Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats
Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats
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DOI：
10.1016/j.ejphar.2009.10.062
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发表时间：
2010-02-10
影响因子：
5
通讯作者：
Xi, Zheng-Xiong
中科院分区：
文献类型：
--
作者：
Peng, Xiao-Qing;Li, Jie;Xi, Zheng-Xiong
我们最近报道了内源性mGlu2/3激动剂n -乙酰甲斯帕基谷氨酸（NAAG）和n -乙酰化- α -连接-酸性二肽酶（NAALADase， NAAG降解酶）抑制剂2-PMPA通过减弱伏隔核中可卡因增强的细胞外多巴胺和谷氨酸，显著抑制可卡因自我给药和可卡因诱导的药物寻求行为的恢复。然而，NAAG和2-PMPA较差的口服生物利用度限制了它们在人类中的实际应用。在本研究中，我们研究了口服活性NAALADase抑制剂GPI-5693及其对映体对可卡因服用和寻求可卡因行为的影响。我们发现口服GPI-5693（15、30、60 mg/kg, p.o）对固定比率（FR2）强化下的静脉可卡因自我给药没有显著影响，但显著抑制了可卡因诱导的已消失的觅药行为的恢复。这种抑制被LY341495预处理阻断，LY341495是一种选择性的mGlu2/3受体拮抗剂。GPI-5693的两种对映体GPI-16476或GPI-16477预处理相同剂量（15、30、60 mg/kg, p.o）也能抑制可卡因诱导的恢复，与GPI-5693相似。相比之下，GPI-5693既没有改变口服蔗糖自我给药，也没有改变蔗糖引发的蔗糖寻求行为的恢复。这些数据表明，口服有效的NAAG肽酶抑制剂作为治疗可卡因成瘾的潜在药物值得进一步研究。Elsevier B.V.出版
We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction. Published by Elsevier B.V.