Abbott Healthcare Products B.V., van Houtenlaan 36, 1380 CP, Weesp, The Netherlands.
Behav Brain Res. 2011 Jun 20;220(1):9-19. doi: 10.1016/j.bbr.2011.01.026. Epub 2011 Jan 22.
The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT(2C) receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D(1) and D(2) receptor antagonists SCH23390 and haloperidol, D(2) partial agonists terguride, (-)3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT(1B) antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT(1A) antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED=0.125 mg/kg), WAY163909 (MED=3mg/kg), Ro 60-0175 (MED=3mg/kg), haloperidol (MED=0.1mg/kg), clozapine (MED=5mg/kg), aripiprazole (MED=1mg/kg), (-)3PPP (MED=3mg/kg), terguride (MED=0.2mg/kg) and SCH23390 (MED=0.001325 mg/kg) attenuated METH-induced locomotor activity. Administration of 20mg/kg fluvoxamine attenuated, while SB242084 (MED=0.25mg/kg) potentiated METH-induced activity. These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT(2A) and 5-HT(2C) receptors, but demonstrate that 5-HT(1B) receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated.
安非他命（METH）增加运动活动的机制可能归因于 5-羟色胺（5-HT）和多巴胺（DA）受体的间接激活。在本研究中，分析了 5-羟色胺再摄取抑制剂氟伏沙明、5-HT（1A）、5-HT（1B）、5-HT（2A）和 5-HT（2C）受体拮抗剂 WAY100635、GR127935、M100907 和 SB242084 以及 5-HT（2C）受体激动剂 WAY163909 和 Ro 60-0175 或 5-HT 合成抑制剂对氯苯丙氨酸（pCPA）改变 METH 诱导的过度活跃的能力。此外，为了比较目的，评估了 DA D（1）和 D（2）受体拮抗剂 SCH23390 和氟哌啶醇、D（2）部分激动剂替古瑞得、（-）3PPP 和阿立哌唑以及最后氯氮平的参与。降低 5-HT 水平的 pCPA 剂量减弱了 METH 活性。5-HT（1B）拮抗剂 GR127935 对 METH 诱导的运动活动没有影响，但阻断了 MDMA 诱导的活动。5-HT（1A）拮抗剂 WAY100635 降低了活动，但这并没有达到显著水平。相比之下，M100907（最小有效剂量；MED=0.125mg/kg）、WAY163909（MED=3mg/kg）、Ro 60-0175（MED=3mg/kg）、氟哌啶醇（MED=0.1mg/kg）、氯氮平（MED=5mg/kg）、阿立哌唑（MED=1mg/kg）、（-）3PPP（MED=3mg/kg）、替古瑞得（MED=0.2mg/kg）和 SCH23390（MED=0.001325mg/kg）减弱了 METH 诱导的运动活动。给予 20mg/kg 氟伏沙明减弱，而 SB242084（MED=0.25mg/kg）增强了 METH 诱导的活动。这些结果对理解这种精神兴奋剂的作用机制有重要意义，并首次表明，5-HT（2A）和 5-HT（2C）受体调节 METH 诱导的运动刺激，但表明 5-HT（1B）受体不直接参与。还证明了多巴胺能系统的参与。
