橋本 謙二

We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of major depressive disorders. Experimental studies suggest that BDNF expression is induced by chronic antidepressant treatments, and that BDNF itself have antidepressant activity in animal models of depression. Furthermore, BDNF may protect neurons against stress-induced damage, and affect neurogenesis in the adult hippocampus. Our clinical study showed that serum levels of BDNF in drug naive patients with depression were significantly decreased as compared with normal controls. These findings suggest that low BDNF levels may play a pivotal role in the pathophysiology of major depression. It is unclear whether low BDNF levels are primary or secondary in patients with depression. One hypothesis would be that reduced BDNF might reflect a genetic vulnerability in patients with depression. Another possible explanation would be that stress-induced BDNF reductions might cause neuronal damage, which would in turn lead to acquired biological vulnerability. In order to determine the precise mechanism underlying the relationship between reduced BDNF levels and the etiology of major depression under both genetic and environmental backgrounds, further detailed study will be necessary.

著者らは,未治療うつ病患者の血清BDNF(脳由来神経栄養因子)濃度が,健常者と比較して有意に減少している一方で,抗うつ薬治療中のうつ病患者では,健常者と同レベルであることを発見した.更に,うつ病患者の血清中BDNF濃度とうつ症状の重症尺度であるHAM-D-17との間に負の相関があることを見出し,BDNF低下がうつ病の病因となっている可能性を示した.そして,未治療の患者に抗うつ薬による薬物治療を施行すると,臨床症状の改善に伴い,低下していた血清中BDNF濃度が増加することを確認した.これらの結果から,BDNFはうつ病の病態および抗うつ薬の作用発現に重要な役割を果たすことが示唆された

ラットを用いた実験において,抗酸化物質NAC(Nアセチルシステイン)が覚せい剤投与による急性の行動異常,繰り返し投与による行動感作の形成,およびドーパミン神経障害を有意に抑制することを見出した.そこで,覚せい剤投与によるドーパミン神経障害の予防及び治療法の開発を目的として,サルを用いたPET研究において,抗酸化物質NACの効果を調べた.覚せい剤の投与によってサル脳内ドーパミントランスポーター(DAT)は著しく減少したが,5-HTTの減少は軽度であった.NACの投与は,覚せい剤投与によるDATの減少を顕著に抑制した.よって,NACなどの抗酸化物質は覚せい剤乱用による脳内のドーパミン神経障害の予防薬および治療薬になる可能性が示唆された

Basic fibroblast growth factor (bFGF) is a multifunctional growth factor that has been implicated in a variety of neurodevelopmental processes. The aim of the present study was to examine whether bFGF contributes to the pathophysiology of schizophrenia. Serum bFGF levels in 40 patients with schizophrenia (15 drug-naive and 25 medicated patients) and in 40 age- and sex-matched healthy normal controls were measured. Serum bFGF levels were significantly higher in the medicated patients than in the normal controls. Analysis of partial correlation coefficients showed that the increased bFGF levels might not be attributable to antipsychotic medication. Although there was no significant overall difference in bFGF levels between drug-naive patients and normal controls, the bFGF levels in these patients significantly correlated with the severity of negative symptoms. Furthermore, we found a significant negative correlation between serum bFGF levels and the age of onset in the entire patient group. Our finding of elevated bFGF levels in the serum of patients with schizophrenia, especially in earlier age-of-onset cases considered to have more neurodevelopmental insults, suggests that bFGF abnormalities may be involved in the pathophysiology of schizophrenia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Wistar系ラット7週齢に覚せい剤(MAP)及びN-acetylcysteine(NAC)を投与し,ラット線条体におけるドーパミン量の変化をHigh Performance Liquid Chromatogaraphy(HPLC)を用いて測定した.MAPのみ投与された群では対照群に比し有意にドーパミン量が低下していた.MAP投与前にNACを投与した群では,NACの用量依存的にドーパミン量の低下を抑制した.以上より,NACがMAPによる神経毒性を予防し,MAP精神病の慢性化を予防し得る可能性が示唆された

In this study, we examined the effect of the acute and chronic administration of the selective 5-HT(2C) receptor antagonist SB-243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB-243213 (0.025-3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle-treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB-243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle-treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB-243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle-treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB-243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle-treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)-apomorphine (50 mug/kg). The repeated administration of either 1 or 3 mg/kg of SB-243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB-243213. Overall, our results indicate that antagonism of the 5-HT(2C) receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration. (C) 2002 Wiley-Liss, Inc.

