Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
Neuropharmacology. 2021 Mar 15;186:108452. doi: 10.1016/j.neuropharm.2021.108452. Epub 2021 Jan 12.
Many studies have demonstrated that negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGlu5) reduce cocaine and methamphetamine seeking in extinction-reinstatement animal models of addiction. Less is known about effects of mGlu5 NAMs in abstinence models, particularly for methamphetamine. We used the incubation of drug craving model, in which cue-induced craving progressively intensifies after withdrawal from drug self-administration, to conduct the first studies of the following aspects of mGlu5 function in the rat nucleus accumbens (NAc) core during abstinence from methamphetamine self-administration: 1) functionality of the major form of synaptic depression in NAc medium spiny neurons, which is induced postsynaptically via mGlu5 and expressed presynaptically via cannabinoid type 1 receptors (CB1Rs), 2) mGlu5 surface expression and physical associations between mGlu5, Homer proteins, and diacylglycerol lipase-α, and 3) the effect of systemic and intra-NAc core administration of the mGlu5 NAM 3-((2-methyl-4-)ethynyl)pyridine (MTEP) on expression of incubated methamphetamine craving. We found that mGlu5/CB1R-dependent synaptic depression was lost during the rising phase of methamphetamine incubation but then recovered, in contrast to its persistent impairment during the plateau phase of incubation of cocaine craving. Furthermore, whereas the cocaine-induced impairment was accompanied by reduced mGlu5 levels and mGlu5-Homer associations, this was not the case for methamphetamine. Systemic MTEP reduced incubated methamphetamine seeking, but also reduced inactive hole nose-pokes and locomotion, while intra-NAc core MTEP had no significant effects. These findings provide the first insight into the role of mGlu5 in the incubation of methamphetamine craving and reveal differences from incubation of cocaine craving.
许多研究表明，代谢型谷氨酸受体 5（mGlu5）的负变构调节剂（NAM）可减少可卡因和安非他命在成瘾的消退-再巩固动物模型中的寻求。mGlu5 NAM 在戒断模型中的作用知之甚少，特别是对于安非他命。我们使用药物渴求模型的孵育，在该模型中，戒断药物自我给药后，线索诱导的渴求逐渐加剧，对大鼠伏隔核（NAc）核心中 mGlu5 功能进行了以下方面的首次研究：1）NAc 中中棘神经元中主要形式的突触抑制的功能，该抑制通过 mGlu5 在后突触诱导，通过大麻素 1 型受体（CB1R）在前突触表达，2）mGlu5 表面表达和 mGlu5、 Homer 蛋白和二酰基甘油脂肪酶-α之间的物理关联，以及 3）系统和内 NAc 核心给予 mGlu5 NAM 3-((2-甲基-4-)乙炔基)吡啶（MTEP）对孵育的安非他命渴求表达的影响。我们发现，mGlu5/CB1R 依赖性突触抑制在安非他命孵育的上升阶段丢失，但随后恢复，与可卡因孵育的平台阶段持续受损形成对比。此外，尽管可卡因引起的损伤伴随着 mGlu5 水平和 mGlu5-Homer 关联的减少，但安非他命并非如此。系统给予 MTEP 可减少孵育的安非他命寻求，但也减少了非活动的鼻洞戳和运动，而内 NAc 核心给予 MTEP 则没有显著影响。这些发现首次提供了 mGlu5 在安非他命渴求孵育中的作用的见解，并揭示了与可卡因渴求孵育的差异。
