Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking
Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking
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DOI：
10.1038/sj.npp.1300845
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发表时间：
2006-04-01
影响因子：
7.6
通讯作者：
Hyytiä, P
中科院分区：
文献类型：
--
作者：
Bäckström, P;Hyytiä, P
神经解剖学和药理学证据表明，谷氨酸传输在药物环境条件反射，部分控制药物寻求和复发。谷氨酸受体可能是药物配对线索的动机特性的药理学衰减和复发预防的目标。因此，本研究的目的是调查参与离子型和代谢型谷氨酸受体亚型线索诱导的可卡因寻求行为的恢复。使用二阶强化时间表（FR 4（FR 5：S））训练大鼠自我施用可卡因，在该时间表下，偶然呈现与可卡因输注相关的复合刺激（光和音调）。在消退后，竞争性NMDA受体拮抗剂CGP 39551（0、2.5、5、10 mg/kg腹腔内（i. p.）），两种竞争性AMPA/红藻氨酸拮抗剂CNQX（0、0.75、1.5、3 mg/ kg i. p.）NBQX（0、1.25、2.5、5mg/ kg i. p.），NMDA/甘氨酸位点拮抗剂L-701，324（0、0.63、1.25、2.5mg/ kg i. p.），mGluR 5拮抗剂MPEP（0、1.25、2.5、5 mg/ kg i.第页）对线索诱导的可卡因寻求恢复的影响进行了研究。AMPA/红藻氨酸受体拮抗剂CNQX和NBQX、NMDA/甘氨酸位点拮抗剂L-701，324和mGluR 5拮抗剂MPEP显著减弱线索诱导的恢复。NMDA拮抗剂CGP 39551不能影响恢复。另外的对照实验表明，CNQX，NBQX，L-701，324和MPEP对线索诱导的恢复的减弱并不伴随着对自发运动活动的显著抑制。这些结果表明，可卡因寻求依赖于谷氨酸传输的条件影响。因此，在各种谷氨酸受体亚型的拮抗剂性质的药物可能是有用的，在预防复发诱导的条件刺激。
Neuroanatomical and pharmacological evidence implicates glutamate transmission in drug-environment conditioning that partly controls drug seeking and relapse. Glutamate receptors could be targets for pharmacological attenuation of the motivational properties of drug-paired cues and for relapse prevention. The purpose of the present study was therefore to investigate the involvement of ionotropic and metabotropic glutamate receptor subtypes in cue-induced reinstatement of cocaine-seeking behavior. Rats were trained to self-administer cocaine using a second-order schedule of reinforcement (FR4( FR5: S)) under which a compound stimulus ( light and tone) associated with cocaine infusions was presented contingently. Following extinction, the effects of the competitive NMDA receptor antagonist CGP 39551 ( 0, 2.5, 5, 10 mg/kg intraperitoneally (i.p.)), two competitive AMPA/kainate antagonists, CNQX ( 0, 0.75, 1.5, 3 mg/ kg i.p.) and NBQX ( 0, 1.25, 2.5, 5 mg/ kg i. p.), the NMDA/ glycine site antagonist L-701,324 ( 0, 0.63, 1.25, 2.5 mg/ kg i. p.), and the mGluR5 antagonist MPEP ( 0, 1.25, 2.5, 5 mg/ kg i. p.) on cue-induced reinstatement of cocaine seeking were examined. The AMPA/kainate receptor antagonists CNQX and NBQX, the NMDA/ glycine site antagonist L-701,324, and the mGluR5 antagonist MPEP attenuated significantly cue-induced reinstatement. The NMDA antagonist CGP 39551 failed to affect reinstatement. Additional control experiments indicated that attenuation of cue-induced reinstatement by CNQX, NBQX, L-701,324, and MPEP was not accompanied by significant suppression of spontaneous locomotor activity. These results suggest that conditioned influences on cocaine seeking depend on glutamate transmission. Accordingly, drugs with antagonist properties at various glutamate receptor subtypes could be useful in prevention of relapse induced by conditioned stimuli.