University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE, University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX.
J Psychopharmacol. 1995 Jan;9(3):214-22. doi: 10.1177/026988119500900303.
The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kg×2; MDMA 20 mg/kg×8; D-fenfluramine 12.5 mg/kg×8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT(1A) and 5-HT(2) receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT(1A) or 5-HT(2) receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.
苯丙胺衍生物对氯苯丙胺（pCA）、3,4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）和 D-苯丙醇胺，如果反复给予大鼠大剂量，会导致 5-羟色胺能神经末梢退化，我们之前已经证明这会导致体内 D-苯丙醇胺诱发的 5-羟色胺释放减少。因此，D-苯丙醇胺诱发的反应可能对人类 5-羟色胺神经退行性变具有探针价值。本研究检查了三种药物（pCA12mg/kg×2；MDMA20mg/kg×8；D-苯丙醇胺 12.5mg/kg×8，在测试前 14 天）预处理对大鼠急性给予 D-苯丙醇胺和其他 5-羟色胺激动剂后的行为（5-羟色胺综合征）和神经内分泌[催乳素和促肾上腺皮质激素（ACTH）]反应的影响。三种预处理均减弱了 D-苯丙醇胺诱发的行为综合征，但不影响急性给予 D-苯丙醇胺时催乳素或 ACTH 的反应（除了 pCA 预处理对 D-苯丙醇胺引起的 ACTH 反应的轻微影响）。为了比较，还检查了 pCA 预处理对急性给予 pCA 以及 5-HT（1A）和 5-HT（2）受体激动剂 8-羟基-2-（二正丙基氨基）四氢呋喃（8-OH-DPAT）和 1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷（DOI）的行为反应的影响。pCA 预处理减弱了 pCA 行为反应的所有成分，但对 8-OH-DPAT 或 DOI 的行为反应几乎没有影响，表明突触后 5-HT（1A）或 5-HT（2）受体功能没有改变。虽然用神经毒性苯丙胺预处理的大鼠中 D-苯丙醇胺的行为效应丧失可以用 5-羟色胺神经退行性变后 D-苯丙醇胺释放作用丧失来解释，但用 D-苯丙醇胺处理的神经内分泌反应没有变化，这很难用这种方式来解释。这些结果强调了在将 D-苯丙醇胺作为人类神经退行性变的探针推进之前，需要进一步研究 D-苯丙醇胺的作用。
