Zhu Huaqiang, Lai Miaojun, Chen Weisheng, Mei Disen, Zhang Fuqiang, Liu Huifeng, Zhou Wenhua
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center School of Medicine, Ningbo University, Ningbo, 315010, China.
Neurosci Bull. 2017 Aug;33(4):396-404. doi: 10.1007/s12264-017-0140-3. Epub 2017 May 22.
Activation of presynaptic group II metabotropic glutamate receptors (mGluR2/3) inhibits drug reward and drug-seeking behavior, but the role of N-acetylaspartylglutamate (NAAG), an agonist of endogenous mGluR2/3, in heroin reward and heroin-seeking behavior remained unclear. Here, we aimed to explore the effects of exogenous NAAG on heroin self-administration and heroin-seeking behavior. First, rats were trained to self-administer heroin under a fixed ratio 1 (FR1) schedule for 10 days, then received NAAG (50 or 100 μg/10 μL in each nostril) in the absence or presence of LY341495 (1 mg/kg, i.p.), an antagonist of mGluR2/3, on day 11 and the effects of NAAG on heroin self-administration under FR1 were recorded for 3 consecutive days. Motivation was assessed in heroin self-administration under a progressive ratio schedule on day 11 in another 5 groups with the same doses of NAAG. Additional rats were withdrawn for 14 days after 14 days of heroin self-administration, then received the same pharmacological pretreatment and were tested for heroin-seeking behaviors induced by heroin priming or cues. The results showed that intranasal administration of NAAG significantly decreased intravenous heroin self-administration on day 12, but not on day 11. Pretreatment with LY341495 prior to testing on day 12 prevented the inhibitory effect of NAAG on heroin reinforcement. The break-point for reward motivation was significantly reduced by NAAG. Moreover, NAAG also significantly inhibited the heroin-seeking behaviors induced by heroin priming or cues and these were restored by pretreatment with LY341495. These results demonstrated that NAAG, via activation of presynaptic mGluR2/3, attenuated the heroin reinforcement, heroin motivational value, and heroin-seeking behavior, suggesting that it may be used as an adjunct treatment for heroin addiction.
突触前II组代谢型谷氨酸受体（mGluR2/3）的激活可抑制药物奖赏和觅药行为，但内源性mGluR2/3的激动剂N-乙酰天门冬氨酰谷氨酸（NAAG）在海洛因奖赏和觅药行为中的作用仍不清楚。在此，我们旨在探究外源性NAAG对海洛因自我给药及觅药行为的影响。首先，将大鼠在固定比率1（FR1）程序下训练10天以自我给药海洛因，然后在第11天于不存在或存在mGluR2/3拮抗剂LY341495（1毫克/千克，腹腔注射）的情况下给予NAAG（每侧鼻孔50或100微克/10微升），并连续3天记录NAAG对FR1条件下海洛因自我给药的影响。在第11天，对另外5组给予相同剂量NAAG的大鼠，采用累进比率程序评估海洛因自我给药中的动机。在14天的海洛因自我给药后，将额外的大鼠撤药14天，然后接受相同的药理学预处理，并测试由海洛因激发或线索诱导的觅药行为。结果显示，第12天经鼻给予NAAG显著减少了静脉注射海洛因的自我给药，但第11天未出现此现象。在第12天测试前用LY341495预处理可防止NAAG对海洛因强化的抑制作用。NAAG显著降低了奖赏动机的断点。此外，NAAG还显著抑制了由海洛因激发或线索诱导的觅药行为，而这些行为经LY341495预处理后得以恢复。这些结果表明，NAAG通过激活突触前mGluR2/3，减弱了海洛因强化、海洛因动机值及觅药行为，提示其可能用作海洛因成瘾的辅助治疗药物。
