter "natto granules") for 14 d to investigate whether natto granules had any effects on mouse behavior. We noted an enhancement of locomotor activity in natto-granule-fed mice compared to control and soybean-pellet-fed mice. This enhanced locomotor activity was blocked by a low dose of haloperidol (1 microg/kg i.p.), a dopamine receptor antagonist, but not by methysergide, a serotonin 5-HT(1/2) receptor antagonist. The results suggest that the enhanced locomotor activity induced by continuous intake of natto granules in mice is sensitive to haloperidol.

We investigated the antidepressant-like effects of pre-germinated brown rice (PGBR) and polished rice (PR) pellets, respectively, in comparison with control (AIN-93G) pellets in the forced swimming test and the learned helplessness paradigm in mice. Mice were fed respective pellets for 30 days. The immobility time on the 2nd day of the forced swimming test was shorter in mice fed with PR or PGBR pellets than in mice fed with control pellets. In the learned helplessness paradigm, the number of escape failures in mice fed with PGBR pellets was significantly smaller than that in mice fed with control pellets. Compared to the control group, an increase in serotonin (5-HT) levels, but not in 5-hydroxyindoleacetic acid (5-HIAA) levels, and a decrease in the 5-HIAA/5-HT ratio were observed in the frontal cortex of the PGBR group. There were no differences among the three groups in terms of 5-HT and 5-HIAA levels and their ratios in the hippocampus and striatum. The levels of noradrenaline and 3-methoxy-4-hydroxyphenylglycol were not affected by the food pellets in all the brain regions tested. Additionally, we could not detect any differences in the expression of the 5-HT1A receptor and the 5-HT transporter in the frontal cortex of the three groups. These results suggest that the increase of 5-HT levels in the mouse frontal cortex contributes to the antidepressant-like effects of PGBR pellets.

Here we review the behavioral characterization of several strains of mice that have generally been used in learning and memory tests. We made behavioral comparisons among inbred (C57BL/6, DBA/1 and 129Sv) and closed colony (ddY and ICR (CD-1)) mice. In the water-maze test, the spatial learning ability of C57BL/6 and ICR was higher than that of the other strains of mice. In the Y-maze, water-finding and step-through type passive avoidance tests, there were some differences among those strains but they were not significant. We have to pay attention to the mouse strain to analyze the behavioral changes when we use different strains of mice.