Accumbens Mechanisms for Cued Sucrose Seeking
Accumbens Mechanisms for Cued Sucrose Seeking
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DOI：
10.1038/npp.2017.153
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发表时间：
2017-11-01
影响因子：
7.6
通讯作者：
Kalivas, Peter W.
中科院分区：
文献类型：
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作者：
Bobadilla, Ana-Clara;Garcia-Keller, Constanza;Kalivas, Peter W.
许多研究支持一种观点，即成瘾药物篡夺了自然奖赏使用的大脑回路，特别是药物和自然奖赏的多巴胺依赖的强化特性。复发动物模型的恢复药物寻找依赖于伏核核心(NAcore)皮质突触的谷氨酸溢出刺激神经元型一氧化氮合酶(NNOS)中间神经元上的代谢性谷氨酸受体5(MGluR5)。与蔗糖和滥用药物共享的多巴胺释放形成对比的是，恢复寻找蔗糖并不会导致谷氨酸溢出。我们假设，在药物上促进NAcore中谷氨酸溢出将模拟可卡因诱导的适应，并加强提示恢复蔗糖寻求。阻断星形胶质细胞谷氨酸转运体(GLT-1)诱导谷氨酸溢出对恢复的蔗糖寻找没有影响。然而，突触前mGluR2/3负性调节谷氨酸释放概率，阻断mGluR2/3后，蔗糖恢复增强。拮抗mGluR5可逆转mGluR2/3阻断的蔗糖恢复作用，但不阻断mGluR2/3的蔗糖恢复作用不受mGluR5的影响。在可卡因训练的啮齿动物中，刺激mGluR5通过激活nNOS来恢复寻找药物，但激活mGluR5并不促进恢复的蔗糖寻找，也没有增强mGluR2/3阻断通过阻断nNOS而减少的恢复。然而，NAcore中nNOS中间神经元的化学激活恢复了蔗糖寻找。这些数据表明，突触前mGluR2/3信号可能是寻求药物和加强恢复蔗糖寻求的共享信号，但不共享突触谷氨酸溢出下调谷氨酸转运和随后激活nNOS的位置。
Many studies support a perspective that addictive drugs usurp brain circuits used by natural rewards, especially for the dopamine-dependent reinforcing qualities of both drugs and natural rewards. Reinstated drug seeking in animal models of relapse relies on glutamate spillover from cortical terminals synapsing in the nucleus accumbens core (NAcore) to stimulate metabotropic glutamate receptor5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons. Contrasting the release of dopamine that is shared by sucrose and drugs of abuse, reinstated sucrose seeking does not induce glutamate spillover. We hypothesized that pharmacologically promoting glutamate spillover in the NAcore would mimic cocaine-induced adaptations and potentiate cued reinstatement of sucrose seeking. Inducing glutamate spillover by blocking astroglial glutamate transporters (GLT-1) had no effect on reinstated sucrose seeking. However, glutamate release probability is negatively regulated by presynaptic mGluR2/3, and sucrose reinstatement was potentiated following mGluR2/3 blockade. Potentiated sucrose reinstatement by mGluR2/3 blockade was reversed by antagonizing mGluR5, but reinstated sucrose seeking in the absence of mGluR2/3 blockade was not affected by blocking mGluR5. In cocaine-trained rodents mGluR5 stimulation reinstates drug seeking by activating nNOS, but activating mGluR5 did not promote reinstated sucrose seeking, nor was potentiated reinstatement after mGluR2/3 blockade reduced by blocking nNOS. However, chemogenetic activation of nNOS interneurons in the NAcore reinstated sucrose seeking. These data indicate that dysregulated presynaptic mGluR2/3 signaling is a possible site of shared signaling in drug seeking and potentiated reinstated sucrose seeking, but that downregulated glutamate transport and subsequent activation of nNOS by synaptic glutamate spillover is not shared.