• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1997년도 춘계학술대회
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• pp.102-102
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• 1997

The purpose of this study was to determine the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both the competitive (AP-5 and D-CPP) and the noncompetitive (MK-801, ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced 5-HT(5-hydroxytryptamine)-induced selective serotonergic behavior, head-twitch response (HTR), in mice. These results suggest that the glutamatergic neurotransmission may modulate serotonergic function at the 5-HT receptor. The precise relationship between glutamatergic and serotonergic system is as yet undefined. However, these are the first data available regarding glutamatergic modulation of serotonergic function at the 5-HT receptor in intact mice, and the present results support the notion that the NMDA receptors may play important roles in the glutamatergic modulation of serotonergic function at the 5-HT receptor.

• Clinical and Experimental Pediatrics
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• 제52권5호
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• pp.594-602
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• 2009

목 적 : $TGF-{\beta}1$는 흥분독성을 억제시키고 질소 산화물 생성 억제를 통한 신경세포 보호 효과가 있다고 알려져 있지만 주산기저산소 허혈 뇌손상에서 그 기전은 아직도 확실히 밝혀져 있지 않고 있다. 따라서 이번 연구에서는 신생 백서의 저산소 허혈 뇌손상에서 산화질소로 인한 신경독성 및 글루탐산염에 의한 흥분독성과 $TGF-{\beta}1$의 관계를 보고자 하였다. 방 법 : 생체외 실험으로 재태 기간 19일된 태아 백서의 대뇌피질 세포를 배양하여 1% O2 배양기에서 저산소 상태로 뇌세포손상을 유도하여 저산소군(Hypoxia), 저산소 손상 30분 전 $TGF-{\beta}1$ (1, 5, 10 ng/mL) 투여군(H+$TGF-{\beta}1$)으로 나누어 정상 산소군 (Control)과 비교하였다. 생체 내 실험은 생후 7일된 백서의 좌측 총 경동맥을 결찰한 후 저산소 (7.5% O2) 상태로 2시간 노출시켜서, 저산소 허혈 뇌손상을 유발하였다. 아무런 처치도 하지 않은 정상 대조군(Control), 경동맥 노출 후 봉합 시술만 시행한 정상 Sham 수술군(Sham-OP), 손상 30분 전 생리식염수를 주입 후 경동맥 결찰과 저산소 노출을 시행한 저산소 허혈 대조군(HI+ Vehicle), 손상 30분 전 $TGF-{\beta}1$을 대뇌로 투여하고 경동맥 결찰과 저산소 노출을 시행한 저산소 허혈 $TGF-{\beta}1$ 투여군(HI+$TGF-{\beta}1$)으로 나누어 비교분석하였다. 흥분독성과의 관련을 알아보기 위하여 NMDA 수용체 아단위를 이용하였고, 질소산화물과의 관련을 알아보기 위해 iNOS, eNOS 및 nNOS를 이용하여 western blotting과 실시간 중합효소연쇄반응을 하였다. 결 과 : 생체 외 실험에서 iNOS의 발현은 정상 산소군과 저산소군 간에 차이가 없었으며, $TGF-{\beta}1$ 투여군에서는 발현이 증가하였으며 이는 농도와는 상관성이 없었다. eNOS, nNOS의 발현은 1 ng/mL의 $TGF-{\beta}1$ 투여군에서 저산소군보다 감소하였다. 생체 내 실험에서는 iNOS와 iNOS mRNA의 발현은 $TGF-{\beta}1$ 투여한 후 저산소 대조군보다 증가하였다. eNOS와 nNOS 발현은 정상 대조군 보다 저산소 대조군에서 감소하였고, eNOS의 발현은 $TGF-{\beta}1$ 투여군에서 증가하였지만 nNOS의 발현은 증가하지 않아 통계적 유의성이 없었다. eNOS mRNA와 nNOS mRNA의 발현은 iNOS와 반대로 $TGF-{\beta}1$ 투여군에서 저산소 대조군보다 감소하였다. NMDA 수용체 아단위 mRNA의 발현은 정상 대조군과 Sham 수술군에 비해 저산소 대조군에서 모두 감소하였으나 $TGF-{\beta}1$ 투여군에서 NR2C를 제외한 나머지 아단위의 발현은 저산소 대조군보다 증가하였다. 결 론 : 신생백서의 저산소 허혈 뇌손상에서 $TGF-{\beta}1$ 치료군에서 저산소로 인하여 감소된 NMDA 수용체 아단위의 발현을 증가시켜 흥분독성 기전과 관련성을 보이며, 증가된 iNOS 발현을 감소시키고 감소된 eNOS 발현을 증가시키는 질소 산화물 중재를 통한 뇌 보호 작용에 연관이 있을 것으로 생각된다.

