Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats.
Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats.
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DOI：
10.1016/j.pbb.2017.08.012
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Reichel CM
中科院分区：
文献类型：
--
作者：
Bernheim A;Leong KC;Berini C;Reichel CM
甲基苯丙胺（冰毒）成瘾是世界范围内普遍存在的健康问题，但仍然没有批准的药物治疗。临床前证据表明，催产素可能会减少复发，但驱动这种效果的神经元基础仍然未知。在这里，我们调查催产素的效果是否是依赖于突触前神经元的调节，在丘脑核的核心（NAcore）通过阻断代谢型谷氨酸受体2/3（mGluR 2/3）。雄性和雌性Sprague-Dawley大鼠以递增的固定比例自我施用甲基或蔗糖，然后进行消退和线索诱导的恢复会话。恢复试验包括全身（实验1）或部位特异性应用药物进入NAcore（实验2和3）。在恢复期之前，大鼠接受LY 341495（mGluR 2/3拮抗剂）或其媒介物，随后第二次输注/注射催产素或盐水。正如预期的那样，男性和女性都恢复了按压杠杆以获得与甲基苯丙胺相关的线索，并且LY 341495单独不影响这种行为。催产素全身注射或注入NAcore减少线索冰毒寻求。重要的是，LY 341495和催产素联合给药恢复了甲基线索的恢复。有趣的是，催产素和LY 341495都不影响蔗糖提示的恢复，表明甲基和蔗糖之间的不同机制。这些结果在雄性和雌性之间一致。总的来说，我们报告说，催产素减少了对甲基相关线索的反应，阻断突触前mGluR 2/3逆转了这种影响。此外，催产素的影响是特定的甲基线索，因为NAcore催产素对蔗糖线索的恢复没有影响。结果进行了讨论，催产素受体的定位在NAcore和调制的突触前谷氨酸调节药物相关的线索。
Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin’s effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin’s effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues.
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