Institute of Behavioral Medicine, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC.
Behav Brain Res. 2011 Jun 20;220(1):126-31. doi: 10.1016/j.bbr.2011.01.031. Epub 2011 Jan 26.
In this study, we decided to use low doses of memantine pretreatment to examine the roles of the immune function in cocaine-supported conditioning. Cocaine-induced conditioned place preference (CPP) was used to assess the hedonic value and/or reinforcing efficacy of cocaine and cocaine-supported conditioning. Systemic pretreatment with memantine (20, 2.0, 0.2, and 0.02 mg/kg/injection) 30 min before each cocaine and saline conditioning trial abolished the acquisition of cocaine-induced CPP in mice. Even a total of 0.12 mg/kg memantine pretreatment in three days was effective in diminishing cocaine-induced CPP. Three consecutive days of cocaine conditioning increased interleukin-6 (IL-6) but decreased tumor necrosis factor (TNF-α) levels in medial prefrontal cortex (mPFC) and nucleus accumbens (Acb). Interestingly, pretreatment with memantine at the lowest effective dose (0.02 mg/kg/injection) reversed cocaine conditioning-enhanced IL-6 and -decreased TNF-α levels in these brain regions. Nevertheless, such a memantine dosing regimen did not affect dopamine metabolism in mPFC and Acb. Single memantine (0.02 mg/kg) injection did not acutely affect mouse locomotor activity or cocaine-increased locomotor activity. Similar memantine dosing regimen was ineffective to affect the maintenance of cocaine-induced CPP. Finally, intra-mPFC infusion of recombinant IL-6, but not thalidomide, reversed memantine (0.02 mg/kg/injection × 6)-decreased cocaine-induced CPP. These results, taken together, suggest that cocaine conditioning-enhanced IL-6 in mPFC may be, in part, involved in the acquisition of cocaine-induced CPP. Moreover, an extremely low dose of memantine may decrease the acquisition of cocaine-induced CPP by reversing cocaine conditioning-increased IL-6 levels in mPFC.
在这项研究中，我们决定使用低剂量美金刚预处理来研究免疫功能在可卡因支持的条件作用中的作用。可卡因诱导的条件位置偏好（CPP）用于评估可卡因的愉悦价值和/或强化效力以及可卡因支持的条件作用。在每次可卡因和盐水条件作用试验前 30 分钟，全身性给予美金刚（20、2.0、0.2 和 0.02 mg/kg/注射）可消除小鼠可卡因诱导的 CPP 的获得。即使在三天内总共给予 0.12 mg/kg 美金刚预处理也可有效减少可卡因诱导的 CPP。连续三天的可卡因条件作用增加了内侧前额叶皮质（mPFC）和伏隔核（Acb）中的白细胞介素-6（IL-6），但降低了肿瘤坏死因子（TNF-α）水平。有趣的是，用最低有效剂量（0.02 mg/kg/注射）的美金刚预处理可逆转这些脑区中可卡因条件作用增强的 IL-6 和降低的 TNF-α水平。然而，这种美金刚剂量方案不会影响 mPFC 和 Acb 中的多巴胺代谢。单次美金刚（0.02 mg/kg）注射不会急性影响小鼠的运动活动或可卡因增加的运动活动。类似的美金刚剂量方案对维持可卡因诱导的 CPP 没有作用。最后，内侧前额叶皮质内注射重组白细胞介素-6（IL-6），而不是沙利度胺（thalidomide），可逆转美金刚（0.02 mg/kg/注射×6）降低的可卡因诱导的 CPP。这些结果表明，mPFC 中的可卡因条件作用增强的 IL-6 可能部分参与了可卡因诱导的 CPP 的获得。此外，极低剂量的美金刚可能通过逆转 mPFC 中可卡因条件作用增加的 IL-6 水平来降低可卡因诱导的 CPP 的获得。
