• The Korean Journal of Physiology and Pharmacology
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• 제19권2호
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• pp.89-97
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• 2015

The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine- and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over-expression in mice. The levels of striatal CART mRNA were significantly increased on the $3^{rd}$ day. CART peptides were over-expressed on the $5^{th}$ day in the striata of behaviorally sensitized mice. A higher proportion of $CART^+$ cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both $D_1R$ and $D_2R$ antagonists, SCH 23390 ($D_1R$ selective) and raclopride ($D_2R$ selective), blocked cocaine induced-behavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/ protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over-expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both $D_1R$ and $D_2R$ knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the $D_1R$-KO mice, but not in the $D_2R$-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by $D_1R$.

• 대한본초학회지
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• 제30권3호
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• pp.13-17
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• 2015

Objectives : Taraxacum platycarpum H. Dahlstedt has been reported to have several biological properties such as skin hydration and antiinflammation. The purpose of this study was to examine the antidepressive effects of water extract of T. platycarpum (WTP) on an animal model of depression. Methods : In the present study, normal ICR mice (4 weeks) were used, and orally administered with WTP (25, 50 and 100 mg/kg). Depression-like behavior was monitored the forced swimming test (FST) and tail suspension test (TST) in mice. The locomotor activity was evaluated to eliminate the false-positive activity in the open field test (OFT). Fluoxetine, the selective serotonin reuptake inhibitor, as a positive control was intraperitoneally administered at a dose of 15 mg/kg at 30 min before starting the behavioral test. Moreover, we evaluated the effects of WTP on the expression of brain-derived neurotrophic factor (BDNF) and the extracellular signal-regulated kinase (ERK)/ cyclic AMP response-element binding protein (CREB) signaling pathway in the hippocampus using Western blot. Results : The administration of WTP (50 and 100 mg/kg) significantly (P < 0.05, respectively) reduced the immobility time during FST and TST without accompanying changes in locomotor activity by OFT. Furthermore, WTP at dose of 100 mg/kg increased the BDNF expression and the phosphorylation of ERK and CREB in the hippocampus region. Conclusions : These results suggest that WTP has a useful anti-depressant effect through the regulation of BDNF/ERK/CREB signaling pathway.

• Biomolecules & Therapeutics
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• 제19권1호
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• pp.45-51
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• 2011

These experiments were designed to use typical makers from behaviors and molecular basis in addicted animals of morphine and cocaine. Morphine has been widely abused with a high physical dependence liability. Morphine withdrawal activates the intracellular cAMP signaling pathway and further leads to changes in the expression of the cAMP response element binding protein (CREB), which may be important to the development and expression of morphine dependence. From these experiments, repeated morphine (10 mg/kg, twice per day for 7 days) developed physical dependence. Withdrawal signs were precipitated by naloxone and also increased the expression of the CREB. In addition, repeated exposure of cocaine (15 mg/kg) to mice develops locomotor sensitization and produced lasting behavioral sensitivity. Cocaine- and amphetamine-regulated transcript peptide (CART) peptide was up-regulated by repeated administration of cocaine in the striatum. Therefore, repeated morphine induced the development of physical dependence and increased pCREB. In addition, repeated cocaine induced locomotor sensitization and over-expressed CART peptide. In conclusion, the development of physical dependence and pCREB for morphine, and locomotor sensitization and CART peptide over-expression for cocaine would be useful markers to predict the abuse potential of opioid analgesics and pychostimulant drugs in animals, respectively.

• The Korean Journal of Physiology and Pharmacology
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• 제5권1호
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• pp.19-25
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• 2001

