Beveridge Thomas J R, Mechan Annis O, Sprakes Marie, Pei Qi, Zetterstrom Tyra S C, Green A Richard, Elliott J Martin
School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
Psychopharmacology (Berl). 2004 May;173(3-4):346-52. doi: 10.1007/s00213-003-1753-y. Epub 2004 Jan 20.
3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces an acute hyperthermic response and induces localised neuronal activation, which can be visualised via expression of immediate-early genes. The pharmacological and anatomical basis of these effects are unclear. At high doses, MDMA also causes selective neurotoxicity at serotonergic nerve terminals.
We investigated the effect of 5-hydroxytryptamine (5-HT) depletion on the acute hyperthermic response to MDMA and the pattern of neuronal excitation indicated by Arc (activity-regulated cytoskeleton associated gene) in naive rats and following administration of MDMA at a neurotoxic dose.
Expression of Arc mRNA was investigated by in situ hybridisation histochemistry using 35S-labelled oligonucleotide probe.
MDMA induced a significant hyperthermia together with increased Arc mRNA expression in cortical regions, caudate-putamen and CA1 hippocampus but not hypothalamus. At 21 days after a neurotoxic dose of MDMA, brain 5-HT and 5-HIAA levels were significantly reduced by 21-32%. In these animals, both the hyperthermic response and the pattern and extent of Arc mRNA expression induced by a subsequent dose of MDMA were unaltered. However, basal Arc expression was significantly increased in cortical regions and CA1 hippocampus.
We conclude that the acute hyperthermic response induced by MDMA is not attenuated by moderate depletion of 5-HT, further questioning mediation via a serotonergic mechanism. Arc mRNA induction by MDMA exhibits highly localised expression, which is not altered following 5-HT depletion. However, following a neurotoxic dose of MDMA, basal expression of Arc is increased, particularly in cortex and CA1, suggesting that mechanisms underlying synaptic plasticity might also be modified.
给大鼠注射3,4-亚甲基二氧甲基苯丙胺（摇头丸）会产生急性体温过高反应，并诱导局部神经元激活，这可以通过即刻早期基因的表达来可视化。这些作用的药理和解剖学基础尚不清楚。高剂量时，摇头丸还会导致血清素能神经末梢出现选择性神经毒性。
我们研究了5-羟色胺（5-HT）耗竭对未接触过摇头丸的大鼠以及给予神经毒性剂量摇头丸后，大鼠对摇头丸急性体温过高反应的影响，以及Arc（活性调节细胞骨架相关基因）所指示的神经元兴奋模式。
使用35S标记的寡核苷酸探针，通过原位杂交组织化学研究Arc mRNA的表达。
摇头丸可引起显著的体温过高，同时皮质区域、尾状核-壳核和海马CA1区的Arc mRNA表达增加，但下丘脑未出现这种情况。在给予神经毒性剂量的摇头丸21天后，脑内5-HT和5-羟吲哚乙酸水平显著降低了21%-32%。在这些动物中，后续剂量的摇头丸所诱导的体温过高反应以及Arc mRNA表达的模式和程度均未改变。然而，皮质区域和海马CA1区的基础Arc表达显著增加。
我们得出结论，5-HT的适度耗竭不会减弱摇头丸诱导的急性体温过高反应，这进一步质疑了血清素能机制的介导作用。摇头丸诱导的Arc mRNA表现出高度局部化的表达，5-HT耗竭后这种表达未发生改变。然而，在给予神经毒性剂量的摇头丸后，Arc的基础表达增加，尤其是在皮质和CA1区，这表明突触可塑性的潜在机制可能也发生了改变。
