Webb Sierra M, Miller Bailey W, Wroten Melissa G, Sacramento Arianne, Travis Katherine O, Kippin Tod E, Ben-Shahar Osnat, Szumlinski Karen K
Department of Psychological and Brain Sciences, MC-9660, University of California Santa Barbara, Santa Barbara, CA 93106-9660, United States of America.
Department of Psychological and Brain Sciences, MC-9660, University of California Santa Barbara, Santa Barbara, CA 93106-9660, United States of America; Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, United States of America.
Pharmacol Biochem Behav. 2024 Dec;245:173889. doi: 10.1016/j.pbb.2024.173889. Epub 2024 Oct 9.
Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this "incubation of cocaine-craving" involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation.
在停止服药后的戒断期内，线索诱发的觅药行为会随着时间的推移而加剧，这种“可卡因渴求的潜伏期”涉及伏隔核（NA）谷氨酸传递的改变。在此，我们采用体内微透析和免疫印迹方法相结合的方式，进一步研究在有10天每天6小时静脉注射可卡因（0.25毫克/次）历史的雄性大鼠所表现出的可卡因渴求潜伏期过程中，NA亚区域内谷氨酸传递生化指标的变化。对核心亚区域（NAc核心）全细胞裂解物进行免疫印迹分析显示，可卡因自我给药历史、戒断和药物线索再次暴露之间存在对Homer2a/b、mGlu1和GluN2b表达以及Akt和ERK活性指标的相互作用。除PKCε磷酸化外，壳亚区域（NAc壳）内的大多数蛋白质变化取决于药物线索再次暴露和可卡因历史，而非以一致的时间依赖性方式变化。仅在长期（30天）戒断期间，有可卡因使用经历的大鼠的NAc核心中基础细胞外谷氨酸含量降低，并且这伴随着mGlu1/5激动剂DHPG在此亚区域内升高谷氨酸水平的能力明显减弱。最后，在长期可卡因戒断期间，在NAc核心内过表达Homer1c或Homer2b均未改变线索诱发反应的幅度、其消退或可卡因引发的觅药行为恢复。本研究结果与现有文献一致，表明NAc核心亚区域内第1组mGlu受体功能的变化是可卡因渴求潜伏期的核心，并提供了进一步证据反驳Homer蛋白在调节可卡因渴求潜伏期方面的主要作用。此外，我们的结果提供了新的相关性证据，表明NAc核心内Akt升高和ERK活性减弱可能是可卡因渴求潜伏期表达的潜在因素，值得未来研究。
