Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine
Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine
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DOI：
10.1007/s00213-006-0357-8
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发表时间：
2006-07-01
影响因子：
3.4
通讯作者：
Koyama, T.
中科院分区：
文献类型：
--
作者：
Ito, K.;Abekawa, T.;Koyama, T.
本课题组最近发现，甲基苯丙胺(METH)(2.5 mg/kg)引起大鼠伏隔核(NAC)谷氨酸(Glu)水平的迟发性升高，并且反复给药导致对选择性非竞争性N-甲基-D-天冬氨酸(NMDA)受体拮抗剂的行为交叉敏化。地佐西平(MK-801)。本研究旨在观察丙戊酸(VPA)是否能抑制MK-801(0.2 mg/kg)引起的谷氨酸迟发性升高，并防止冰毒(2.5 mg/kg)诱导的行为交叉敏化。在每次注射冰毒(2.5 mg/kg，隔日1次，共5次)后120min注射VPA(50 mg/kg)，并在足够的戒断时间后测定MK-801(0.2 mg/kg)或冰毒(0.15 mg/kg)刺激所引起的小鼠的运动活动。最后，我们测量了竞争性NMDA受体拮抗剂CPP(30 mg/kg)预处理后MK-801(0.2 mg/kg)诱导的运动。用在体微透析法检测VPA对细胞外Glu水平的影响。注射冰毒120min后给予丙戊酸对冰毒诱导的大鼠多动无影响，但可抑制冰毒诱导的谷氨酸水平的迟发性升高。丙戊酸重复给药可阻止冰毒对MK-801的行为交叉增敏，但不能阻止冰毒对冰毒的增敏作用。竞争性NMDA受体拮抗剂CPP可增强MK-801诱导的超速运动。这些结果表明，VPA可抑制大剂量冰毒引起的迟发性Glu水平升高，以防止对NMDA拮抗剂的行为交叉敏化，但不能阻止对冰毒的敏化。
Our group has recently shown that methamphetamine (METH) (2.5 mg/kg) induced delayed increases in glutamate (Glu) levels in the rat nucleus accumbens (NAC), and that its repeated administration leads to behavioral cross-sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801).The present study aims to examine whether valproate (VPA) would inhibit the delayed increases in Glu levels and prevent METH (2.5 mg/kg)-induced behavioral cross-sensitization to MK-801 (0.2 mg/kg).We examined the effects of post-treated VPA (50 mg/kg) on METH (2.5 mg/kg)-induced delayed increases in Glu levels. We injected VPA (50 mg/kg) at 120 min after each METH (2.5 mg/kg, once every other day, total of five times) administration and measured locomotor activity induced by challenge with MK-801 (0.2 mg/kg) or METH (0.15 mg/kg) after sufficient withdrawal period. Finally, we measured locomotion induced by MK-801 (0.2 mg/kg) after pretreatment of a competitive NMDA receptor antagonist, CPP (30 mg/kg). Effects of VPA on extracellular Glu levels were examined by using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor.VPA administered 120 min after METH injection had no effect on METH-induced hyperlocomotion, and inhibited METH-induced delayed increases in Glu levels. Repeated VPA administration prevented METH-induced behavioral cross-sensitization to MK-801, but not sensitization to METH. MK-801-induced hyperlocomotion was enhanced when pretreated with the competitive NMDA receptor antagonist, CPP.These results suggest that VPA inhibits high-dose METH-induced delayed increases in Glu levels to prevent development of behavioral cross-sensitization to an NMDA antagonist, but not sensitization to METH.