We have studied the effects of excitatory amino acids on the expression of the c-fos and c-jun mRNA in rat C6 glioma cells. The glutamate, $N-methyl-_D-aspartate$ (NMDA), and kainic acid (KA) increased c-fos mRNA level in a concentration-dependent manner. However, they did not affect c-jun mRNA level. In addition, forskolin and phorbol 12-myristate 13-acetate (PMA) increased c-fos mRNA level. Furthermore, PMA increased c-jun mRNA level whereas forskolin downregulated c-jun mRNA level. The glutamate, NMDA and KA, at a concentration of 0.25 mM, did not affect the basal c-fos and c-jun mRNA levels, and also did not affect forskolin- and PMA-induced responses. Furthermore, both forskolin and PMA itself increased the phosphorylation of ERK (extracellular signal regulated kinase) and CREB (cyclicAMP responsible element binding protein) proteins. The KA, NMDA, and glutamate did not affect forskolin- induced increase of ERK and CREB phosphorylation. The KA decreased PMA-induced increase of phosphorylation of ERK and CREB proteins, whereas glutamate and NMDA did not affect the phosphorylation of ERK and CREB proteins induced by PMA. These findings suggest that, in C6 glioma cells, c-fos mRNA induction induced by EAAs is not mediated by phosphorylation of ERK and CREB proteins.

• Molecules and Cells
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• 제42권4호
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• pp.301-312
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• 2019

Post-transcriptional regulation underlies the circadian control of gene expression and animal behaviors. However, the role of mRNA surveillance via the nonsense-mediated mRNA decay (NMD) pathway in circadian rhythms remains elusive. Here, we report that Drosophila NMD pathway acts in a subset of circadian pacemaker neurons to maintain robust 24 h rhythms of free-running locomotor activity. RNA interference-mediated depletion of key NMD factors in timeless-expressing clock cells decreased the amplitude of circadian locomotor behaviors. Transgenic manipulation of the NMD pathway in clock neurons expressing a neuropeptide PIGMENT-DISPERSING FACTOR (PDF) was sufficient to dampen or lengthen free-running locomotor rhythms. Confocal imaging of a transgenic NMD reporter revealed that arrhythmic Clock mutants exhibited stronger NMD activity in PDF-expressing neurons than wild-type. We further found that hypomorphic mutations in Suppressor with morphogenetic effect on genitalia 5 (Smg5) or Smg6 impaired circadian behaviors. These NMD mutants normally developed PDF-expressing clock neurons and displayed daily oscillations in the transcript levels of core clock genes. By contrast, the loss of Smg5 or Smg6 function affected the relative transcript levels of cAMP response element-binding protein B (CrebB) in an isoform-specific manner. Moreover, the overexpression of a transcriptional repressor form of CrebB rescued free-running locomotor rhythms in Smg5-depleted flies. These data demonstrate that CrebB is a rate-limiting substrate of the genetic NMD pathway important for the behavioral output of circadian clocks in Drosophila.

• Molecules and Cells
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• 제45권4호
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• pp.180-192
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• 2022

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator of nuclear receptors and other transcription factors. A general Ncoa6 knockout mouse was previously shown to be embryonic lethal, but we here generated liver-specific Ncoa6 knockout (Ncoa6 LKO) mice to investigate the metabolic function of NCOA6 in the liver. These Ncoa6 LKO mice exhibited similar blood glucose and insulin levels to wild type but showed improvements in glucose tolerance, insulin sensitivity, and pyruvate tolerance. The decrease in glucose production from pyruvate in these LKO mice was consistent with the abrogation of the fasting-stimulated induction of gluconeogenic genes, phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc). The forskolin-stimulated inductions of Pck1 and G6pc were also dramatically reduced in primary hepatocytes isolated from Ncoa6 LKO mice, whereas the expression levels of other gluconeogenic gene regulators, including cAMP response element binding protein (Creb), forkhead box protein O1 and peroxisome proliferator-activated receptor γ coactivator 1α, were unaltered in the LKO mouse livers. CREB phosphorylation via fasting or forskolin stimulation was normal in the livers and primary hepatocytes of the LKO mice. Notably, it was observed that CREB interacts with NCOA6. The transcriptional activity of CREB was found to be enhanced by NCOA6 in the context of Pck1 and G6pc promoters. NCOA6-dependent augmentation was abolished in cAMP response element (CRE) mutant promoters of the Pck1 and G6pc genes. Our present results suggest that NCOA6 regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.

