Dopamine-related Mechanism In Different Susceptibility Of Heroin Addiction In Sprague-Dawley Rats

Objective:To establish the rats model of different susceptibility of heroin-induced conditioned place preference(CPP) and investigate the effects of heroin on dynamic changes and differences of extracellular DA and DOPAC concentrations in the nucleus accumbens shell between the different susceptibility rats on the addiction phase and withdrawal phase and the relations between the responsivity to novel environment and the susceptibility to heroin addiction.Methods:152 male Sprague-Dawley (SD) rats were carried out open-field experiments in order to investigate their response to novel environments. And then rats were randomly assigned into heroin exposure group (n=120) and saline control group (SC, n=32). Herion was administered subcutaneously twice a day for seven days according to an escalating dose (ED) schedule, from 0.5 mg/kg per dose at the first day, to the 3.5 mg/kg per dose at the seventh day increasing 0.5 mg/kg per dose per day. Rats in control groups were correspondingly injected with same volume saline. The experiment group were re-classified into two groups according to the numerical value of the CPP-Pre(the testing score minus that of the pretest):high preference group(HP group) and low preference group(LP group),each group account for 30% of the total rats. SC Group 8, HP, LP group 12 rats respectively were operated cerebral stereotactic surgery, and In vivo microdialysis was used to examine dynamic changes in extracellular DA and DOPAC in AcbSH (30min and 1,3,7,14 days after the last injection respectively) in freely moving rats. Analyses of dialysate samples were performed by High-Performance Liquid Chromatography with a Coulometric Electrode Array SystemResults:1. The test scores of the CPP is significant higher than the pretest scores in the total rats after exposed to heroin. Compared to LP group, the HP group have more higher scores of open field test. The test scores of the CPP-Pre was significant positive correlations with the results of open-field test in all groups.2.Compared with SC group rats, chronic heroin exposure increased extracellular DA and DOPAC significantly in AcbSH at 30min after the last injection, but there were significant low level DA in heroin exposure group on 1,3 days after the last injection.3. Compared with LP group rats, HP rats displayed a higher heroin-induced increase in DA concentration at 30min after the last heroin injection but not on withdrawal phase, and higher DOPAC and DOPAC/DA ratios continued to exist until the 14th day after the last injection.Conclusions:1. The model of different susceptibility to heroin-induced CPP can be successfully established by the chronic heroin exposure.2. The individual's response to novel environment is a reliable predictor of its susceptibility to develop heroin dependence.3. Heroin exposure can induce DA release and metabolism increase in AcbSH.4. Heroin high preference rats have a higher DA system responsivity in AcbSH, which is possibly one of the neural biochemical basics of differences in susceptibility to heroin addiction. Objective:To investigate the time-point dopamine D2 receptor(D2R) and dopamine transptor(DAT) protrin expression located in the prefrontal contex(PFC), shell of accumbens nucleus (AcbSH) and ventral tegmental area(VTA) in high and low susceptibility to heroin addiction rats,and to explore the possible mechanism lead to the different susceptibility.Methods:The D2R and DAT protein expression of high-and low-preference group and saline control group rats were detected with immunohistochemical method in various brain regions at 30 minutes and 1,3,7,14 daysafter the last injection of heroin respectively.Results:1. At all testing time-points of various brain regions,the D2R protein expression of heroin exposure group rats were significantly lower than those of saline control group, and increased gradually after withdrawal, but D2R protein expression was still significantly lower than that of the control group on 14th days after the last injection.2. At all testing time-points of various brain regions, the D2R protein expressions of HP rats were significantly lower than those of the LP rats.3. At all testing time-points of various brain regions,the DAT protein expressions of heroin exposure group rats were significantly lower than those of saline control group, and increased gradually after withdrawal, but the difference between heroin exposure group and saline control group was no significant after 7th days of the last injection.4. At all testing time-points of various brain regions, the DAT protein expressions were no significant difference between HP and LP group.Conclusions:1. D2R of the rats appears lasting down-regulation in the various addiction-related brain regions after chronic heroin exposure.2. Different individuals have different D2R sensitivity or receptor levels, and lower D2R related to the high susceptibility to heroin.3. DAT of the rats appears lasting down-regulation in the various addiction-related brain regions after chronic heroin exposure 4. Susceptibility to heroin addiction may not be directly related to the expression of DAT.