健康与遗传心理学研究室知识库

药物成瘾是一种反复发作的慢性脑疾病。药物成瘾的核心特征是精神类药物能够形成药物依赖;核心问题是机体对成瘾药物的强迫性复用;而用药相关环境线索是诱导药物强迫性复用的重要原因之一，是非常棘手和普遍的临床问题。用药相关环境线索引发的渴求反应是以成瘾记忆为基础的。成瘾记忆，被神经科学界广泛认为是药物成瘾现象的重要神经生物学基础，药物成瘾的“形成”和“复用”包含成瘾记忆的“巩固”与“表达”，又与行为学动物模型一一“成瘾药物诱导的条件位置偏爱”的“形成”和“表达”相对应。因此，本研究对药物成瘾的两个关键环节一一“形成”和“复用”的神经生物学机理进行研究，探讨成瘾记忆的形成和表达在其中的作用。中央杏仁核和背侧海马是参与学习记忆的重要脑区;脑内神经元胞内细胞信号转导系统-一 “丝裂原激活性蛋白激酶" ( MAPK)与学习记忆密切相关。由此，本研究以大鼠的“吗啡诱导条件位置偏爱”为模型，运用行为药理学方法，探讨吗啡引发药物成瘾记，忆巩固与表达过程中央杏仁核和背侧海马MAPK信号转导通路的作用。

主要结果如下:

1. CPP条件训练后，双侧中央杏仁核微量注射ERK-MAPK磷酸化抑制剂，能削弱大鼠在实验周期的第7天、第14天、第21天CPP的表达;而P38-MAPK和JNK-MAPK磷酸化抑制剂则不影响CPP的表达。

2.条件训练后，双侧背侧海马微量注射ERK-MAPK磷酸化抑制剂，能抑制大鼠在实验周期的第7天、第14天、第21天CPP的表达;条件训练后，双侧背侧海马微量注射P38-MAPK磷酸化抑制剂，能削弱第7天的CPP表达;而JNK-MAPK磷酸化抑制剂不影响CPP的表达。

3. CPP表达前30分钟，双侧中央杏仁核微量预注射MAPKs磷酸化抑制剂，不影响CPP的表达。

4. CPP表达前30分钟，双侧背侧海马微量预注射ERK-MAPK磷酸化抑制剂，削弱CPP的表达，而P38-MAPK和JNK-MAPK磷酸化抑制剂不影响CPP的表达。

综上，本研究结果提示，背侧海马ERK-MAPK, P38-MAPK和中央杏仁核ERK-MAPK参与介导吗啡诱导的CPP过程中对用药相关环境线索记，)乙的巩固形成过程，背侧海马ERK-MAPK可能介导CPP形成过程中对用药环境线索的长程记忆。背侧海马ERK-MAPK参与吗啡诱导的条件位置偏爱过程中所获取的用药相关环境线索记，忆的表达过程。因此，本研究提示，背侧海马(主要涉及CA1和CA2区神经元)和中央杏仁核的ERK-MAPK以及P38-MAPK参与介导成瘾记忆的形成，以及成瘾记忆诱发的药物成瘾复发。

As a chronic relapsing brain disease characterized by formation of persistent drug dependence, Drug Addiction has a critical core clinical problem: compulsive drug use, also called "relapse". Markedly, the drug-related environmental cue is one of the important reasons accounting for the compulsive drug use. The drug-craving triggered by drug-related environmental cue is based on the addiction memory. Addiction memory or aberrant memory is one of the foundational significant mechanisms of Drug Addiction. The consolidation and expression of addiction memory are involved in the formation and relapse of drug addiction; which both processes also correspond to the formation and expression of the addiction-drug-induced conditioned place preference (CPP). So, this study focused on the mechanisms of the two key points: Drug Addiction's formation and relapse; explored the functions of formation and expression of addiction memory in the processes. Central nucleus of amygdala (CeA) and dorsal hippocampus (DH) are pivotal brain regions involved in learning and memory. Intracerebral neurons' intracellular signal transduction pathway: mitogen activated protein kinases (MAPKs), are closely associated with learning and memory. Therefore, using the morphine-induced CPP as a model, with the behavioral pharmacological methods, we explored the roles of MAPKs signal pathways of DH and CeA in the formation and expression processes of morphine-induced CPP.

The main results are as follows:

5. After conditioned training of CPP, microinfusion of ERK-MAPK's phosphorylation inhibitor into bilateral CeA could attenuate the CPP expressions at 7th, 14th, and 21St days of CPP procedure. Microinfusions of phosphorylation inhibitors of P38-MAPK and JNK-MAPK did not affect the CPP expression.

6. After conditioned training of CPP, microinfusions of ERK-MAPK's phosphorylanon inhibitor into bilateral DH could block the CPP expression at 7th, 14th, and 21St days of the CPP procedure; microinfusion of P38-MAPK's phosphorylation inhibitor could attenuate CPP expression at 7th day; microinfusions of phosphorylation inhibitors of JNK-MAPK did not affect CPP expression.

7. At 30 min prior to CPP expression, microinfusion of MAPK's phosphorylation inhibitor into bilateral CeA did not influence on the CPP expression.

8. At 30 min prior to CPP expression, microinfusion of ERK-MAPK's phosphorylation inhibitor into bilateral DH attenuated CPP expression; microinfusion of phosphorylation inhibitors of P38-MAPK and JNK-MAPK did not affect CPP expression.

In conclusion, the results of this study suggest that ERK-MAPK and P38-MAPK in DH, as well as ERK-MAPK in CeA are involved in the formation of memory for the drug-related environmental cue in the morphine-induced CPP. ERK-MAPK in DH mediates the long-term memory for the drug-related environmental cue in the formation of CPP. ERK-MAPK in DH is also involved in the expression of memory of the drug-related environmental cue what formed and consolidated in the morphine-induced CPP. Thus, this study implies that ERK-MAPK and P38-MAPK in DH as well as ERK-MAPK in CeA may be involved in the formation of addiction memory, as well as the compulsive drug craving induced by the addiction memory.