According to the United State Diagnostic and Statistical Manual Mental Disorders DSM-IV, compulsive drug-taking behavior is one of the most important diagnostic criterias in drug addiction. Previous studies suggest that the rats received escalated high-dose drug pretreatment perform compulsive drug-taking behavior, which is measured by abnormally enhanced drug-seeking motivation, continued drug seeking and taking despite adverse consequences, as well as compulsive drug-seeking motivation. Continued drug-seeking behavior even when the drug is known to be unavailable is one of the most important behavioral indicators of compulsive drug-seeking motivation. One could become drug-addictive when the drug-seeking motivation is no longer limited by the drug-paired environment. And compulsive drug-taking behavior is accompanied by the neuroplasticity change of mesolimbic dopamine pathway and nigro-striatal pathway. The present study would probe (1) whether rats pretreated with escalati high-dose or fixed low-dose morphine could express non-context-specific behavioral sensitization when exposed to morphine challenge after 1-week abstinence period; (2) By double labeling immunohistochemistry of Tyrosine hydroxylase (TH) and Fos protein, we disclose the plasticity of neuronal activity in ventral tegmental area and substantia nigra of rats response to morphine challenge after pretreated with morphine or saline. TH is limiting enzyme in dopamine synthesis which is distributed in the cytoplasm and neuronal synapses. It is usually used to label dopaminergic neurons in specific brain regions. Fos protein is a sign of neuronal activity which expresses in the nucleus. Double labeling immunohistochemistry of TH and Fos protein can detect the activity of dopaminergic and nondopaminergic neurons in ventral tegmental area and substantia nigra which may underline the neural mechanism of drug addiction. The main findings are described as bellows: (1) After pretreated by escalated high-dose morphine, rats could express behavioral sensitization without limitation of drug-paired environment. The sensitized behavior could be express in a novelty environment and could not be inhibited by the distinct morphine-unpaired environment. (2) If pretreated by fixed low-dose morphine, rats could just express the behavioral sensitization in morphine-paired environment and the sensitized behavior would be inhibited in the distinct morphine-unpaired environment. (3) The results of immunohistochemistry showed that the activity of dopaminergic neurons in midbrain hadn’t significant change in all groups after morphine challenge, while Fos protein expression in the lateral substantia nigra pars reticulate is significantly higher in the escalated high-dose morphine pretreated rats. In conclusion, pretreatment with escalated high-dose morphine could make rats become compulsive drug-seeking. And the neuroplasticity change of the lateral substantia nigra pars reticulate and it’s neural pathway may involved in the neural mechanisms in compulsive drug-seeking.
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