Effects of dexmedetomidine on anxiety and cognitive function in rats with post-traumatic stress disorder
Objective : To investigate the effects of dexmedetomidine on anxiety and cognitive function in rats with post-traumatic stress disorder (PTSD).
METHODS : Male Sprague-Dawley rats were randomly divided into five groups: control group (C group), PTSD model group (P group), dexmedetomidine 10 ug/kg group (D1 group), and 20 ug/kg group (D2 group). And 40 ug/kg group (D3 group), the fear memory of rats was determined by conditional fear test, the autonomic activity ability and anxiety state of rats were determined by open field experiment, and the anxiety state and water maze test of rats were measured by elevated plus maze. The spatial learning and memory ability of the rats was measured. Results Compared with group P, the percentage of stiffness time, total movement distance and latency in D1, D2 and D3 groups were significantly lower (P<0.05), while the percentage of central compartment retention time, open loop time and target quadrant exploration time increased significantly. P < 0.05). Conclusion Dexmedetomidine can significantly reduce the fear memory and autonomic activity of PTSD rats, improve anxiety and enhance the spatial learning and memory ability of PTSD rats.
Key words : post-traumatic stress disorder; anxiety state; cognitive function; dexmedetomidine
Post-traumatic stress disorder (PTSD) refers to the chronic spirit that occurs under severe traumatic stress.
Dysfunction, characterized by increased trauma-related memory and excessive fear of appropriate stimuli, the core symptoms of which include traumatic re-experience, avoidance and emotional numbness, and increased alertness. According to statistics, about 90% of the population experienced traumatic events, of which 5% to 15% can develop into PTSD. For surgical patients, the incidence of PTSD was as high as 71% in patients with intraoperative knowledge. PTSD has a slow course and poor treatment, which places a heavy burden on patients, families and society. Although studies have reported that multiple drugs are effective in treating PTSD, they only partially relieve PTSD symptoms. Dexmedetomidine is widely used in surgery because of its sedative, analgesic, anti-anxiety, inhibition of sympathetic activity, reduction of anesthetic dose and light respiratory depression. Intraoperative awareness is a common complication of anesthesia patients, and studies have shown that dexmedetomidine can reduce the incidence of intraoperative awareness in patients with single lung ventilation. However, whether dexmedetomidine can improve the symptoms of PTSD remains unclear. In this study, we established a model of PTSD and used different doses to investigate whether dexmedetomidine has a dose-dependent effect on PTSD symptoms, providing a reference for clinical treatment.
Materials and Methods:
Animal selection and grouping: 60 male SD rats, 8 to 10 weeks, weighing 240-360 g, were provided by the Department of Comparative Medicine, Nanjing Military Region General Hospital. Animal license number: SCXK (Su) 2011-0003]. They were randomly divided into five groups, 12 in each group: control group (C group), PTSD model group (P group), dexmedetomidine 10 pg/kg group (D1 group), 20 ug/kg group (D2 group), and 40ug/kg group (D3 group). Group C and group P were given normal saline at 1 ml/kg, and dexmedetomidine was administered intraperitoneally at 10, 20 and 40 ug/kg in groups D1, D2 and D3, respectively. Dexmedetomidine is dissolved in physiological saline to concentrations of 10, 20 and 40
Gg/ml, then dosed. Saline and dexmedetomidine were administered immediately after the establishment of the PTSD model for 3 days. PTSD model establishment and conditional fear experiment Pavlov conditional fear PTSD model trains animals through unconditional stimulation (electric stimulation) with conditional stimulation (sound stimulation or environmental stimulation), which causes them to produce fear memory. Conditional stimuli control the fear response; subsequent assessment of the formation and severity of fear memory by detecting the animal's re-exposure to the conditional stimuli [8]. The PTSD model in this experiment was established in the Conditional Fear Experimental Analysis System of Shanghai Xinsoft Information Technology Co., Ltd. The rats in the P group and the D1, D2, and D3 groups were placed on the 0th, 1st, and 2nd days.
In the Jinna box (length 30 cm, width 26 cm, height 22 cm), paired sound stimulation (30 S, 5 kHz, 75 dB) was given after 5 minutes of adaptation, and 5 electrical stimulations were randomly given within the next 15 minutes. (2 mA, 2s). On days 7, 14, and 21, the rats were again exposed to the same environment for 5 min with sound stimulation without electrical stimulation, and the rat's stiffness time was recorded. On day 0, 1, and 2 of group C, only the same sound stimulation was given without electrical stimulation, and the rest of the process was the same.
The open field experiment was conducted on the 23rd day to determine the autonomous activity and anxiety of the rats. The rats were placed in a black open box of 100 cm×100 cm×40 cm, and the bottom edge was divided into 9 grids. Each rat was placed in the grid and the time was 5 min. The total distance of the rats' movement and the time spent in the central compartment were recorded by the data acquisition system. Each rat was wiped with 75% alcohol after the end of the experiment.
On the 25th day of the elevated plus maze experiment, an elevated plus maze experiment was performed to determine the anxiety state of the rats. The elevated cross maze consists of a pair of open loops (10 cm wide and 50 cm long), a pair of closed loops (10 cm wide, 50 cm long, 40 cm high) and a central section (10 cmX 10 cm). The rat was placed in a closed loop from the central area and placed in an elevated cross maze for 5 min. The time during which the rat stayed in the open loop and closed loop was recorded by the data acquisition system (the rat had at least two anterior melons entering the loop). Each rat was wiped with 75% alcohol after the end of the experiment.
