Edwards Scott, Graham Danielle L, Bachtell Ryan K, Self David W
Department of Psychiatry and the Neuroscience Graduate Program, The Seay Center for Basic and Applied Research in Psychiatric Illness, UT Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Eur J Neurosci. 2007 Apr;25(7):2201-13. doi: 10.1111/j.1460-9568.2007.05473.x.
Chronic cocaine self-administration can produce either tolerance or sensitization to certain cocaine-regulated behaviours, but whether differential alterations develop in the biochemical response to cocaine is less clear. We measured cocaine-induced phosphorylation of multiple cAMP-dependent and -independent protein substrates in mesolimbic dopamine terminal regions following chronic self-administration. Changes in self-administering rats were compared to changes produced by passive yoked injection to identify reinforcement-related regulation, whereas acute and chronic yoked groups were compared to identify the development tolerance or sensitization in the biochemical response to cocaine. Microwave-fixed brain tissue was collected immediately following 4 h of intravenous cocaine administration, and subjected to Western blot analysis of phosphorylated and total protein substrates. Chronic cocaine produced region- and substrate-specific tolerance to cAMP-dependent protein phosphorylation, including GluR1(S845) phosphorylation in striatal and amygdala subregions and NR1(S897) phosphorylation in the CA1 subregion of the hippocampus. Tolerance also developed to cAMP-independent GluR1(S831) phosphorylation in the prefrontal cortex. In contrast, sensitization to presynaptic regulation of synapsin(S9) phosphorylation developed in the hippocampal CA3 subregion while cAMP-dependent tyrosine hydroxylase(S40) phosphorylation decreased in striatal dopamine terminals. Cocaine-induced ERK and CREB(S133) phosphorylation were dissociated in many brain regions and failed to develop either tolerance or sensitization with chronic administration. Positive reinforcement-related correlations between cocaine intake and protein phosphorylation were found only in self-administering animals, while negative dose-related correlations were found primarily with yoked administration. These regional- and substrate-specific adaptations in cocaine-induced protein phosphorylation are discussed in view of their potential impact on the development of cocaine addiction.
长期自我给药可卡因可导致对某些受可卡因调节行为产生耐受或敏感，但对可卡因生化反应是否存在差异变化尚不清楚。我们检测了长期自我给药后中脑边缘多巴胺终端区域中多种环磷酸腺苷（cAMP）依赖性和非依赖性蛋白底物的可卡因诱导磷酸化情况。将自我给药大鼠的变化与被动配对注射产生的变化进行比较，以确定强化相关调节，而将急性和慢性配对组进行比较，以确定对可卡因生化反应中耐受性或敏感性的发展。在静脉注射可卡因4小时后立即收集经微波固定的脑组织，并对磷酸化和总蛋白底物进行蛋白质印迹分析。长期使用可卡因会对cAMP依赖性蛋白磷酸化产生区域和底物特异性耐受，包括纹状体和杏仁核亚区域中GluR1（S845）磷酸化以及海马CA1亚区域中NR1（S897）磷酸化。前额叶皮质中对cAMP非依赖性GluR1（S831）磷酸化也产生了耐受。相比之下，海马CA3亚区域中对突触素（S9）磷酸化的突触前调节出现敏感，而纹状体多巴胺终端中cAMP依赖性酪氨酸羟化酶（S40）磷酸化减少。可卡因诱导的细胞外信号调节激酶（ERK）和环磷腺苷反应元件结合蛋白（CREB，S133）磷酸化在许多脑区中出现解离，并且长期给药后未产生耐受或敏感。仅在自我给药动物中发现可卡因摄入量与蛋白磷酸化之间存在正强化相关关系，而主要在配对给药中发现负剂量相关关系。鉴于它们对可卡因成瘾发展的潜在影响，讨论了可卡因诱导蛋白磷酸化中的这些区域和底物特异性适应性变化。