• 대한본초학회지
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• 제28권3호
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• pp.69-74
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• 2013

Objectives : Since hypopigmentation is known to increase the risk of skin cancer, melanogenesis in the skin needs to be regulated. Here, we evaluated the melanogenesis stimulatory effects of a modified Goagium herbal remedy (HR) and HR+ox bile (Bos taurus domesticus) extract (OBE) to address hypopigmentation disorders. Methods : B16F10 melanoma cells were treated with different dosages of HR and HR+OBE for 24 to 48 h after 1 h of 10 nM ${\alpha}$-melanocyte stimulating hormone (${\alpha}$-MSH). After the treatment, cell viability, tyrosinase activity, melanin synthesis and the expression of genes related to melanin synthesis were measured and the regulation of the ${\alpha}$-MSH signalling through cAMP responding element binding protein (CREB) was determined. Results : HR and HR+OBE with the ranges of $15{\sim}100{\mu}g/mL$ did not affect cell viability in melanoma cells. The 1 h treatment of HR+OBE (50 and $100{\mu}g/mL$) potentiated the phosphorylation of CREB by enhancing ${\alpha}$-MSH signaling and its 24 h treatment increased CREB expression. Consistent with CREB potentiation, their treatment for 24 h, the expression of microphthalmia-associated transcription factor (MIFT), tyrosinase, tyrosinase related protein (TRP)-1 and TRP-2 were increased in realtime PCR. Ultimately, the 48 h treatment of HR+OBE (50 and $100{\mu}g/mL$) increased tyrosniase activity and melanin contents in the melanoma cells in comparison to the control. Conclusions : HR+OBE (50 and $100{\mu}g/mL$) increases melanin synthesis in B16F10 melanoma cells via the stimulation of tyrosinase activity and expression of MIFT, tyrosinase, TRP-1 and TRP-2. HR+OBE can be used as the a possible treatment for hypopigmentation of the skin.

• Clinical and Experimental Pediatrics
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• 제53권6호
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• pp.718-721
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• 2010

Rubinstein-Taybi syndrome (RTS) is a congenital disorder characterized by typical facial features, broad thumbs and toes, with mental retardation. Additionally, tumors, keloids and various congenital anomalies including congenital heart defects have been reported in RTS patients. In about 50% of the patients, mutations in the $CREB$ $binding$ $protein$ ($CREBBP$) have been found, which are understood to be associated with cell growth and proliferation. Here, we describe a typical RTS patient with Arnold-Chiari malformation. A mutation in the CREBBP gene, c.4944_4945insC, was identified by mutational analysis.

• 생명과학회지
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• 제26권4호
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• pp.475-483
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• 2016

본 연구는 동의보감을 근거로 선별된 백수오, 지황, 원지 및 석창포로 구성된 복합추출물의 해마신경세포에 대한 보호 및 기억력의 개선효과를 살펴보았다. 복합추출물의 신경보호효과를 검증하기 위해 HT22해마신경세포의 생존율, 세포독성 및 활성산소를 분석하였으며, 허혈성 뇌손상 마우스모델을 이용하여 기억에 대한 동물행동학적 변화와 단백질 발현을 측정하였다. 해마신경세포에서 복합추출물의 전 처리는 glutamate에 의해 유도된 활성산소의 축적을 억제하였으며 세포사멸을 감소시켰다. 허혈성 뇌손상 마우스모델에서 복합추출물은 동물행동학적으로 공간 및 단기 기억능력을 개선시켰다. 뇌허혈로 인해 증가된 p38 MAPK의 인산화는 복합추출물에 의해 현저히 감소하는 반면, 감소된 PI3K와 CREB의 인산화는 현저히 증가하였다. 이를 면역조직화학분석을 통해 복합추출물을 투여한 그룹이 해마에서 발현되는 CREB의 인산화가 현저히 증가되는 것을 확인하였다. 이상의 결과는 복합추출물이 CREB 단백질과 관련된 신경보호 신호기전을 조절함으로써 인지기능을 개선시키는 것으로 사료된다.

• 한국생명과학회:학술대회논문집
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• 한국생명과학회 2008년도 제49회 학술심포지움 및 국제학술대회
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• pp.96.2-96.2
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• 2008