Myers R D
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858-4354.
Alcohol. 1990 Sep-Oct;7(5):449-59. doi: 10.1016/0741-8329(90)90031-7.
The involvement of aldehyde adducts in the etiology of alcoholism continues to be supported by a number of experimental findings. These metabolites are synthesized endogenously from a condensation reaction of a biogenic aldehyde with a catechol- or indole-amine and act in the brain to augment or suppress the drinking of ethyl alcohol. When given by the intracerebroventricular route in an animal which does not prefer alcohol, certain tetrahydro-isoquinolines and beta-carbolines can augment significantly the voluntary intake of alcohol even in aversive concentrations. This paper describes the historical background and current status of the "Multiple Metabolite" theory of alcoholism. The recent identification of anatomical structures in the limbic-midbrain, limbic-forebrain of the Sprague-Dawley rat, which mediate changes in the intake of alcohol induced by tetrahydropapaveroline (THP) is also described. When injected in a low dose of 25 ng in a specific site, over a 3-day period, THP induces persistent increases in the intake of alcohol even in aversive concentrations. These THP-reactive sites comprise the substantia nigra, reticular formation, medial lemniscus, zona incerta, medial forebrain bundle, nucleus accumbens, olfactory tubercle, lateral septal nucleus, preoptic area, stria terminalis, and rostral hippocampus. A higher dose of 250 ng THP microinjected at homologous loci tends to inhibit the rat's self-selection of alcohol or exert no effect on drinking. Morphological mapping of histologically identified sites sensitive to THP revealed a distinct "circuitry" of neuronal structures overlapping both dopaminergic and enkephalinergic pathways. This "circuit" extends from the tegmental-nigral area of the midbrain rostrally to structures within the limbic-forebrain. When a THP-reactive structure, the N. accumbens, was lesioned by either of two neurotoxins, 6-hydroxydopamine or 5.7-dihydroxytryptamine, the rats' preference for alcohol increased sharply. This suggests that impairment of transmitter release, denervation supersensitivity or other perturbation of receptor function within this and other structures play a part in the aberrant drinking of alcohol. It is envisaged that a dopamine-enkephalin link underlies the mechanism for the onset, maintenance and permanency of alcohol preference generated by an aldehyde adduct. Finally, the "Two-Channel, Brain Metabolite" theory of alcoholism proposes that the transitory presence of an endogenously formed aldehyde adduct within cells of the brain causes a permanent perturbation of normal receptor processes and transmitter activity within synapses of specific structures of the limbic system. This theory thus explains the nature of the rewarding properties of alcohol as well as its complex addictive liability which is physiologically irreversible.
醛加合物参与酒精中毒病因的观点，仍然得到了许多实验结果的支持。这些代谢产物是由生物源性醛与儿茶酚胺或吲哚胺通过缩合反应内源性合成的，在大脑中发挥作用，增强或抑制乙醇的摄入。在对酒精无偏好的动物中，通过脑室内途径给予某些四氢异喹啉和β-咔啉，即使在厌恶浓度下，也能显著增加酒精的自愿摄入量。本文描述了酒精中毒“多种代谢产物”理论的历史背景和现状。还介绍了最近在斯普拉格-道利大鼠的边缘中脑、边缘前脑中鉴定出的解剖结构，这些结构介导了四氢罂粟碱（THP）诱导的酒精摄入量变化。当以25 ng的低剂量在特定部位注射，持续3天时，即使在厌恶浓度下，THP也会导致酒精摄入量持续增加。这些对THP有反应的部位包括黑质、网状结构、内侧丘系、未定带、内侧前脑束、伏隔核、嗅结节、外侧隔核、视前区、终纹床核和海马前部。在同源位点微量注射250 ng的高剂量THP往往会抑制大鼠对酒精的自我选择，或对饮酒没有影响。对组织学鉴定的对THP敏感部位的形态学绘图显示，神经元结构有一个独特的“回路”，与多巴胺能和脑啡肽能通路重叠。这个“回路”从中脑的被盖-黑质区域向前延伸到边缘前脑内的结构。当对THP有反应的结构——伏隔核，被两种神经毒素（6-羟基多巴胺或5,7-二羟基色胺）中的任何一种损伤时，大鼠对酒精的偏好会急剧增加。这表明，在这个结构以及其他结构内，递质释放受损、去神经超敏反应或受体功能的其他扰动，在异常饮酒中起作用。据设想，多巴胺-脑啡肽联系是醛加合物产生酒精偏好的起始、维持和持久性机制的基础。最后，酒精中毒的“双通道、脑代谢产物理论”提出，内源性形成的醛加合物在脑内细胞中的短暂存在，会导致边缘系统特定结构突触内正常受体过程和递质活性的永久性扰动。因此，这个理论解释了酒精奖励特性的本质，以及其生理上不可逆的复杂成瘾倾向。
