Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.
Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.
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DOI：
10.1111/j.1471-4159.2009.06478.x
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发表时间：
2010-01
影响因子：
4.7
通讯作者：
Ashby CR Jr
中科院分区：
文献类型：
--
作者：
Xi ZX;Li X;Peng XQ;Li J;Chun L;Gardner EL;Thomas AG;Slusher BS;Ashby CR Jr
II 类代谢型谷氨酸受体 (mGluR2/3) 的药理学激活可抑制可卡因自我给药和寻药行为的恢复，表明 mGluR2/3 激动剂可能用于治疗可卡因依赖。在本研究中，我们研究了用 N-乙酰化-α-连接酸性二肽酶 (NAALADase) 抑制剂 2-PMPA 提高内源性 mGluR2/3 配体 N-乙酰基-天冬氨酸谷氨酸 (NAAG) 水平是否会减弱可卡因自我给药和可卡因诱导的药物寻求恢复。 NAALADase 是一种 NAAG 降解酶，可将 NAAG 水解为 N-乙酰天冬氨酸和谷氨酸。全身给予 2-PMPA（10-100 mg/kg，腹腔注射）可抑制由低单位剂量可卡因和可卡因（但不是蔗糖）诱导的药物寻求行为恢复维持的静脉内自我给药。将 2-PMPA（3-5 μg/侧）或 NAAG（3-5 μg/侧）微量注射到伏隔核 (NAc)，但不注射到背侧纹状体，也会抑制可卡因诱导的恢复，这种作用被 NAc 内注射 LY341495（一种选择性 mGluR2/3 拮抗剂）所阻断。体内微透析表明，2-PMPA（10-100 mg/kg，腹膜内注射）可产生剂量依赖性的细胞外 DA 和谷氨酸减少，这种效应也被 LY341495 阻断。最后，在恢复测试期间，用 2-PMPA 预处理可部分减弱大鼠体内可卡因增强的细胞外 NAc DA，同时完全阻断可卡因增强的细胞外 NAc 谷氨酸。 LY341495 的 NAc 内灌注可阻断 2-PMPA 诱导的可卡因增强的细胞外 NAc 谷氨酸的减少，但不能阻断 DA。这些发现表明，2-PMPA 可有效减弱可卡因诱导的寻药行为恢复，可能是通过突触前 mGluR2/3s 减弱可卡因诱导的 NAc DA 和谷氨酸的增加。
Pharmacological activation of group II metabotropic glutamate receptors (mGluR2/3) inhibits cocaine self-administration and reinstatement of drug-seeking behavior, suggesting a possible use of mGluR2/3 agonists in the treatment of cocaine dependence. In the present study, we investigated whether elevation of the endogenous mGluR2/3 ligand N-acetyl-aspartatylglutamate (NAAG) levels with the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-PMPA attenuates cocaine self-administration and cocaine-induced reinstatement of drug seeking. NAALADase is a NAAG degradation enzyme that hydrolyzes NAAG to N-acetylaspartate and glutamate. Systemic administration of 2-PMPA (10–100 mg/kg, i.p.) inhibited intravenous self-administration maintained by low unit doses of cocaine and cocaine (but not sucrose)-induced reinstatement of drug-seeking behavior. Microinjections of 2-PMPA (3–5 μg/side) or NAAG (3–5 μg/side) into the nucleus accumbens (NAc), but not into the dorsal striatum, also inhibited cocaine-induced reinstatement, an effect that was blocked by intra-NAc injection of LY341495, a selective mGluR2/3 antagonist. In vivo microdialysis demonstrated that 2-PMPA (10–100 mg/kg, i.p.) produced a dose-dependent reduction in both extracellular DA and glutamate, an effect that was also blocked by LY341495. Finally, pretreatment with 2-PMPA partially attenuated cocaine-enhanced extracellular NAc DA, while completely blocking cocaine-enhanced extracellular NAc glutamate in rats during reinstatement testing. Intra-NAc perfusion of LY341495 blocked 2-PMPA-induced reductions in cocaine-enhanced extracellular NAc glutamate, but not DA. These findings suggest that 2-PMPA is effective in attenuating cocaine-induced reinstatement of drug-seeking behavior, likely by attenuating cocaine-induced increases in NAc DA and glutamate via presynaptic mGluR2/3s.
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影响因子：
5.3
作者：
Baptista, MAS;Martin-Fardon, R;Weiss, F
通讯作者：
Weiss, F
影响因子：
5.3
作者：
Cornish, JL;Kalivas, PW
通讯作者：
Kalivas, PW
影响因子：
5.3
作者：
Liechti, Matthias E.;Lhuillier, Loic;Markou, Athina
通讯作者：
Markou, Athina
影响因子：
25
作者：
Baker, DA;McFarland, K;Kalivas, PW
通讯作者：
Kalivas, PW
影响因子：
7.3
作者：
Johnson, MP;Baez, M;Schoepp, DD
通讯作者：
Schoepp, DD