Johnson M, Sonsalla P K, Letter A A, Hanson G R, Gibb J W
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
J Pharmacol Exp Ther. 1994 Jul;270(1):97-103.
The possibility that serotonin (5-HT) modulates dopamine (DA) synthesis by acting at 5-HT2 receptor sites during methamphetamine (METH) treatment was investigated. The neostriatal accumulation of 3,4-dihydroxyphenylalanine was not altered by ritanserin (1 mg/kg i.p.), a 5-HT2/1c receptor antagonist, or by METH (15 or 25 mg/kg s.c.), which indicates that METH-induced DA and 5-HT release did not invoke increased DA synthesis. Interestingly, the combined treatment of METH with ritanserin reduced 3,4-dihydroxyphenylalanine formation. We also examined the possibility that 5-HT2 receptors participate in the mechanism by which METH alters central tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities as well as the concentration of neurotensin-like and substance P-like immunoreactivity. Five administrations of METH given at 6-hr intervals reduced neostriatal TH and TPH activity to 27 and 13% of control, respectively, 18 to 20 hr after the last drug administration; ritanserin failed to alter these decreases significantly. Ritanserin also failed to alter the METH-induced increase in neostriatal neurotensin-like immunoreactivity or in nigral neurotensin-like immunoreactivity and substance P-like immunoreactivity. Finally, the administration of ICS 205-930, a 5-HT3/4 receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 micrograms/kg, whereas a dose of 500 micrograms/kg potentiated the effect of METH. These results suggest that 5-HT2 does not modulate DA synthesis nor does it mediate the changes in central TH and TPH activity, or neurotensin-like immunoreactivity and substance P-like immunoreactivity content induced by METH. Because 3,4-methylenedioxymethamphetamine is reported to stimulate DA synthesis by a 5-HT2 receptor-dependent mechanism, these observations suggest that METH and 3,4-methylenedioxymethamphetamine regulate the central dopaminergic system in a different manner.
研究了在甲基苯丙胺（METH）治疗期间，血清素（5-HT）通过作用于5-HT2受体位点调节多巴胺（DA）合成的可能性。5-HT2/1c受体拮抗剂利坦色林（1mg/kg腹腔注射）或METH（15或25mg/kg皮下注射）均未改变3,4-二羟基苯丙氨酸在新纹状体中的蓄积，这表明METH诱导的DA和5-HT释放并未引起DA合成增加。有趣的是，METH与利坦色林联合治疗减少了3,4-二羟基苯丙氨酸的生成。我们还研究了5-HT2受体是否参与METH改变中枢酪氨酸羟化酶（TH）和色氨酸羟化酶（TPH）活性以及神经降压素样和P物质样免疫反应性浓度的机制。每隔6小时给予5次METH，在最后一次给药后18至20小时，新纹状体TH和TPH活性分别降至对照的27%和13%；利坦色林未能显著改变这些降低。利坦色林也未能改变METH诱导的新纹状体神经降压素样免疫反应性增加，或黑质神经降压素样免疫反应性和P物质样免疫反应性增加。最后，5-HT3/4受体拮抗剂ICS 205-930在低于200μg/kg的剂量下也未能预防METH诱导的TH和TPH活性降低，而500μg/kg的剂量增强了METH的作用。这些结果表明，5-HT2既不调节DA合成，也不介导METH诱导的中枢TH和TPH活性变化，或神经降压素样免疫反应性和P物质样免疫反应性含量变化。由于据报道3,4-亚甲基二氧基甲基苯丙胺通过5-HT2受体依赖性机制刺激DA合成，这些观察结果表明METH和3,4-亚甲基二氧基甲基苯丙胺以不同方式调节中枢多巴胺能系统。