The authors examined the correlations among plasma levels of ACTH, cortisol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) and their relationship with the scales for assessment of negative symptoms (SANS) in the male schizophrenic patients with negative symptoms. The subjects were 28 male schizophrenic patients categorized as with low negative symptoms (N = 14) and with moderate negative symptoms (N = 14) and 13 healthy subjects. Plasma levels of neurosteroids were measured by radioinununoassay. Significant correlations of SANS scores with plasma levels of ACTH, cortisol and testosterone, but not progesterone and DHEA-S, were found in the male schizophrenic patients. Furthermore, plasma levels of ACTH, cortisol, and testosterone in the male schizophrenic patients with moderate negative symptoms, but not low negative symptoms, were significantly different from normal controls. The measurements of plasma neurosteroid levels could be a useful biological marker for the severity of negative symptoms in schizophrenic patients. (C) 2002 Elsevier Science B.V. All rights reserved.

Serotonin (5-HT) is considered to be an important transmitter underlying mood and behaviour. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. A number of ligands have been developed to visualise the 5-HT transporter in vivo, but only a few have successfully visualised specific binding in vivo. In this study, we comparatively evaluated two ligands for 5-HT transporter, [C-11](+)McN5652 and [C-11]cyanoimipramine, in the human brain. Brain uptake of [C-11](+)McN5652 and [C-11]cyanoimipramine was measured with PET in 15 healthy volunteers. Second PET scans were performed after pretreatment with the potent 5-HT reuptake inhibitor clomipramine. Data were analysed as regional brain uptake as well as whole brain uptake. In six healthy volunteers uptake of the two ligands was also measured in the lung since it is one of the high-uptake organs in the body. In the brain, high accumulation was observed in the thalamus and striatum, the regions known to contain high densities of 5-HT transporter, for both [C-11](+)McN5652 and [C-11]cyanoimipramine. The average ratio of thalamus to cerebellum uptake at 90 min after the tracer injection was approximately 1.6 for [C-11](+)McN5652 and 1.7 for [C-11]cyanoimipramine, while the ratios obtained after pretreatment with clomipramine were approximately 1.2. However, the whole brain uptake of [C-11](+)McN5652 was approximately twice that of [C-11]cyanoimipramine, while the lung uptake of [C-11](+)McN5652 was approximately half that of [C-11]cyanoimipramine. Both [C-11](+)McN5652 and [C-11]cyanoimipramine showed sufficient specific binding for performance of a quantitative analysis in the brain. [C-11](+)McN5652 could be superior because of its higher distribution to the brain.

We investigated the roles of endogenous glutathione on 6-hydroxydopamine (6-OHDA)-induced apoptosis in human neuroblastoma SK-N-SH Cells using DNA fragmentation enzyme-immunoassay and the DNA dye Hoechst 33,258 staining. We observed that exogenous reduced glutathione (GSH), but not oxidized glutathione (GSSG), protected 6-OHDA (25 muM)-induced apoptosis in a dose-dependent manner. Preincubation (18 h) with the glutathione synthesis inhibitor DL-buthionine(S,R)-sulfoximine (BSO) significantly potentiated the toxic effects of 6-OHDA (12.5 or 25 muM). In contrast to BSO, N-acetylcysteine (NACP) blocked, and L-(-)-cystine, the glutathione precursor, significantly attenuated 6-OHDA (25 muM)-induced apoptosis, respectively. No alterations in endogenous glutathione concentrations were detected at 5, 15, 30, 60 min, 1 hour, 3 hours, or 6 hours after 6-OHDA (25 muM) treatment. However, we found a 3.5-fold increase of intracellular glutathione levels 24 hours later. On the contrary, higher concentration (100 muM) of 6-OHDA treatment, which caused more severe cell death, showed no changes of glutathione levels. These results suggest that delayed induction of endogenous glutathione might play an important role in the neuroprotective mechanism against dopamine cell death. In addition, we found that NAC might work as a beneficial catecholaminergic neuron-survival factor more efficiently than exogenous glutathione or L-cystine. (C) 2002 Elsevier Science Ltd. All rights reserved.

The lifetime prevalence rate of obsessive-compulsive disorder (OCD) is more than 2 percent of the population. Its contemporary pathophysiological models have been explored. As serotonin reuptake inhibitors and cognitive behavior therapy are both considered first-line treatments of OCD, the treatment interventions provide us with clues. In this review, the authors summarized that genetics, neuropathology in the cortico-striatal-thalamic-cortical (CTSC) circuits, the association between OCD and Tourette's syndrome, the possibility of autoimmune-mediated pathophysiology containing PANDAS, serologic surveys of patients, and animal models including transgenic mice. Further research, genetic, neuroimmunological, and neuroimaging works may ultimately be useful in developing new treatments of OCD.

