N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats.
N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats.
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DOI：
10.1016/j.neuropharm.2009.06.016
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发表时间：
2010-01
影响因子：
4.7
通讯作者：
Gardner EL
中科院分区：
文献类型：
--
作者：
Xi ZX;Kiyatkin M;Li X;Peng XQ;Wiggins A;Spiller K;Li J;Gardner EL
II组代谢型谷氨酸（mGlu 2和mGlu 3）受体的药理学激活可抑制药物（可卡因、尼古丁）或自然奖励（食物、蔗糖）诱导的寻求奖励行为和/或奖励功效。在本研究中，我们调查是否升高脑N-乙酰谷氨酸（NAAG），内源性II组mGlu受体激动剂，由NAAG肽酶抑制剂2-PMPA减弱可卡因的奖励作用，通过静脉内可卡因自我管理和颅内电脑刺激奖励（BSR）大鼠进行评估。全身施用2-PMPA（10、30、100 mg/kg，i. p.）NAAG（100、300 μg/10 μl/μ l）或鼻内给药显著抑制了递增比例（PR）强化条件下的静脉内可卡因自我给药，但在固定比例2（FR 2）强化条件下则无此作用。此外，2-PMPA（1，10，30 mg/kg，i.p）或NAAG（50，100 μg/10 μl/ml）可显著抑制可卡因增强的BSR，但对基础BSR无明显影响。用LY 341495（lmg/kg，i. p.）预处理，一种选择性mGlu 2/3受体拮抗剂，阻止了2-PMPA或NAAG在自我给药和BSR模式中产生的抑制作用。在体微透析实验表明，2-PMPA（10，30，100 mg/kg）剂量依赖性地减弱可卡因增强的延髓核（NAc）细胞外多巴胺（DA）。2-PMPA单独抑制基础NAc DA释放，LY 341495阻止了这种作用。这些发现表明，全身给予2-PMPA或鼻内给予NAAG抑制可卡因的奖励功效和可卡因增强的NAc DA -可能通过激活NAc中的突触前mGlu 2/3受体。这些数据表明2-PMPA或NAAG在治疗可卡因成瘾中的潜在效用。
Pharmacological activation of group II metabotropic glutamate (mGlu2 and mGlu3) receptors inhibits reward-seeking behavior and/or rewarding efficacy induced by drugs (cocaine, nicotine) or natural rewards (food, sucrose). In the present study, we investigated whether elevation of brain N-acetylaspartatylglutamate (NAAG), an endogenous group II mGlu receptor agonist, by the NAAG peptidase inhibitor 2-PMPA attenuates cocaine's rewarding effects, as assessed by intravenous cocaine self-administration and intracranial electrical brain-stimulation reward (BSR) in rats. Systemic administration of 2-PMPA (10, 30, 100 mg/kg, i.p.) or intranasal administration of NAAG (100, 300 μg/10 μl/nostril) significantly inhibited intravenous cocaine self-administration under progressive-ratio (PR), but not under fixed-ratio 2 (FR2), reinforcement conditions. In addition, 2-PMPA (1, 10, 30 mg/kg, i.p) or NAAG (50, 100 μg/10 μl/nostril) significantly inhibited cocaine-enhanced BSR, but not basal BSR. Pretreatment with LY341495 (1 mg/kg, i.p.), a selective mGlu2/3 receptor antagonist, prevented the inhibitory effects produced by 2-PMPA or NAAG in both the self-administration and BSR paradigms. In vivo microdialysis demonstrated that 2-PMPA (10, 30, 100 mg/kg) dose-dependently attenuated cocaine-enhanced extracellular dopamine (DA) in the nucleus accumbens (NAc). 2-PMPA alone inhibited basal NAc DA release, an effect that was prevented by LY341495. These findings suggest that systemic administration of 2-PMPA or intranasal administration of NAAG inhibits cocaine's rewarding efficacy and cocaine-enhanced NAc DA - likely by activation of presynaptic mGlu2/3 receptors in the NAc. These data suggest a potential utility for 2-PMPA or NAAG in the treatment of cocaine addiction.
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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
作者：
Bäckström, P;Hyytiä, P
通讯作者：
Hyytiä, P
影响因子：
3.6
作者：
Arnold, JM;Roberts, DCS
通讯作者：
Roberts, DCS
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：
7.3
作者：
Johnson, MP;Baez, M;Schoepp, DD
通讯作者：
Schoepp, DD