Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Addict Biol. 2014 Jan;19(1):87-101. doi: 10.1111/adb.12061. Epub 2013 May 27.
Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7-10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration.
可卡因成瘾是一种慢性、复发性疾病，其特征是无法调节觅药行为。在这里，我们研究了腹侧纹状体和背侧纹状体中的 mGluR5 在可卡因寻求行为中的作用，包括戒断和消退后的可卡因寻求行为。动物接受了 2 周的可卡因自我给药，然后进行了 3 周的笼内戒断。然后，动物被重新引入操作室进行情境诱导复吸测试，随后进行 7-10 天的消退训练。一旦反应被消除，就进行线索诱发的复吸测试。在给予 mGluR5 负变构调节剂 MTEP 或载体的情况下，进行了两种觅药测试，药物分别输注到伏隔核（NA）核心或背外侧纹状体（dSTR）。我们发现，NA 核心内的 MTEP 输注可减弱戒断后的情境诱导复吸和消退训练后的线索诱发复吸。阻断 dSTR mGluR5 对情境或线索诱导的可卡因觅药没有影响。然而，在 dSTR 内的 MTEP 输注会减弱在输注后 4 天内的消退学习。此外，在经历了 3 周可卡因自我给药戒断的动物的 dSTR 切片中，mGluR5 表面表达减少，LTD 缺失，但蔗糖自我给药的动物则没有。用 mGluR5 的正变构调节剂 VU-29 进行浴内应用可恢复 LTD。MTEP 的浴内应用可防止蔗糖动物的 dSTR 切片中 LTD 的诱导。总的来说，这些数据表明，dSTR mGluR5 在消退学习中起着至关重要的作用，但在可卡因戒断和消退后的觅药中不起作用，而 NA 核心 mGluR5 调节可卡因自我给药戒断和消退后的觅药。
