The post-genomic research for the pathophysiology and treatment of alcohol and drug addictions.

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We have previously demonstrated that the cellular cAMP-signaling is changed in blood cells in family-history positive alcoholic patients : quantitative reduction of type 1 adenylyl cyclase(AC1), ACVIII and G_<sα> mRNA. Since the cellular Ca^<2+> signaling alternation by the chronic alcohol consumption has been attended as well as cAMP signaling, we investigated the effect of alcohol on the Ca^<2+> signaling, using postmortem human brains and cultured cells. The Ca^<2+>-binding protein, annexinIV was increased in the alcoholic patients, and the level of annexinIV was increased in alcohol-treated A549 cells. The cellular downstream signaling molecule of cAMP,cAMP responsive element binding protein(CREB) helps to regulate long-term potentiation and synaptic plasticity, it is plausible that EtOH affects the CREB-induced gene transcriptions, which may affect neural differentiation/development. We focused on the mechanism of the EtOH induced cell damage and examined the role of the neurotrop … More hic factor on the effect of EtOH with neurobalstoma cells(SH-SY5Y). The cellular damage was induced by Ethanol treatment in dose-dependently. The CREB activity and the secretion of brain-derived neurotrophic factor(BDNF) which expression is regulated by CREB were both diminished in the ethanol treated SH-SY5Y cells. On the other hand, the transcriptional activity of NF-κB was activated by Ethanol. These are demonstrated that the decrased CREB-BDNF pathway impairment and NE-κB activation are involved in the mechanisms of Ethanol induced damage and neuronalplasticity change. We next investigated the effects of EtOH on neuronal differentiation in neural stem cells(NSCs). EtOH(20 to 100mM) inhibited neuronal differentiation, without affecting survival rate. The addition, of either IGF-1 or BDNF diminished inhibitory effect of EtOH on NSC differentiation. Thus, it is suggested that neurotrophic factors play important roles not only in differentiation but also defense from EtOH-induced cellular damage. Less