• Archives of Pharmacal Research
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• 제22권2호
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• pp.113-118
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• 1999

Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) receptor antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of serotonergic function at the postsynaptic $5-HT_{2}$ receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti-tive (MI-801, ketamine, dextrorphan and dextromethorphan) NMDA receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA receptor in 5-HT-induced HTR at the postsyaptic $5-HT_{2}$receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA receptor antagonist, NMDA and a serotonin $5-HT_{2}$receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA receptors play an important role in the glutamatergic modulation of serotonergic function at the poststynaptic $5-HT_{2}$ receptors.

• Archives of Pharmacal Research
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• 제22권1호
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• pp.48-54
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• 1999

These studies were designed to examine the differential effect of nitric oxide (NO) and cGMP on glutamate neurotransmission. In primary cultures of rat cerebellar granule cells, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulates the elevation of intracellular calcium concentration ($[Ca^{2+}]_i$), the release of glutamate, the synthesis of NO and an increase of cGMP. Although NO has been shown to stimulate guanylyl cyclase, it is unclear yet whether NO alters the NMDA-induced glutamate release and ${[Ca^{2+}]}_i$ elevation. We showed that the NO synthase inhibitor, NG-monomethyl-L-arginine (NMMA), partially prevented the NMDA-induced release of glutamate and elevation of ${[Ca^{2+}]}_i$ and completely blocked the elevation of cGMP. These effects of NO on glutamate release and [Ca2+]i elevation were unlikely to be secondary to cGMP as the cGMP analogue, dibutyryl cGMP (dBcGMP), did not suppress the effects of NMDA. Rather, dBcGMP slightly augmented the NMDA-induced elevation of ${[Ca^{2+}]}_i$ with no change in the basal level of glutamate or ${[Ca^{2+}]}_i$. The extracellular NO scavenger hydroxocobalamine prevented the NMDA-induced release of glutamate providing indirect evidence that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining the NMDA receptor activation in a cGMP-independent manner.

• The Korean Journal of Physiology and Pharmacology
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• 제2권4호
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• pp.427-433
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• 1998

In brain hypoxic-ischemia, an excess release of glutamate and a marked production of reactive oxygen species (ROS) occur in neuronal and non-neuronal cells. The present study investigated the effect of the biological antioxidants dihydrolipoic acid (DHLA) and lipoic acid (LA) on N-methyl-D-aspartate (NMDA)- and ROS-induced neurotoxicity in cultured rat cortical neurons. DHLA enhanced NMDA-evoked rises in intracellular calcium concentration ($[Ca^{2+}]_i$). In contrast, LA did not alter the NMDA-evoked calcium responses but decreased after a brief treatment of dithiothreitol (DTT), which possesses a strong reducing potential. Despite the modulation of NMDA receptor-mediated rises in $[Ca^{2+}]_i$, neither DHLA nor LA altered the NMDA receptor-mediated neurotoxicity, as assessed by measuring the amount of lactate dehydrogenase released from dead or injured cells. DHLA, but not LA, prevented the neurotoxicity induced by xanthine/xanthine oxidase-generated superoxide radicals. Both DHLA and LA decreased the glutathione depletion-induced neurotoxicity. The present data may indicate that biological antioxidants DHLA and LA protect neurons from ischemic injuries via scavenging oxygen free radicals rather than modulating the redox modulatory site(s) of NMDA receptor.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.209-214
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• 2009

The striatum receives glutamatergic afferents from the cortex and thalamus, and these synaptic transmissions are mediated by ${\alpha}$-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl D-aspartate (NMDA) receptors. The purpose of this study was to characterize glutamate receptors by analyzing NMDA/AMPA ratio and rectification of AMPA and NMDA excitatory postsynaptic currents (EPSCs) using a whole-cell voltage-clamp method in the dorsal striatum. Receptor antagonists were used to isolate receptor or subunit specific EPSC, such as (DL)-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, ifenprodil, an NR2B antagonist, CNQX, an AMPA receptor antagonist and IEM-1460, a GluR2-lacking AMPA receptor blocker. AMPA and NMDA EPSCs were recorded at - 70 and + 40 mV, respectively. Rectification index was calculated by current ratio of EPSCs between + 50 and - 50 mV. NMDA/AMPA ratio was 0.20${\pm}$0.05, AMPA receptor ratio of GluR2-lacking/GluR2-containing subunit was 0.26${\pm}$0.05 and NMDA receptor ratio of NR2B/NR2A subunit was 0.32${\pm}$0.03. The rectification index (control 2.39${\pm}$0.27) was decreased in the presence of both APV and combination of APV and IEM-1460 (1.02${\pm}$0.11 and 0.93${\pm}$0.09, respectively). These results suggest that the major components of the striatal glutamate receptors are GluR2-containing AMPA receptors and NR2A-containing NMDA receptors. Our results may provide useful information for corticostriatal synaptic transmission and plasticity studies.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1995년도 제3회 추계심포지움
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• pp.125-132
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• 1995