人口の2%以上に見られる強迫性障害(OCD)は,セロトニン再取り込み阻害剤と曝露反応妨害法を主要な治療とする.common diseaseであるOCDの生物学的研究に関して,遺伝,CSTC回路を中心とした神経機能解剖,emotional Stroopテストによる情動レベルの検討,線条体機能とimplicit learningに関する学習理論,ドパミン・ブロッカーである抗精神病薬が治療に用いられるTourette's syndromeとの関連性,PANDASという自己免疫疾患との関連性,ヒト血液検体を用いた研究,トランスジェニックマウスを含めた動物モデルの各領域に分けて文献的概説を行った

The neuropharmacological profile of Y-931, 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno [2,3-b][1,5]benzodiazepine maleate, was investigated in comparison with those of typical and claimed atypical antipsychotic drugs. Similar to clozapine and olanzapine, Y-931 interacted with multiple neurotransmitter receptors such as dopaminergic, serotonergic, alpha-adrenergic, muscarinic and histaminergic receptors. Y-931, as well as the other antipsychotics, was active in a dose-dependent manner in established tests which are indicative of potential antipsychotic activity such as inhibition of apomorphine-induced hyperactivity and suppression of conditioned avoidance responses, however, only Y-931 and clozapine were devoid of cataleptogenic potential. In models of No methyl-D-aspartate (NMDA) receptor hypofunction, Y-931 demonstrated the most potent protective action against the dizocilpine-induced neurotoxicity (neuronal vacuolization) in the rat retrosplenial cortex ([Y-931 (ED50; 0.20 mg/kg, p.o.), olanzapine (1.1), clozapine (5.7), risperidone (6.9), haloperidol (19)). Furthermore, Y-931 and clozapine, unlike the other antipsychotics Used, reversed the dizocilpine-induced social deficits at the same doses at which their neuroprotective action was exhibited. The present results suggest that Y-931 may be a novel potential atypical antipsychotic drug with a low risk of extrapyramidal syndrome (EPS) and the property to ameliorate NMDA receptor hypofunction. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.

覚醒剤長期使用に伴う精神障害の発現予防薬の開発から,ELISAを用いたDNA断片化検出により,ヒト神経芽腫培養細胞株SK-N-SHの6-hydroxydopamineによる神経細胞死(apoptosis)に対する抗酸化剤の神経細胞死抑止効果を検討した.神経細胞死は,還元型グルタチオンにより,用量依存的に抑制され,逆に,グルタチオン合成阻害剤DL-buthionine-(S,R)-sulfoximineによって有意に増強した.グルタチオン前駆体2剤のうち,N-acetylcysteine(NAC)は,完全にapoptosisを阻害し,L-cystineも,apoptosisを有意に減弱した.よって,外因性及び内因性グルタチオンがドパミン神経細胞死に対する神経防護機構に重要な役割を果たすことが示唆された.特に,NACは,その著明な細胞死抑止作用から,覚醒剤精神病に対して予防的治療薬となる可能性が示された

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine have been known to cause schizophrenia-like psychosis (positive symptoms, negative symptoms, cognitive dysfunction) in humans. A dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia. In this review, the glutamate hypothesis of schizophrenia, especially the mechanism of neurotoxicity of NMDA receptor antagonist in the posterior cingulate cortex and retrosplenial cortex of the brain, is summarized. Furthermore, the roles of the posterior cingulate cortex and the retrosplenial cortex in the pathophysiology of schizophrenia and Alzheimer's disease are also discussed. Moreover, the glycine site of the NMDA receptor, metabotropic glutamate receptor, AMPA receptor, and antioxidant glutathione as novel potential targets for the treatment of schizophrenia are discussed.

It is known that β amyloid protein (Aβ) plays an important role in the pathology of Alzheimer's disease (AD). In this review, the role of cellular signaling in the protective action of nicotine for Aβ-induced neurotoxicity is described. Recent biochemical and functional studies have demonstrated that Aβ interacts directly with the α7 nicotinic receptor, suggesting that Aβ might have a function as an endogenous ligand for this receptor. Thus the role of α7 nicotinic receptor in the Aβ cascade hypothesis of AD and the possibility of α7 nicotine receptor agonists as the therapeutic drugs for AD are discussed.

