慢性吗啡给予、戒断及再给药过程中大鼠海马感觉门控的动态变化

Dynamics of hippocampal sensory gating during the chronic morphine administration, withdrawal and re-exposure to morphine in rats

药物成瘾被认为是药物长期作用于脑而产生的一种慢性复吸性脑疾病，长期反复的药物（如吗啡）滥用会导致一系列严重后果，如药物依赖、药物耐受、强迫性药物寻求等。本实验利用条件化位置偏好（conditioned place preference，CPP）模型来检测大鼠对吗啡依赖和心理渴求等过程；采用双声刺激听觉诱发电位来研究大鼠在慢性吗啡给予、戒断以及再给药过程中海马感觉门控（N40）的动态变化。吗啡组大鼠注射吗啡（10mg／kg，i．p．）12d，经历第一次戒断12d，再次注射吗啡（2．5mg／kg，i．P．）1d，之后经历第二次戒断2d；对照组大鼠注射同体积生理盐水，其余实验条件与吗啡组相同。CPP实验表明，这种药物给予方法促使大鼠对吗啡产生药物依赖和心理渴求。双声刺激诱发电位实验表明，吗啡组大鼠在吗啡给予期间海马感觉门控受到损伤；第一次戒断期的第1～2天海马感觉门控能力减弱，第3天增强，第4～12天逐渐恢复到正常水平；再次给予吗啡后海马感觉门控能力与对照组相比显著降低，并且随后2d的戒断期内海马感觉门控能力也一直保持较低水平，表明再次给药使大鼠海马感觉门控对吗啡更加敏感化。结果提示，长期反复的吗啡给予及再给药干扰了海马的感觉门控能力，吗啡成瘾对大脑可能产生长期影响。

Drug addiction is considered as a chronic, recurrent brain disease characterized by relapse. Repeated exposure to certain drugs, such as morphine, can produce deleterious sequelae, such as drug dependence, tolerance and compulsive drug seeking. In the present study, we investigated the dependence and psychological craving for morphine in rats using the conditioned place preference （CPP） paradigm. On the other hand, to study the effect of morphine on hippocampal sensory gating （N40）, double click auditory-evoked potential was recorded during the chronic morphine administration, withdrawal and re-exposure to morphine in rats. The rats in morphine group received a course of morphine （10 mg/kg, i.p.） injection for 12 d, followed by 12 d of withdrawal, 1 d of re-exposure to morphine（2.5 mg/kg, i.p.） and 2 d of the second withdrawal. The rats in the control group were treated in the same way except that saline was applied instead of morphine. CPP test demonstrated that the method of drug administration in the present study induced dependence and psychological craving for morphine in rats. The results in the double click auditory-evoked potential experiment showed that during the chronic morphine administration, hippocampal N40 gating was damaged. In the initial 2 d of the fLrst withdrawal hippocampal N40 gating in morphine group was reduced compared with that in the control group and it was significantly greater on the 3rd. day, and then recovered gradually to the normal level from day 4 to day 12. After re-exposure to morphine, hippocampal N40 gating in morphine group was significantly reduced compared with that in the control group, and it remained at a lower level during the following 2 d, suggesting that hippocampal N40 gating in rats was more sensitive to morphine during re-exposure. Our results suggest that long-term repeated morphine administration and re-exposure to morphine disrupt hippocampal N40 gating, and that the effect of morphine addiction on the brain is possibly long-term.