Georgiou Polymnia, Zanos Panos, Ehteramyan Mazdak, Hourani Susanna, Kitchen Ian, Maldonado Rafael, Bailey Alexis
Sleep, Chronobiology & Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
Department of Experimental and Health Sciences, University of Pompeu Fabra, Spain.
Addict Biol. 2015 Sep;20(5):902-12. doi: 10.1111/adb.12208. Epub 2014 Dec 17.
The key problem for the treatment of drug addiction is relapse to drug use after abstinence that can be triggered by drug-associated cues, re-exposure to the drug itself and stress. Understanding the neurobiological mechanisms underlying relapse is essential in order to develop effective pharmacotherapies for its prevention. Given the evidence implicating the metabotropic glutamate receptor 5 (mGlu5 R), μ-opioid receptor (MOPr), κ-opioid receptor (ΚOPr) and oxytocin receptor (OTR) systems in cocaine addiction and relapse, our aim was to assess the modulation of these receptors using a mouse model of cue- and priming-induced reinstatement of cocaine seeking. Male mice were trained to self-administer cocaine (1 mg/kg/infusion, i.v.) and were randomized into different groups: (1) cocaine self-administration; (2) cocaine extinction; (3) cocaine-primed (10 mg/kg i.p.); or (4) cue-induced reinstatement of cocaine seeking. Mice undergoing the same protocols but receiving saline instead of cocaine were used as controls. Quantitative autoradiography of mGlu5 R, MOPr, KOPr and OTR showed a persistent cocaine-induced upregulation of the mGlu5 R and OTR in the lateral septum and central amygdala, respectively. Moreover, a downregulation of mGlu5 R and MOPr was observed in the basolateral amygdala and striatum, respectively. Further, we showed that priming- but not cue-induced reinstatement upregulates mGlu5 R and MOPr binding in the nucleus accumbens core and basolateral amygdala, respectively, while cue- but not priming-induced reinstatement downregulates MOPr binding in caudate putamen and nucleus accumbens core. This is the first study to provide direct evidence of reinstatement-induced receptor alterations that are likely to contribute to the neurobiological mechanisms underpinning relapse to cocaine seeking.
药物成瘾治疗的关键问题是戒断后复吸，这可能由与药物相关的线索、再次接触药物本身以及压力引发。了解复吸背后的神经生物学机制对于开发有效的预防药物疗法至关重要。鉴于有证据表明代谢型谷氨酸受体5（mGlu5 R）、μ-阿片受体（MOPr）、κ-阿片受体（ΚOPr）和催产素受体（OTR）系统与可卡因成瘾及复吸有关，我们的目的是使用线索和启动诱导的可卡因觅求恢复小鼠模型来评估这些受体的调节情况。雄性小鼠经训练可自行注射可卡因（1毫克/千克/注射，静脉注射），并随机分为不同组：（1）可卡因自我给药组；（2）可卡因消退组；（3）可卡因启动组（腹腔注射10毫克/千克）；或（4）线索诱导的可卡因觅求恢复组。接受相同方案但注射生理盐水而非可卡因的小鼠用作对照。对mGlu5 R、MOPr、KOPr和OTR进行的定量放射自显影显示，可卡因分别持续诱导外侧隔区和中央杏仁核中的mGlu5 R和OTR上调。此外，分别在基底外侧杏仁核和纹状体中观察到mGlu5 R和MOPr下调。此外，我们发现启动诱导而非线索诱导的恢复分别上调伏隔核核心和基底外侧杏仁核中的mGlu5 R和MOPr结合，而线索诱导而非启动诱导的恢复下调尾壳核和伏隔核核心中的MOPr结合。这是第一项提供恢复诱导的受体改变直接证据的研究，这些改变可能有助于阐明可卡因觅求复吸背后的神经生物学机制。
