低可卡因运动反应大鼠和高可卡因运动反应大鼠在可卡因觅求恢复及纹状体代谢型谷氨酸受体5(mGluR5)蛋白表达方面存在差异。
Low- and high-cocaine locomotor responding rats differ in reinstatement of cocaine seeking and striatal mGluR5 protein expression.
作者信息
Simmons Diana L, Mandt Bruce H, Ng Christopher M C, Richards Toni L, Yamamoto Dorothy J, Zahniser Nancy R, Allen Richard M
机构信息
Department of Pharmacology, University of Colorado Anschutz Medical Campus, MS 8303, Aurora, CO 80045, USA.
Department of Psychology, University of Colorado Denver, CB 173, PO Box 173364, Denver, CO 80217, USA.
出版信息
Neuropharmacology. 2013 Dec;75:347-55. doi: 10.1016/j.neuropharm.2013.08.001. Epub 2013 Aug 22.
Behavioral responsiveness to initial cocaine use varies among individuals and may contribute to differential vulnerability to cocaine addiction. Rats also exhibit individual differences in cocaine's effects and can be classified as low or high cocaine responders (LCRs or HCRs, respectively), based on their initial cocaine-induced locomotor activity (10 mg/kg, i.p.). Here, we used the extinction/reinstatement model to address whether or not LCRs and HCRs differ in (i) extinction/reinstatement of cocaine self-administration behavior and (ii) levels of metabotropic glutamate receptors (mGluRs) following these behaviors. During the earliest acquisition sessions, LCRs exhibited significantly greater cocaine intake (0.8 mg/kg/infusion) and cocaine-paired lever responding than HCRs, but intake and lever responding converged by the end of the cocaine self-administration portion of the study. LCRs and HCRs did not differ in cocaine seeking during the first extinction session and extinguished cocaine seeking similarly. HCRs exhibited greater reinstatement than LCRs to lower (2.5 and 5 mg/kg), but not higher (10 mg/kg), i.p. priming doses of cocaine. The effect of drug-paired cues on reinstatement following extinction was complex, with HCRs and LCRs showing the greater effect of cue depending on the order in which cue- and drug-primed tests were given. Western blot analysis revealed that mGluR5 heteromers were significantly higher in the dorsal striatum of HCRs than LCRs following reinstatement testing. Although our previous findings with the LCR/HCR model have uniformly supported the idea that lower initial cocaine-induced activation predicts more ready development of cocaine addiction-like behaviors, here, we show a more complex relationship with cocaine reinstatement.
个体对初次使用可卡因的行为反应各不相同,这可能导致对可卡因成瘾的易感性存在差异。大鼠对可卡因的反应也存在个体差异,根据其初次可卡因诱导的运动活性(腹腔注射10mg/kg),可分为低可卡因反应者或高可卡因反应者(分别为LCR和HCR)。在此,我们使用消退/复吸模型来探讨LCR和HCR在以下方面是否存在差异:(i)可卡因自我给药行为的消退/复吸,以及(ii)这些行为后代谢型谷氨酸受体(mGluR)的水平。在最早的获取阶段,LCR比HCR表现出显著更高的可卡因摄入量(0.8mg/kg/注射)和与可卡因配对的杠杆反应,但在研究的可卡因自我给药部分结束时,摄入量和杠杆反应趋于一致。在第一次消退阶段,LCR和HCR在寻求可卡因方面没有差异,并且可卡因寻求行为的消退情况相似。对于较低(2.5和5mg/kg)但不是较高(10mg/kg)的腹腔注射可卡因启动剂量,HCR比LCR表现出更大的复吸。药物配对线索对消退后复吸的影响很复杂,HCR和LCR根据线索和药物启动测试的顺序不同,表现出线索的更大影响。蛋白质免疫印迹分析显示,复吸测试后,HCR背侧纹状体中的mGluR5异聚体显著高于LCR。尽管我们之前使用LCR/HCR模型的研究结果一致支持较低的初次可卡因诱导激活预示着更易发展出类似可卡因成瘾行为的观点,但在此我们发现与可卡因复吸存在更复杂的关系。