In neurons, nitric oxide(NO) is produced by neuronal nitric oxide synthase following stimulation of N-methyl-D-aspartate(NMDA) receptors and the subsequent influx of Ca$\^$2+/. NO, induced in this manner, reportedly plays critical roles in neuronal plasticity, including neurite outgrowth, synaptic transmission, and long-term potentiation(LTP) (1-7). However, excessive activation of NMDA receptors has also been shown to be associated with various neurological disorders, including focal ischemia, epilepsy, trauma, neuropathic pain and chronic neurodegenerative maladies, such as Parkinson's disease, Hungtington's disease and amyotrophic lateral sclerosis(8). The paradox that nitric oxide(NO) has both neuroprotective and neurodestructive effects may be explained, at least in part, by the finding that NO effects on neurons are dependent on the redox state. This claim may be supported by the recent finding that tissue concentrations of cysteine approach 700 ${\mu}$M in settings of cerebral ischemia (9), levels of thiol that is expected to influence both the redox state of the system and the NO group itself(10).

• Archives of Pharmacal Research
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• 제23권5호
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• pp.488-494
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• 2000

Cerebellar granule and glial cells prepared from 7 day-old rat pups were used to investigate the effects of sub-acute nicotine exposure on the glutamatergic nervous system. These cells were exposed to nicotine in various concentrations for 2 to 10 days in situ. Nicotine-exposure did not result in any changes in cerebellar granule and glial cell viability at concentrations of up to 500 $\mu\textrm{M}$. In cerebellar granule cells, the basal extracellular levels of glutamate, aspartate and glycine were enhanced in the nicotine-exposed granule cells. In addition, the responses of N-methyl-D-aspartate (NMDA)-induced glutamate release were enhanced at low NMDA concentrations in the nicotine-exposed granule cells. However, this decreased at higher NMDA concentrations. The glutaminase activity was increased after nicotine exposure. In cerebellar glial cells, glutamate uptake in the nicotine-exposed glial cells were either increased at low nicotine exposure levels or decreased at higher levels. The inhibition of glutamate uptake by L-trans-pyrollidine-2,4-dicarboxylic acid (PDC) was lower in glial cells exposed to 50 $\mu\textrm{M}$ nicotine. Glutamine synthetase activity was lower in glial cells exposed to 100 or 500 $\mu\textrm{M}$ of nicotine. These results indicate that the properties of cerebellar granule and glial cells may alter after subacute nicotine exposure. Furthermore, they suggest that nicotine exposure during development may modulate glutamatergic nervous activity.

• 생명과학회지
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• 제27권3호
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• pp.355-360
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• 2017

다량의 에탄올을 섭취하면 기억 상실로 이어질 수 있으며, 종종 blackout으로 나타난다. Blackout의 불균형은 알코올 소비에 있어 다양한 사회 문제의 주요 원인이 될 수 있다. 그러나 이러한 알코올 유발 문제를 예방하는 치료법은 아직 존재하지 않는다. Hydrangeae dulcis folium은 Hydrangea serrata Seringe의 잎을 발효가공을 통해 만든 민간약 또는 차이다. 본 연구에서는 에탄올로 유도한 정신적 결핍에 대한 Hydrangeae dulcis folium의 에탄올 추출물(EHDF)의 효과를 평가하였다. 행동적 결핍 또는 장애를 테스트하기 위해 마우스에서 물체 인식 테스트가 수행하였다. 또한 시냅스 결손을 평가하기 위해, 마우스 해마 조각에서 에탄올에 취약한 것으로 알려져 있고 에탄올로 유발한 기억 상실과 관련이 있는 N-methyl-D-aspartate (NMDA) 수용체-매개 흥분성 시냅스 후 전위 및 long-term potentiation (LTP)을 측정하였다. 본 연구에서 에탄올(1 g/kg, i.p.)은 물체 인식 메모리를 손상 시켰지만, EHDF (10 또는 30 mg/kg)는 물체 인식 테스트에서 이러한 장애를 극복하였다. 흥미롭게도, EHDF ($30{\mu}g/ml$)는 해마 절편에서 에탄올 처리 후 억제되었던 LTP 및 NMDA 수용체 매개 시냅스 전달을 유의하게 개선시켰다. EHDF는 에탄올에 의해 유발된 물체 인식 기억력 결핍을 개선하였고, 또한 EHDF는 해마 절편에서 에탄올 유도성 LTP 및 NMDA 수용체 매개성 시냅스 전달을 상당히 개선시켰다.

• 대한약리학회지
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• 제29권2호
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• pp.189-193
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• 1993

흰쥐태 뇌간의 세포를 배양하여 glutamate에 6시간까지 노출시 glutamate의 농도 및 노출 시간에 의존적으로 세포내 5-HT 및 5-HIAA의 함량이 감소하였고, 배양액으로 LDH의 유출이 증가하였다. Tetrodotoxin은 glutamate의 작용을 차단하지 못하였다. NMDA 수용체 통로 봉쇄제인 MK-801에 의해 glutamate의 작용이 효과적으로 차단되었고, non-NMDA 길항제인 CNQX는 효과가 없었으므로, serotonin 신경세포에 대한 glutamate의 작용은 NMDA 수용체의 자극에 의한 것으로 사료된다.