1 We destroyed dentate granule cells unilaterally or bilaterally by means of intrahippocampal injection of colchicine in rats. Subsequently, we observed behavioural changes following the intraperitoneal injection of 2 mg kg(-1) methamphetamine or saline, in addition to quantitatively assessing Fos protein expression in several brain regions, including the medial prefrontal cortex, cingulate cortex, piriform cortex, dorsal striatum, and nucleus accumbens. 2 Bilaterally lesioned animals, when administered saline, showed a marked increase in locomotor activity compared with those of non-lesioned animals. With respect to the methamphetamine response, bilateral destruction resulted in a marked enhancement of locomotor activity, while the unilateral destruction led to a marked increase in rotation predominantly contralateral to the lesioned side, with no identifiable change in locomotor activity. 3 Bilaterally lesioned animals, when administered saline and having undergone an immunohistological examination, showed a marked increase in Fos expression in both sides of the nucleus accumbens. Bilaterally lesioned animals administered methamphetamine showed a marked increase in Fos expression in the right and left sides of all regions tested. Unilaterally lesioned animals administered methamphetamine showed a significant and bilateral enhancement in Fos expression in the medial prefrontal and cingulate cortices, and a marked and unilateral (ipsilateral to the lesioned side) enhancement of Fos protein in the piriform cortex, dorsal striatum, and nucleus accumbens. 4 The present findings suggest that dentate granule cells regulate methamphetamine-associated behavioural changes through the function of widespread areas of the brain, mostly the nucleus accumbens.

Rationale: FK506 inhibits calcineurin activity, resulting in the inhibition of calcium-dependent intracellular processes. Recent studies have suggested that intracellular calcium is likely to be involved in methamphetamine (MAP)-induced locomotor activity and stereotyped behavior, and in the development of sensitization to MAP. Objectives: We investigated the effects of FK506 on MAP-induced behavioral changes and the development of sensitization in rats. Methods: In experiment 1, animals were administered IP 2 mg/kg FK506 or vehicle followed 10 min later by MAP (1, 2, 4 and 8 mg/kg, IP). Another set of animals were administered FK506 (0.1, 2, 5 and 10 mg/kg) followed by 2 mg/kg MAP Locomotor activity and stereotyped behavior were assessed. In experiment 2, animals received repeated IP injections of 2 mg/kg MAP pretreated with 2 mg/kg FK506 or vehicle for 5 consecutive days. One week later, rats were challenged with 1 mg/kg MAP. Results: Pretreatment with 2 mg/kg FK506 caused a rightward shift of the inverted U-shaped response curve of the locomotor activity induced by 1-8 mg/kg MAP The same pretreatment significantly attenuated augmentation of the MAP-induced stereotyped behavior. FK506 at doses of 0.1-10 mg/kg dose-dependently inhibited the behavioral response induced by 2 mg/kg MAP. Coadministration of 2 mg/kg FK506 with 2 mg/kg MAP for 5 consecutive days resulted in significant suppression of the behavioral response to challenge with 1 mg/kg MAP. Conclusions: These results suggest that calcineurin plays an important role in MAP-induced behavioral changes and sensitization, especially the latter.

Using in situ hybridization, we studied the effects of age and gender on the expression of brain-derived neurotrophic factor (BDNF) mRNA and heat shock protein hsp-70 mRNA in the rat retrosplenial cortex following administration of the noncompetitive NMDA receptor antagonist (+)-MK-801 (dizocilpine). Male and female Sprague-Dawley rats (5 weeks, 12 weeks, or 10 months old) were given a single intraperitoneal injection of saline (1 ml/kg) or dizocilpine (0.3, 1.0, or 3.0 mg/kg). No expression of BDNF mRNA and hsp-70 mRNA was detected in the rat retrosplenial cortex after administration of saline (1 ml/kg, IP). Administration of dizocilpine (0.3, 1.0, or 3.0 mg/kg, IP) caused a marked induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex of male and female rats, in a dose-dependent manner. Female rats were more sensitive to the induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine as compared to male rats. It was also found that adult (12 weeks old) and aged (10 months old) rats were more sensitive to the induction of hsp-70 mRNA and BDNF mRNA in the retrosplenial cortex by dizocilpine as compared to young (5 weeks old) rats. These results suggest that the age and gender differences observed in the expression of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine may be associated with the differences in dizocilpine-induced neurotoxicity observed with gender and age within the same region. [Neuropsychopharmacology 25:258-266, 2001] (C) 2001 American College of Neuropsychology. Published by Elsevier Science Inc.

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT2A receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01-0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats. Synapse 40:102-112, 2001, (C) 2001 Wiley-Liss, Inc.

Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the K-d, but not B-max, values of [H-3]1,3-dipropyl-8-cyclopentylxanthine ([H-3]DPCPX) binding to adenosine A(1) receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the K-d and B-max values of [H-3]DPCPX binding to adenosine A(1) receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the B-max and K-d values of [H-3]2-p-(2-carboxyehyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine ([H-3]CGS21680) binding to adenosine A(2A) receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [H-3]CGS21680 to adenosine A(2A) receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A(2A) receptors, but not adenosine A(1) receptors in rat brain.

