Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors
Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors
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DOI：
10.1007/s00213-003-1404-3
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发表时间：
2003-05-01
影响因子：
3.4
通讯作者：
Koonse, SA
中科院分区：
文献类型：
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作者：
Broadbent, J;Kampmueller, KM;Koonse, SA
理由：行为敏化在当代毒瘾理论中发挥着核心作用。因此，已经做出了大量努力来确定介导对精神兴奋剂的敏化的过程。然而，很少有研究探讨乙醇过敏的机制。目的：进行实验以评估 N-甲基-D-天冬氨酸 (NMDA) 和非 NMDA 谷氨酸受体在乙醇运动刺激作用敏化表达中的作用。方法：在四次活动试验前，通过腹膜内 (i.p.) 施用乙醇 (2 g/kg) 来诱导 DBA/2 J 小鼠致敏。在每次活动试验前，对照组给予生理盐水（12.5 ml/kg i.p.）。随后，评估了两种 NMDA 受体拮抗剂 MK-801 和艾芬地尔以及两种非 NMDA 谷氨酸受体拮抗剂 DNQX 和 GYKI 52466 对敏化运动反应表达的影响。结果：MK-801 在剂量超过 0.075 mg/kg 时可降低乙醇的刺激作用并完全阻止致敏的表达。相反，虽然艾芬地尔也降低了乙醇的刺激作用，但拮抗剂并没有改变致敏的表达。非 NMDA 谷氨酸拮抗剂的致敏作用更加一致。 DNQX 在低剂量下降低了敏化反应的程度，但不改变乙醇的刺激作用。更具选择性的 AMPA 拮抗剂 GYKI 52466 可降低乙醇的刺激作用并完全阻断致敏的表达。结论：结果提供了初步证据，表明 NMDA 和非 NMDA 谷氨酸受体在乙醇致敏表达中发挥作用。需要进行更多研究来阐明谷氨酸拮抗剂功效差异的潜在机制。
Rationale: Behavioral sensitization has been accorded a central role in contemporary theories of drug addiction. Accordingly, a substantial effort has been made to determine the processes mediating sensitization to psychostimulants. However, few studies have examined the mechanisms underlying sensitization to ethanol. Objectives: Experiments were conducted to assess the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in expression of sensitization to ethanol's locomotor stimulant effects. Methods: Sensitization was induced in DBA/2 J mice by administering ethanol (2 g/kg) intraperitoneally (i.p.) before four activity trials. Control groups were given saline (12.5 ml/kg i.p.) before each activity trial. Subsequently, the effects of two NMDA receptor antagonists, MK-801 and ifenprodil, and two non-NMDA glutamate receptor antagonists, DNQX and GYKI 52466, were assessed on expression of the sensitized locomotor response. Results: MK-801 reduced the stimulant effects of ethanol and completely prevented expression of sensitization at doses exceeding 0.075 mg/kg. In contrast, although ifenprodil also reduced the stimulant effects of ethanol, the antagonist did not alter expression of sensitization. Non-NMDA glutamate antagonists were more consistent in their effects on sensitization. DNQX reduced the magnitude of the sensitized response at a low dose that did not alter the stimulant effects of ethanol. The more selective AMPA antagonist GYKI 52466 reduced the stimulant effects of ethanol and completely blocked expression of sensitization. Conclusions: The results provide initial evidence to suggest that both NMDA and non-NMDA glutamate receptors play a role in expression of sensitization to ethanol. Additional research will be required to elucidate the mechanisms underlying differences in the efficacy of glutamate antagonists.