Gibb J W, Bush L, Hanson G R
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):630-5.
Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.
大剂量反复给予甲基苯丙胺（METH）会损害多巴胺能和5-羟色胺能系统，这表现为酪氨酸羟化酶和色氨酸羟化酶活性的长期抑制以及多巴胺和5-羟色胺含量的同时降低。由于多巴胺是这些多巴胺能和5-羟色胺能缺陷所必需的，我们推测多巴胺和/或其活性代谢产物是这些退行性改变的原因。因为我们之前证明在体外还原条件下可逆转色氨酸羟化酶活性的降低，所以我们推断褪黑素（一种所谓的内源性抗氧化剂）可能会改变这种反应。给大鼠施用METH和/或褪黑素，并评估色氨酸羟化酶活性和5-羟色胺含量；同时也测量酪氨酸羟化酶活性和多巴胺含量。褪黑素不仅不能预防METH诱导的5-羟色胺能和多巴胺能参数缺陷，而且褪黑素与METH共同给药实际上增强了METH的大多数单胺能效应。这种增强作用不能归因于体温的改变。由于滥用METH会导致失眠，且在一些国家褪黑素被用于治疗失眠，这两种药物之间相互作用的影响在临床上可能具有重要意义。