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects. (C) 2000 Elsevier Science Inc. All rights reserved.

Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3,4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N-methyl-D-aspartate (NMDA) receptor, dopamine D-1 receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT2A receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA. (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R,10S)-(+)5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5,10-imine ((+)-MK801; 1 mg/kg), dopamine D-1 receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT2A receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D-1 receptor and 5-HT transporter. (C) 2000 Elsevier Science B.V. All rights reserved.

In this study, we examined the effect of clozapine, olanzapine, risperidone and haloperidol on the neuropathology (i.e. neuronal vacuolization) and the expression of Fos-like protein and c-fos mRNA in the retrosplenial cortex of female Sprague-Dawley rats induced by the NMDA receptor antagonist dizocilpine. Pretreatment (15 min) with clozapine or olanzapine, but not risperidone or haloperidol, blocked the neuronal vacuolization produced by dizocilpine (0.5 mg/kg, s.c.) in the rat retrosplenial cortex in a dose-dependent manner. Furthermore, pretreatment (15 min) with clozapine or olanzapine, but not risperidone or haloperidol, significantly attenuated the expression of Fos-like protein in the retrosplenial cortex induced by dizocilpine (0.5 mg/kg, s.c.) in a dose- dependent manner. The marked expression of c-fos mRNA in the rat retrosplenial cortex induced by the administration of dizocilpine (0.5 mg/kg, s.c.) was significantly attenuated by pretreatment (15 min) with clozapine (10 mg/kg) or olanzapine (10 mg/kg), but not risperidone (10 mg/kg) or haloperidol (10 mg/kg). The present results suggest that pharmacologically relevant doses of clozapine or olanzapine, but not risperidone or haloperidol, block the neuropathological changes and the expression of Fos- like protein and c-fos mRNA in the rat retrosplenial cortex elicited by the administration of dizocilpine. It is possible that the blockade of dizocilpine-induced neuropathological changes by clozapine and olanzapine may be related to the unique antipsychotic actions of these drugs in schizophrenic patients, although this remains to be verified. © 2000 Elsevier Science B.V.

In this study, we examined the effect of post-treatment with clozapine on the neuropathological changes in the rat retrosplenial cortex induced by the administration of non-competitive NMDA receptor antagonist dizocilpine ((+)-MK-801). The maximal increase in vacuolized: neurons, which are representative of neuropathology, was observed 4 hours: after a single injection of dizocilpine (0.5 mg/kg s.c.), with a complete reversal of the neuropathology after 16-24 hours. The administration of clozapine (10 mg/kg, i.p.,) 4 hours after the administration of dizocilpine significantly decreased the number of vacuolized neurons in the retrosplenial cortex 6, 8 or 10 hours after administration of dizocilpine, compared to vehicle-treated animals. Furthermore, the administration of clozapine (5, 10 or 20 mg/kg i.p.) 4 hours after the administration of dizocilpine produced a significant decrease in the number of vacuolized neurons in the retrosplenial cortex in a dose-dependent manner when measure 6 hours post-dizocilpine. These results show that neuropathological changes in the rat retrosplenial cortex produced by dizocilpine can be attenuated by post-treatment with clozapine.

Phencyclidine (PCP) has been shown to cause neurotoxicity in rat retrosplenial cortex following a single administration, although the precise mechanism underlying PCP-induced neurotoxicity is unclear. Using in situ hybridization and immunohistochemistry, we studied the effects of PCP on expression of immediate early gene zif268 mRNA and zif268 protein in the rat brain. High constitutive levels of zif268 mRNA and zif268 immunoreactivity were observed in the brain of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of zif268 mRNA in the rat retrosplenial cortex, in a dose-dependent manner. However, the basal levels of zif268 mRNA in the other regions of cerebral cortex were decreased by administration of PCP. Emulsion-autoradiographical study suggested that marked expression of zif268 mRNA was observed in the layers III and IV of retrosplenial cortex where the neurotoxicity of PCP was detected. Furthermore, zif268 immunoreactivity in the layer IV of retrosplenial cortex was not changed by administration of PCP (25 mg/kg, i.p., 5 h), but that in the other layers of retrosplenial cortex was reduced by PCP. These results suggest that immediate early gene zif268 may, in part, play a role in the neurotoxicity of NMDA receptor antagonists such as PCP. (C) 1999 Elsevier Science B.V. All rights reserved.

