Onaivi Emmanuel S, Ali Syed F, Chirwa Sanika S, Zwiller Jean, Thiriet Nathalie, Akinshola B Emmanuel, Ishiguro Hiroki
Department of Biology, William Paterson University, Wayne, New Jersey 07470, USA.
Ann N Y Acad Sci. 2002 Jun;965:28-46. doi: 10.1111/j.1749-6632.2002.tb04149.x.
The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.
人类遗传密码的绘制将使我们能够识别与人类成瘾及具有遗传成分的疾病相关的潜在基因产物。因此，微阵列技术的进步使得大规模、平行基因表达研究成为可能，这些研究揭示了特定基因或基因集与人类疾病之间的联系。尽管存在不良后果，但成瘾物质的强迫性使用仍在持续影响社会，人们对这些成瘾现象背后的科学进行了深入研究。药物和酒精成瘾的药物治疗在很大程度上令人失望，需要新的治疗靶点和假说。由于成瘾药物治疗的效果有限，一种新兴的、但存在争议的治疗药物是天然生物碱伊博格碱。我们继续在体内和体外模型中研究基因表达程序以及苯丙胺等精神兴奋剂所使用的假定信号分子。我们的工作以及其他人的工作表明，复杂但明确的信号转导途径与精神兴奋剂的给药有关，并且伊博格碱对这些信号具有广谱调节作用。我们报告说，甲基苯丙胺的作用与可卡因相似，包括改变大鼠脑海马体中长时程增强（LTP）的倾向。这一作用表明，可能存在一个“阈值”，超过该阈值，强迫性使用精神兴奋剂可能导致的过度脑刺激会导致LTP的阻断。伊博格碱对即刻早期基因（IEGs）和其他可能受精神兴奋剂及其他滥用物质调节的候选基因的影响，需要在强迫使用、奖赏、复发、耐受、渴望和戒断反应方面进行进一步评估。因此，有人认为伊博格碱可能是成瘾基因产物的信号。
