| Drug addiction is defined as a chronic and relapsing brain disease with several prominent hallmarks, including compulsive drug-taking, drug-seeking and high rate of relapse to drug resumption. Relapse is the most important problem in clinical treatment for drug addiction. Recently, drug addiction has been considered as a pathological emotional memory. It has been reported that the disruption of the reconsolidation of drug reward memory suppresses drug-seeking behaviors. Stress plays an important role on regulation of memory acquisition, consolidation, recall and reconsolidation. However, the role of stress in the reconsolidation of drug reward memory is not well elucidated. Activity-regulated cytoskeleton-associated protein (Arc) is used as a biomarker in detecting activation of neurons in the entire encephalic region. Additionally, Arc has been demonstrated involves in the formation of the learning and memory, especially in reconsolidation of the various kinds of memory. However, the role of Arc in the reconsolidation of drug reward memory has not been studied.Therefore, in the current study we studied whether stress impairs the reconsolidation of morphine reward memory using morphine induced conditioned place preference model in rats. Furthermore, we studied the Arc expression in the drug addiction associated cerebral regions, such as the basolateral amygdale nucleus (BLA), hippocampus (Hip), corpus striatum (Cpu) and prefrontal cortex (PFC). The findings of the current study would provide new evidence for neurobiological mechanisms of addiction and novel clinic treatment method for addiction.1. Effect of stress on impairment of reconsolidation of morphine reward memoryRats were trained for morphine-induced conditioned place preference (CPP). Then, the rats were divided into four groups to test the effect of stress administered immediately after exposure to morphine-paired context: no exposure+no stress (control group); no exposure+stress (stress group); exposure+no stress (exposure goup); exposure+stress (exposure and stress group).5minutes cold water exposure is served as stress for rats, Results showed that the CPP scores of rats in the exposure and stress group is significant different from other groups (P<0.05). To further identify that stress impaired the reconsolidation of morphine reward memory, rats in the exposed and stressed group were given low dose (3mg·kg-1) of morphine five minutes before the priming test. We found that the priming injection of morphine could not reinstate the CPP behaviors of the rats in the exposure and stress group (P>0.05).In order to exclude the possibility that the impairment of morphine-induced conditioned place preference in rats was caused by aversive effects induced by stress immediately after morphine-paired context exposure, additional two groups rats receiving no morphine CPP training were used: one group was exposed to A box immediately followed by5minutes cold water stress; another group of exposure to B box immediately followed by5minutes cold water stress,. We then tested the CPP scores24hours later. We found that the cold water stress did not induce place aversion in the both groups (P>0.05), indicating that the impairment of morphine CPP is not due to the aversion induced by stress after the exposure.To summarize, reconsolidation was impaired by a stress immediately after retrieval of morphine reward memory.2The time window of the effect of stress on reconsolidation of morphine reward memoryRats were trained for morphine-induced conditioned place preference (CPP). Then, the rats were divided into four groups to test the effect of stress administered6hours after exposure to morphine-paired context:(no exposure+6h+stress; exposure+6h+stress. We found that stress administered6hours after the exposure to morphine-paired context had no effect on the reconsolidation of morphine reward memory (P>0.05), indicating that stress given outside of the time windows of the reconsolidation had no effect on morphine reward memory.3. Relationship between impairment of the reconsolidation of morphine reward memory induced by stress and Arc expression in brain.3.1Effect of stress administered immediately after exposure on the Arc expression in brain regions of the rats assessed by immunofluorescenceTo analysis the effect of stress on the Arc expression in associated cerebral regions of morphine CPP trained rats by immunofluorescence,5rats in the each group were randomly selected from the above40rats after the last CPP test,. After fixation and dehydration, the brain serial sections were collected, including PFC, CPu, CA1and BLA regions. Each slice was20μ m thick, took1slices from every5slices,3slices from each specimen, and totally15slices in each group.We found that in BLA, CA1, Cpu and PFC, the number of Arc positive cells in rats of the exposed group or stressed group had no significant difference (P>0.05) compared with the control group. But the number of Arc positive cells in rats of the exposed and stressed group showed significantly lower (P<0.05) than that in control group.3.2Effect of stress administered immediately after exposure on the Arc expression in brain regions of the rats assessed by western blotTo analysis the effect of stress on the Arc expression in associated cerebral regions of morphine CPP trained rats by western blot,5rats in the each group were randomly selected from the above40rats after the last CPP test. Using nucleus localization sampling method, we analyzed the expression of Arc in several brain areas involved in the expression of the drug memory, including BLA, CA1, CPu and PFC.We found that in BLA, CA1, Cpu and PFC, the expression of Arc in rats of the exposed group or stressed group had no significant difference (P>0.05) compared with the control group. But the expression of Arc in rats of the exposed and stressed group was significantly lower (P<0.05) than control group. In summary, we found that stress given immediately after the exposure to morphine-paired context impaired the reconsolidation of morphine reward memory, as well as decreased the expression of Arc in the brain areas involved in the expression of morphine reward memory, including BLA, CA1, CPu and PFC, assessed both by immunofluorescence and western blot, indicating that impairment of reconsolidation of morphine reward memory might relate to the downregulation of the expression of Arc in several brain areas involved in the drug addiction.To conclusion, the main findings of the current study are as the following:1. Stress given within the time window of the reconsolidation impairs the morphine reward memory.2. Stress impairs the reconsolidation of morphine reward memory, which might be related to decreased expression of Arc in the BLA, CA1, CPu and PFC. |
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