The effects of acute and chronic administration of methamphetamine (MAP) or phencyclidine (PCP) on the plasma adrenocorticotropin (ACTH), corticosterone and progesterone in rats were examined. Acute administration of MAP (4.6 mg/kg i.p.) or PCP (10 mg/kg i.p.) increased significantly plasma ACTH, corticosterone and progesterone. In contrast, no changes of ACTH, corticosterone, and progesterone were found with chronic administration of MAP (4.6 mg/kg i.p. once daily for II days) or PCP (10 mg/kg i.p. once daily for II days). These results suggest that acute, but not chronic, administration of MAP or PCP could modify hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadotropin (HPG) axis endocrine responses in rats.

N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine [4-PBFBP] shows highly selective binding to serotonin 5-HT(2A) receptors with high affinity. In this study, we prepared [18F]4-PBFBP for in vivo study of 5-HT(2A) receptors in the brain using positron emission tomography (PET). Nucleophilic aromatic displacement of N-(4-phenylbutyl)-4-(4-nitrobenzoyl)piperidine by no carrier added [18F]fluoride which was solubilized by Kryptofix 222 in DMSO produced [18F]4-PBFBP with high specific radioactivity. The product was purified by reversed phase preparative HPLC and was extracted from the collected eluate by SEP-PAK® C18 cartridge prior to formulation. The radiochemical yield of the final product was 15 ± 1.8% (mean ± S.D. of three experiments) with decay correction and the specific activity was 113 ± 27 GBq/μmol (mean ± S.D. of three experiments) at E.O.S. after a total preparation time of about 160 min. The radiochemical purity of [18F]4-PBFBP was more than 99%. The regional distribution of [18F]4-PBFBP in mouse brain was also examined.

Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. However, it is well-known that behavioral responses to the systemic administration of kainic acid are inconsistent between animals. In this study, we examined the relationship between expression of genes, neuropathological damage, and behavioral changes (seizure intensity and body temperature) in rats after systemic administration of kainic acid. The considerable differences in the response to kainic acid-induced seizures were observed in rats after a single administration of kainic acid (12 mg/kg i.p.). There was no detection of the expression of heat shock protein hsp-70 mRNA and HSP-70 protein in brain of vehicle-treated controls and in animals exhibiting weak behavioral changes (stage 1-2). A moderate expression of hsp-70 mRNA was detected throughout all regions (the pyramidal cell layers of CA1-3 and dentate gyrus) of the hippocampus, the basolateral, lateral, central and medial amygdala, the piriform cortex, and the central medial thalamic nucleus of rats that developed moderate seizures (stage 3-4). Marked,expression of hsp-70 mRNA was detected in the all regions (cingulate, parietal, somatosensory, insular, entorhinal, piriform cortices) of cerebral cortex and all regions of hippocampus, and the central medial thalamic nucleus of the rats that developed severe seizures (stage 4-5). In addition, marked HSP-70 immunoreactivity was detected in the pyramidal cell layers of CA1 and CA3 regions of hippocampus, all regions (cingulate, parietal, somatosensory, insular, piriform cortices) of cerebral cortex, and the striatum of rats that developed severe seizures (stage 4-5). Furthermore, a marked expression of cyclooxygenase-2 (COX-2) mRNA and brain-derived neurotrophic factor (BDNF) mRNA levels by kainic acid-induced behavioral seizures (stage 3-4 or stage 4-5) was detected in all hippocampal pyramidal cell layers, granule layers of dentate gyrus, piriform cortex, neocortex, and amygdala. The present study suggest that the behavioral changes (seizure intensity and body temperature) and neuropathological damage after systemic administration of kainic acid are inconsistent between animals, and that these behavioral changes (severity of kainic acid-induced limbic seizures) might be correlated with gene expression of hsp-70 mRNA, COX-2 mRNA, and BDNF mRNA in rat brain. (C) 1998 Elsevier Science B.V. All rights reserved.

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D1 and D2 receptors and the N-methyl-D-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 μg/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D1 receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5.0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 μg/kg). Pretreatment with sulpiride, a dopamine D2 receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D1 receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D2 receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.

1)最初期遺伝子c-fosのアンチセンスODNsのラット脳室内投与を行い海馬部分発作への影響を見た.アンチセンス投与群では有意な後発射の短縮を見たが,センス,スクランブルODNs群では変化なかった. 2)NMDA受容体拮抗薬投与によるラット帯状回HSP-70タンパク質,HSP-70mRNAの発現をAMPA受容体拮抗薬,cAMP分解酵素阻害薬,抗コリン剤が抑制した. 3)ラットCA1,及び貫通路にLTD誘発様刺激(0.4mA,1Hz×900)を単回,7日間繰り返し加えた後海馬部分発作をおこし,その影響をみたがCA1及び歯状回てんかん焦点に明らかな抗てんかん作用を示さなかった

The non-competitive NMDA receptor antagonists such as phencyclidine (PCP) cause neurotoxicity in the retrosplenial cortex of rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is currently unclear. Using an in situ hybridization technique, we studied the effects of PCP on expression of brain-derived neurotrophic factor (BDNF) nRNA in the rat brain. No expression of BDNA mRNA was observed in the retrosplenial cortex of rats treated with vehicle, although a high basal level of BDNF mRNA was detected in the hippocampus of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 hours) caused marked induction of BDNF mRNA in the retrosplenial cortex, in a dose-dependent manner. These results suggest that the expression of BDNF mRNA may occur as a trophic response to the neurotoxicity of NMDA receptor antagonists such as PCP.

