In Vivo Effects of Amphetamine Analogs Reveal Evidence for Serotonergic Inhibition of Mesolimbic Dopamine Transmission in the Rat
In Vivo Effects of Amphetamine Analogs Reveal Evidence for Serotonergic Inhibition of Mesolimbic Dopamine Transmission in the Rat
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DOI：
10.1124/jpet.110.176271
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发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Rothman, Richard B.
中科院分区：
文献类型：
--
作者：
Baumann, Michael H.;Clark, Robert D.;Rothman, Richard B.
有证据表明，脑内细胞外5-羟色胺(5-HT)的升高可以减弱多巴胺(DA)的刺激作用。为了评估这一建议，我们评估了苯丙胺类似物(间氟苯丙胺、对氟苯丙胺、间甲基苯丙胺、对甲基苯丙胺)的药理作用，它们在体外显示出与DA释放剂相似的效力(EC50=24-52 nM)，但与5-羟色胺释放剂的效力不同(EC50=53-1937 nM)。在体微透析法观察药物对大鼠伏隔核细胞外多巴胺和5-羟色胺的影响，同时测定前向运动和刻板印象。大鼠分两次静脉注射给药，0时1 mg/kg，60min后3 mg/kg。所有类似物都使透析液中DA和5-羟色胺呈剂量相关增加，但对DA的影响与体外预测不一致。透析液DA的最大升高范围为基线的5-14倍，与5-羟色胺的反应成反比，5-羟色胺的反应范围为基线的6-24倍。所有类似物都增加了行走和刻板印象，但引起更多5-羟色胺释放的药物(例如，对甲基苯丙胺)与显著减少前向运动有关。行走幅度与细胞外DA呈正相关(p<；0.001)，与DA释放与5-HT释放的比率(即DA增加的百分比除以5-HT的增加百分比)呈负相关(p<；0.029)。总而言之，我们的发现与5-羟色胺释放抑制苯丙胺类药物的兴奋作用的假设是一致的，但需要进一步的研究来解决这一现象背后的确切机制。
Evidence suggests that elevations in extracellular serotonin (5-HT) in the brain can diminish stimulant effects of dopamine (DA). To assess this proposal, we evaluated the pharmacology of amphetamine analogs (m-fluoroamphetamine, p-fluoroamphetamine, m-methylamphetamine, p-methylamphetamine), which display similar in vitro potency as DA releasers (EC50 = 24-52 nM) but differ in potency as 5-HT releasers (EC50 = 53-1937 nM). In vivo microdialysis was used to assess the effects of drugs on extracellular DA and 5-HT in rat nucleus accumbens, while simultaneously measuring ambulation (i.e., forward locomotion) and stereotypy (i.e., repetitive movements). Rats received two intravenous injections of drug, 1 mg/kg at time 0 followed by 3 mg/kg 60 min later. All analogs produced dose-related increases in dialysate DA and 5-HT, but the effects on DA did not agree with in vitro predictions. Maximal elevation of dialysate DA ranged from 5- to 14-fold above baseline and varied inversely with 5-HT response, which ranged from 6- to 24-fold above baseline. All analogs increased ambulation and stereotypy, but drugs causing greater 5-HT release (e. g., p-methylamphetamine) were associated with significantly less forward locomotion. The magnitude of ambulation was positively correlated with extracellular DA (p < 0.001) and less so with the ratio of DA release to 5-HT release (i.e., percentage DA increase divided by percentage 5-HT increase) (p < 0.029). Collectively, our findings are consistent with the hypothesis that 5-HT release dampens stimulant effects of amphetamine-type drugs, but further studies are required to address the precise mechanisms underlying this phenomenon.