On the 27th day of the water maze experiment, a water maze experiment was performed to evaluate the spatial learning and memory ability of the rats. The water maze experiment was carried out in a circular pool of 120 cm in diameter and 50 cm in height. Divide the pool into four quadrants and place the platform in the upper left quadrant. The platform is 10 cm in diameter and 1 cm below the surface. After 4 days of continuous training, the rats were randomly placed in the water from the four different quadrants in the pool wall, and the latency of the platform was found by the data acquisition system. The rat boarded the platform to stop recording. If the rat did not find the platform within 60 s, it was guided to find the platform and placed on the platform for 15 S. The escape latency of the training phase of each group of rats was recorded. On the fifth day, the platform was removed, and the memory of the rats was tested by the space exploration experiment. The percentage of exploration time in the target quadrants of each group was recorded. The water temperature was controlled at (25 ± 1) °C throughout the experiment.
Statistical analysis was performed using SPSS 16.0. The measurement data were expressed as mean ± standard deviation (z ± s), the normal distribution data was analyzed by K-S test, and the non-normally distributed data was analyzed by rank sum test. Comparisons between groups were analyzed by one-way analysis of variance.
Results
Compared with group C, the percentage of stiffness time in group P increased significantly on days 7, 14, and 21, indicating that the PTSD model was successfully modeled. Compared with the P group, the percentage of stiffness in the D1, D2, and D3 groups in the FC was significantly lower (P < 0.05) (Fig. 1).
Compared with group C, the total distance of movement in group P increased and the residence time in central group decreased significantly (P There was no significant difference in the proportion of time between the five groups of rats in the closed loop. Compared with the P group, the proportion of time in the open loop of the D1, D2, and D3 groups was significantly increased (P<0.05) (Fig. 4, 5). Compared with group C, the latency of rats in group P was significantly prolonged, and the percentage of exploration time in target quadrants was significantly reduced (P<0.05). Compared with the P group, the latency of the rats in the D1, D2, and D3 groups was significantly reduced and their percentage of target imaging time was significantly increased (P < 0.05) (Fig. 6, 7). DISCUSSION Clinical studies have shown that dexmedetomidine can make patients with more stable hemodynamics, the incidence of postoperative agitation is significantly reduced, and the quality of life is significantly improved. The occurrence of PTSD is closely related to the previous exposure to traumatic events. Surgery is a traumatic event. Dexmedetomidine can reduce the impact of this traumatic event on patients. However, whether it can improve the symptoms of patients with PTSD needs further study. . In this experiment, dexmedetomidine can improve the anxiety state and cognitive dysfunction of PTSD rats, which showed that the percentage of rat stiffness time was significantly reduced, the total movement distance was shortened and the time spent in the central compartment increased, and the open loop time ratio Increase, the latency of finding the platform decreases and the percentage of exploration time in the target quadrant increases. This study was designed to determine whether dexmedetomidine can improve PTSD symptoms in a new way to treat PTSD. One of the distinguishing features of PTSD is the enhancement of fear memory, which includes stages of acquisition, consolidation, and reproduction. The acquisition of fear memory occurs during the occurrence of conditional fear and unconditional fear in pairs, followed by the consolidation of fear memory. Reproduction refers to a conditional response that reappears according to the conditional stimulus-unconditional stimulus during fear stimulation. Studies have shown that norepinephrine can affect the formation of fear memory in PTSD. When the patient is exposed to an acute stressful environment, there is a high reactivity of the sympathetic-norepinephrine system, and the risk of developing PTSD is also significantly increased. Excitatory a-adrenergic receptors can affect the process of fear memory consolidation in patients with PTSD, significantly improving their anxiety and symptoms of excessive arousal. In addition, Hayama et al [research found that dexmedetomidine can be excited by a. Adrenergic receptors affect the brainstem blue nucleus and interfere with the acquisition of fear memory. In this study, dexmedetomidine reduced fear memory, reduced autonomic activity and improved anxiety in PTSD rats, suggesting that the d-adrenergic receptor agonist dexmedetomidine may be a new method for the treatment of PTSD. Patients with PTSD are often associated with cognitive dysfunction. This study found that dexmedetomidine can reverse the impairment of spatial learning and memory in PTSD rats. This result is similar to previous studies, indicating that dexmedetomidine has neuroprotection. effect. There was no difference in the improvement of PTSD symptoms between the different doses of dexmedetomidine in this experiment. The reason for this is for further study and may be related to the dose given. The general dose of dexmedetomidine in patients with general anesthesia is 10 ug / kg, the maintenance dose is 0.2 ~ 0.4 ug / kg, and the lowest dose we give is 10 ug / kg, follow-up studies need to further find suitable doses to relieve PTSD . In addition, in addition to the adrenergic system, PTSD is also associated with hypothalamic-pituitary-adrenal axis, r-aminobutyric acid, and glutamate signaling pathways. Whether dexmedetomidine alleviates the effects of PTSD symptoms associated with other signaling pathways remains to be further studied. In summary, this experiment shows that repeated administration of dexmedetomidine can significantly alleviate PTSD anxiety and spatial learning and memory dysfunction. 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