Ago Yukio, Nakamura Shigeo, Kajita Naoko, Uda Misato, Hashimoto Hitoshi, Baba Akemichi, Matsuda Toshio
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Synapse. 2007 Sep;61(9):757-63. doi: 10.1002/syn.20421.
Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.
长期给予甲基苯丙胺（METH）会引发运动活动的渐进性增强，即行为敏化。我们最近发现，长期给予METH会增强METH激发诱导的前额叶皮质中5-羟色胺（5-HT）水平的升高，并且5-HT（1A）受体激活会减弱这种神经化学敏化以及行为敏化。本研究考察了非选择性5-HT（2）受体拮抗剂利坦色林是否会影响小鼠中METH诱导的行为和神经化学敏化。剂量为1和3mg/kg的利坦色林以剂量依赖的方式抑制了METH诱导的行为敏化的发展和表达。此外，连续一周给予利坦色林会减弱行为敏化的维持，表明已建立的行为敏化得到改善。微透析分析表明，长期给予利坦色林会抑制神经化学敏化，即长期给予METH增强了METH激发诱导的前额叶皮质细胞外5-HT水平的升高。此外，急性给予利坦色林会抑制METH激发诱导的前额叶皮质细胞外5-HT水平的升高，但不会抑制多巴胺（DA）水平的升高。这些结果表明，5-HT（2）受体参与了小鼠中METH诱导的多动和行为敏化。
