Animals will respond with stress-like behavioral and biochemical changes when exposed to a neutral stimulus that had previously been paired with a stressful stimulus. This phenomenon is generally known as aversive conditioning or conditioned fear. We tested the effect of prior exposure to cocaine on rats subjected to an aversive conditioning paradigm. Rats were given repeated doses of cocaine to develop a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. We blocked this sensitization to cocaine in one cocaine-exposed group by co-administering an antagonist of the strychinine-insensitive glycine site of the N-methyl-D-aspartate receptor complex, R-(+)-HA-966, which prevented the development of locomotor sensitization to cocaine. After about three weeks, we examined the effect of cocaine sensitization and the prevention of sensitization by R-(+)-HA-966 on aversive conditioning. Rats were exposed to 10 tones (neutral stimuli) paired with footshock (stressful stimuli) over 30 min for the conditioning session. The following day, rts were returned to the cages, received 10 tones only over 30 min and were killed. No drugs were given to any rat before either session and control rats received the tones without footshock in both sessions. Prior exposure to cocaine caused an attenuation of the behavioral effects of aversive conditioning, namely the amount of time spent immobilized and the number of fecal boli expelled. Additionally, the elevated metabolic activity of dopamine in the medial prefrontal cortex, nucleus accumbens and ventral tegmental area associated with aversive conditioning was diminished in rats pre-exposed to cocaine. The behavioral and biochemical effects of pre-exposure to cocaine were reversed in rats that receive R-(+)-HA-966 co-treatment with the five day cocaine sensitization regimen. These data suggest that prior behavioral sensitization to cocaine diminishes the stressful effect of conditioned fear and that these effects are reversed when sensitization is prevented with R-(+)-HA-966.

译文

当暴露于先前与压力刺激配对的中性刺激时,动物会做出类似压力的行为和生化变化。这种现象通常被称为厌恶条件或条件恐惧。我们测试了先前暴露于可卡因对遭受厌恶条件范例的大鼠的影响。给大鼠重复剂量的可卡因,以对可卡因的运动刺激特性产生反向耐受性或敏感性。我们通过共同施用N-甲基-D-天冬氨酸受体复合物R-(+)-HA-966的马胆酸对甘氨酸不敏感的甘氨酸位点的拮抗剂,在一个可卡因暴露组中阻止了对可卡因的这种敏化,这阻止了对可卡因的运动敏化。大约三周后,我们检查了可卡因致敏作用以及R-()-HA-966对厌恶性条件的预防致敏作用。在30分钟内,将大鼠暴露于10个音调 (中性刺激) 与脚休克 (压力刺激) 配对以进行调理。第二天,rts被送回笼子,仅在30分钟内收到10个音调,并被杀死。在任何一个疗程之前都没有给任何大鼠服用药物,并且对照组大鼠在两个疗程中都接受了没有脚电击的音调。先前暴露于可卡因会导致厌恶性条件的行为影响减弱,即固定时间和排出粪便的数量。此外,在暴露于可卡因的大鼠中,与厌恶性条件相关的内侧前额叶皮层,伏隔核和腹侧被盖区中多巴胺的代谢活性升高。在接受R-()-HA-966与5天可卡因致敏方案的联合治疗的大鼠中,预暴露于可卡因的行为和生化作用被逆转。这些数据表明,先前对可卡因的行为敏化会减少条件性恐惧的压力作用,并且当用R-()-HA-966阻止敏化时,这些作用会逆转。

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