The non-competitive NMDA receptor antagonists, such as (+)-MK-801 (dizocilpine), cause the expression of heat shock protein HSP-70 and pathomorphological damage in the retrosplenial cortex of the rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is unknown. The present study was undertaken to examine the role of phosphodiesterase type IV in the expression of heat shock genes induced by dizocilpine. Heat shock protein HSP-70, which is known as a sensitive marker of neuron injury, was induced in the retrosplenial cortex of the rat brain 24 h after a single administration of dizocilpine (1 mg/kg). Pretreatment with the specific phosphodiesterase type IV inhibitor rolipram (2.5, 5 or 10 mg/kg, 15 min before dizocilpine) attenuated the expression of HSP-70 and hsp-70 mRNA induced by dizocilpine (1 mg/kg) in a dose-dependent manner. Furthermore, another phosphodiesterase type IV inhibitor, Ro 20-1724 (5 or 10 mg/kg, 15 min before dizocilpine), and a non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) (5 or 10 mg/kg, 15 min before dizocilpine), significantly attenuated the expression of HSP-70 protein and hsp-70 mRNA induced in the retrosplenial cortex try dizocilpine. However, the induction of the immediate early gene c-fos and microglial activation in the retrosplenial cortex after administration of dizocilpine was not attenuated by pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine). Moreover, histopathological study indicated that pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine) did not prevent the formation of vacuoles caused by treatment with dizocilpine. The present findings suggest that phosphodiesterase type IV may play a significant role in the expression of HSP-70 protein and hsp-70 mRNA in the rat retrosplenial cortex after administration of dizocilpine, and that phosphodiesterase type IV may not play a role in the neurotoxicity of NMDA receptor antagonists such as dizocilpine.

Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.

The effect of NMDA receptor antagonist phencyclidine (PCP) on expression of cyclooxygenase (COX)-2 mRNA in the rat brain was studied. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of COX-2 mRNA and heat shock gene hsp-70 mRNA, a marker of neuronal injury, in the retrosplenial cortex, in a dose-dependent manner. These results suggest that COX-2 may play a role in the neurotoxicity of NMDA receptor antagonists. (C) 1997 Elsevier Science B.V.

Psychostimulant drugs have been reported to increase the expression of some immediate-early genes in the brain. In the present study, immunohistochemical techniques were used to assess the pattern of Fos protein produced by 3,4-methylenedioxymethamphetamine (MDMA) in several brain regions. Furthermore, we also studied the role of the dopamine D-1 and D-2 receptors and the N-methyl-D-aspartate (NMDA) receptor in the induction of Fos protein by MDMA. A single administration of MDMA (5, 10 or 20 mg/kg) caused marked induction of Fos-immunoreactivity in several regions including frontal cortex, striatum and olfactory tubercle of rat brain, in a dose-dependent manner. However, in the hippocampus and cerebellum, there were few or no Fos immunoreactive cells induced by MDMA. Furthermore, the induction of Fos protein in the striatum and olfactory tubercle after administration of MDMA (10 mg/kg) was blocked by pre-treatment with the dopamine D-1 receptor antagonist SCH 23390 (1 mg/kg) or the NMDA receptor antagonist dizocilpine (1 mg/kg), but not by the dopamine D-2 receptor antagonist (-)-sulpiride (100 mg/kg). However, the induction of Fos protein in the frontal cortex and hippocampus by MDMA was unaltered by pretreatment with SCH 23390 (1 mg/kg) or (-)-sulpiride (100 mg/kg). These results suggest that MDMA induces the expression of Fos protein in several regions of rat brain, and that the expression of Fos protein by MDMA in the striatum and olfactory tubercle appears to be mediated at least in part by the dopamine D-1 and NMDA receptors.

