Study On The Role Of Ventral Tegmental Area In Metham-phetamine-enhanced Aggressive Behavior In Mice

Objective: This project is based on the resident-intruder model to observe the effect of methamphetamine(METH)on pathological aggressive behavior,focus on dopamine neurons in the ventral tegmental area(VTA)of the midbrain.To explore the mechanism of central targets and cytological of METH-enhanced aggressive pathological behavior in mice and the role of real social factors such as age,gender,and social class in this process.Our study will provide a theoretical basis for the forensic identification on METH abuserelated malignant injury cases.Methods:1.Constructing a paradigm of mouse aggression using a resident-intrude model,METH(1,3,10 mg/kg)was injected intraperitoneally.To observe the effect of METH on aggressive behavior.2.Mice of different age,gender and social class were used to construct the resident-intrude model,1 mg/kg METH was injected intraperitoneally.To observe the effect of age,gender and social class in METH enhances aggressive behavior in mice.3.Constructing a paradigm of mouse aggression using a resident-intrude model,and METH was injected intraperitoneally(10 mg/kg,4 times/day for 3days).After 7 days of withdrawal,changes in aggressive behavior were observed in METH-exposed mice.4.The activation of VTA neurons in METH-exposed mice was observed by c-Fos immunofluorescence staining with dopamine transporter(DAT)tags.Inhibition of VTA neuronal excitability by VTA microinjection of potassium channel opener Retigabine(RTG)to elucidate the role of VTA neuron in METH-enhanced aggressive behavior in mice.Results:1.Using the resident-intrude mouse aggressive behavior model.The incidence of aggression,number of attack and latency of initial attack of 1mg/kg METH-exposed mice were not significantly changed compared with the control group,while the total duration of attack was significantly increased.The latency of initial attack was significantly higher and the number of attack and the total duration of attack were significantly lower in the 3 mg/kg METH-exposed mice group compared to the 1 mg/kg METH-exposed group.After 10 mg/kg METH exposed,the mice showed obvious stereotyped behavior and the incidence of aggressive behavior were significantly lower than that of 1 mg/kg METH-exposed groups;2.Mice of different age(8,12,16,20W)were intraperitoneally injected with METH and the control group was given an equal volume of saline.The results of two-way ANOVA showed that both age and METH intraperitoneal injection had significant effects on the latency of initial attack,the number of attack and total duration of attack,but there was no interaction between them on the latency of initial attack,the number of attacks,while there was a significant interaction on the total duration of attack.Post hoc analysis showed that in the control group,compared to 8W mice,12 W mice had a significantly lower the latency of initial attack and a significantly higher number of attacks;16W mice had a significantly lower the latency of initial attack and a significantly higher the number and length of attack.However,there were no significant differences between 20 W mice and 8W mice in the latency of initial attack,the number of attacks and total duration of attack.Compared with the control mice at the same age,METH intraperitoneal injection significantly increased the number and total duration of attack in 12 W mice and significantly increased total duration of attack in 16 W mice;however,the number of attacks and total duration of attack in 8W and 20 W mice were not significantly different from those in the control mice;3.Female mice were injected intraperitoneally with 1 mg/kg METH and the control group was given an equal volume of saline.The results showed that no aggressive behavior occurred in the control mice,and METH-exposed group did not increase the incidence of aggressive behavior in female mice;4.The mice were divided into two groups of high and low social class by tube test and then METH was injected intraperitoneally,the control group was given equal volume saline.The results showed no significant difference in aggressive behavior between the high and low social class in control group.But in the METH-exposed group,the number of attack and the total duration of attack were significantly higher in the high social class group than in the low social class group;5.Using the resident-intrude aggressive behavior model.After chronic 10mg/kg METH-exposed and withdrawal for 7 days,the latency of initial attack was significantly decreased,the number of attacks and the total duration of attack were significantly increased,compared with the control group;6.Acute intraperitoneal injection of 1 mg/kg METH significantly activated VTA neurons in mice.Microinjection of RTG,a potassium channel opener,into the VTA significantly reduced the total duration of attacks and average duration of attack in mice.Conclusions:1.1 mg/kg METH acute exposure enhanced aggressive behavior in mice.10 mg/kg METH acute exposure reduced the incidence of aggressive behavior in mice.10 mg/kg METH subacute intraperitoneal injection and withdrawal enhances aggressive behavior in mice.2.Acute exposure to 1 mg/kg METH significantly increased aggression in 12 and 16-week-old mice.The aggressive behavior of mice of high social class was significantly higher than that of mice of low social class after 1 mg/kg METH intraperitoneal injection.3.Inhibition of VTA neuronal excitability reduces enhanced aggression in 1 mg/kg METH-exposed mice.