Antkiewicz-Michaluk L, Filip M, Michaluk J, Romańska I, Przegaliński E, Vetulani J
Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Cracov, Poland.
J Neural Transm (Vienna). 2007 Mar;114(3):307-17. doi: 10.1007/s00702-006-0546-y. Epub 2006 Aug 10.
Drug abuse disorder is induced by a variety of substances and results from their interaction with the brain reward system. It is characterized by a high frequency of relapse, usually associated with to craving. In this study we investigated the effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound with antidopaminergic and neuroprotective activity, on cocaine-induced reinstatement in cocaine-dependent, self-administering rats. 1-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg/kg i.p.) completely inhibited the expression of reinstatement of cocaine self-administration and accompanying neurochemical changes induced by a single priming cocaine dose (10 mg/kg i.p.). The priming cocaine dose inhibited dopamine metabolism in the structures containing nerve endings (frontal cortex, nucleus accumbens, and striatum) but not in the substantia nigra and ventral tegmental area. A behaviorally active dose of 1-methyl-1,2,3,4-tetrahydroisoquinoline administered 30 min before a priming dose of cocaine significantly increased the dopamine concentration in the limbic structures, and strongly inhibited dopamine metabolism in the substantia nigra and ventral tegmental area. Cocaine also inhibited noradrenaline and serotonin metabolism, and 1-methyl-1,2,3,4-tetrahydroisoquinoline abolished the inhibition in noradrenaline metabolism, while it intensified the inhibition of serotonin metabolism. Our results strongly support the view that 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound, has considerable potential as a drug for combating substance abuse disease through the attenuation of craving.
药物滥用障碍由多种物质诱发，是这些物质与大脑奖赏系统相互作用的结果。其特征为复发频率高，通常与渴望相关。在本研究中，我们调查了1-甲基-1,2,3,4-四氢异喹啉（一种具有抗多巴胺能和神经保护活性的内源性化合物）对可卡因依赖且自行给药的大鼠中可卡因诱导的复吸的影响。1-甲基-1,2,3,4-四氢异喹啉（腹腔注射50毫克/千克）完全抑制了可卡因自行给药复吸的表达以及单次引发剂量可卡因（腹腔注射10毫克/千克）诱导的伴随神经化学变化。引发剂量的可卡因抑制了含有神经末梢的结构（额叶皮质、伏隔核和纹状体）中的多巴胺代谢，但在黑质和腹侧被盖区未产生抑制作用。在引发剂量的可卡因给药前30分钟给予具有行为活性剂量的1-甲基-1,2,3,4-四氢异喹啉，可显著增加边缘系统结构中的多巴胺浓度，并强烈抑制黑质和腹侧被盖区的多巴胺代谢。可卡因还抑制去甲肾上腺素和5-羟色胺代谢，1-甲基-1,2,3,4-四氢异喹啉消除了对去甲肾上腺素代谢的抑制作用，同时增强了对5-羟色胺代谢的抑制作用。我们的结果有力地支持了这样一种观点，即内源性化合物1-甲基-1,2,3,4-四氢异喹啉具有通过减轻渴望来对抗物质滥用疾病的巨大潜力。