We examined the effects of antisense oligodeoxynucleotides (ODNs) to c-fos mRNA on hippocampal partial seizures in rats. As control, sense and scrambled control ODNs were also tested. Each ODN (10 nmol/10 μl) was injected into the lateral ventricles for 2 consecutive days. Fifteen hours after the last injection, electrical stimulation was delivered to assess the effects on afterdischarge threshold and afterdischarge duration (ADD). One hour after seizures, c-Fos and Jun-B immunocytochemistries were performed. Antisense ODNs significantly decreased ADD and control ODNs failed to change any parameters. In the antisense ODNs group, c-Fos expression occurred ipsilateral to the stimulation site in dentate granule cells, while Jun-B expression was seen bilaterally. In the majority of control ODNs animals, c-Fos and Jun-B expression in dentate granule cells occurred bilaterally. These findings suggest that the injection of antisense ODNs selectively inhibit contralateral c-Fos expression and that c-fos plays a key role in hippocampal excitability and seizure expression during hippocampal partial seizures.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist such as an abused drug phencyclidine (PCP) causes the induction of heat shock protein HSP-70, a sensitive marker of neuronal injury, in the retrosplenial cortex of rat brain. The present study was undertaken to examine the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the expression of heat shock protein HSP-70 and hsp-70 mRNA in the retrosplenial cortex by PCP. Administration of PCP (50 mg/kg, i.p.) caused the induction of heat shock protein HSP-70 in the retrosplenial cortex of rat brain, whereas no HSP-70 immunoreactivity was detected in the vehicle-treated group. Pretreatment with a potent and selective AMPA receptor antagonist YM90K (1, 3 or 10 mg/kg, i.p 15 min) inhibited in a dose dependent manner, the induction of heat shock protein HSP-70 by PCP (50 mg/kg). Furthermore, administration of PCP (50 mg/kg, i.p) caused marked expression of hsp-70 mRNA in the retrosplenial cortex of rat brain, whereas the expression of hsp-70 mRNA was NOT found in the vehicle-treated group. Pretreatment with YM90K (1, 3 or 10 mg/kg, i p 15 min) also inhibited the expression of hsp-70 mRNA by PCP (50 mg/kg), in a dose-dependent manner. These results suggest that AMPA receptor may play a role in the expression of heat shock protein HSP-70 and heat shock gene hsp-70 mRNA in the retrosplenial cortex of rat brain by non-competitive NMDA receptor antagonists such as PCP.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

Effects of an interaction between rolipram, a cyclic adenosine 3',5'-monophosphate (cyclic AMP) phosphodiesterase inhibitor, and methamphetamine on the development of behavioral sensitization were observed in rats. In vivo microdialysis showed that a single dose of 4 mg/kg methamphetamine (i.p.) significantly increased striatal dopamine levels while coadministration with 4 mg/kg rolipram (i.p.) did not affect these levels. Also, methamphetamine alone did not alter striatal cyclic AMP levels but coadministration with rolipram and rolipram alone significantly increased these levels. The administration of 4 mg/kg methamphetamine (i.p.) once a day for 5 days significantly enhanced hyperlocomotion and rearing induced by a 2-mg/kg methamphetamine challenge (i.p.) after a I-week withdrawal period, compared with controls or coadministration with 4 mg/kg rolipram (i.p.). Striatal dopamine levels, detected by in vivo microdialysis, were increased following the challenge but were comparable between the groups. These findings suggest that rolipram prevents methamphetamine-induced behavioral sensitization by increasing cyclic AMP levels while not affecting dopamine-releasing processes.

Dextromethorphan, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, is one of the most widely used non-opioid cough suppressants, and it is generally considered to be a safe drug. In this study, we have examined whether dextromethorphan is neurotoxic to rat cerebrocortical neurons. Induction of heat shock protein HSP-70, an indicator of cellular stress, was observed in the posterior cingulate and retrosplenial cortex of rat brain after a single administration of dextromethorphan (75 mg/kg). Furthermore, administration of dextromethorphan (75 mg/kg) caused vacuolization in the same regions. These results suggest that high doses of dextromethorphan could cause neuronal injury in the cerebrocortical neurons.

The interactions of selective serotonin reuptake inhibitors and tricyclic antidepressants with subtypes of σ receptors were investigated. The rank order of affinity (K(i) values) from competition experiments of [3H](+)-pentazocine binding to σ1 sites was: fluvoxamine &gt sertraline &gt S(+)-fluoxetine &gt (±)-fluoxetine &gt citalopram &gt imipramine, &gt paroxetine &gt desipramine &gt R (-)-fluoxetine &gt (±)-norfluoxetine. The K(i) values of all drugs for σ2 sites were more than 1000 nM. Furthermore, all drugs were more potent at σ1 sites than at σ2 sites. These findings suggest that a receptors (σ1 Site) may play, in some way, a role in the actions-of selective serotonin reuptake inhibitors.