抑郁行为及不同抑郁亚型的多巴胺机制研究

The conceptualization of “depression” as a heterogenous disease has been widely accepted by most researchers. However, controlled experiments are rather sparse. To date, most studies demonstrated that animals with helplessness, a widely recognized behavioral index of “depression” also show varied comobidity expressions of other emotional behaviors, such as hightened or lightened anxiety level compared with controls. This means that distinct subtypes of “depression” may exist, in which different neural mechanisms may play roles. The present study aims to explore the possibility of behaviorally categorizing two depressive subtypes, referred as anxious helplessness and non-anxious helplessness, respectively. Then, by using RT-PCR, the dopamine D1, D2, D3 receptors mRNA expressions in medial prefrontal cortex (mPFC) and nucleus accubems (NAc) were quantified. The main findings are described as belows: 1. Uncontrollable shock could readily induce helpless behavior in shocked animals as a whole but with salient individual differences. Prior inescaoable shock induces subsuquent helplessness in approximately 40% shocked animals, while the other animals showed no sign of helpless expression, and were classified as non-helplessness. 2. Among helpless animals, the “subtype” of anxious helpless and non-anxious helpless could be identified according to the anxiety level evaluated by elevated plus maze. 3. D3 receptors mRNA expressions in the mPFC and NAc were increased in stressed animals after uncontrollable shock treatment. At the meanwhile, significant lower expressions of D2 receptors in the mPFC and NAc, and much lower expressions of D1 receptors in the mPFC were found in rats that did not become helpless after stress. In contrast, no significant difference between helpless and control animals was found in D1/D2 receptors mRNA expressions. 4. Based on above mentioned results, the up-regulation of D3 receptors in the mPFC and NAc may reflect a generalized effect of exposure to uncontrollalbe shock. While the down-regulation of D1\D2 receptors in the mPFC and decreased expression of D2 receptors in the NAc may be associated with adaptive or protective mechnisms which protecting animals from helplessness after uncontrollable shock treatment. 5. Futhermore, a significant negative relationship was found between anxiety level and D1 receptors expressions in the mPFC in helpless animals. Compared to the non-anxious helpless and control rats, the D1 receptors mRNA of anxious helpless rats were down-regulation in the mPFC. The present study indicated that the D1 dopamine receptor gene is associated with co-morbid depression and anxiety.

影响吗啡动物行为效应的因素及其机制

Credible and stable animal behavioral models are necessary to research the mechanisms of addiction in vivo, especially to study the relationship between memory or stress and drug addiction, which has been one of the focuses in this field. So the object of this study was to observe the influences of several factors on the behavioral effects of morphine shown in the paradigms of conditioned place preference (CPP) and locomotor activity (LA), and to explore the effects of adrenalectomy on LA induced by morphine in rats. In addition, the cortexes of rats were examined, which were exposed to chronic administration of several doses of morphine with or without foot shock. Moreover, a new behavioral model was built to quantify the motivation of drug seeking. The results showed that CPP was more sensitive to low dose of morphine than to high dose. The period of experiment could be shortened by increasing the training times everyday, whereas in this way the dose of morphine should be low enough to avoid the impact between the near two exposures to morphine. Effects of chronic administration of morphine on LA in rats were dose- and time- dependent, which supplied evidence to choose parameters in other behavioral models. The results obtained by the simplified LA paradigm showed that hyperactivity of low dose of morphine following hypoactivity, and naloxone had no effects on LA but blocked the locomotion effects of morphine. Obvious effects of morphine on LA of rats might depend on a reasonable level of plasma corticosterone, which may determine individual vulnerability to drug addiction. Stress may also potentiate the vulnerability by aggravating damage to cortex of rats induced by drug dose-dependently, which is suggested by the results of histological examination. The result that frontal and temporal cortexes and hippocampus were injured suggests that there may be a close relationship between memory and drug addiction. It was showed that the new behavioral model on the basis of Morris water maze might be used to quantify the motivation of drug-craving.

隔区损毁对大鼠空间认知能力的影响及其在Morris迷宫中搜索策略的比较

Separate groups of rats with bilateral or unilateral lesions in septum were tested for acquisition and retention of the Morris water maze spatial cognitive task. Some of the animals in each lesion group received preoperative training in the task. Other animals in each group received no preoperative training. The results indicate that although both lesions lead to a spatial cognitive impairment in both the acquisition and retention of the task, the animals with bilateral lesions were more severely impaired than were the animals with unilateral, as indicated by quantitative measure. Searching strategies were used as an index to eximine the qualitative difference in the animals swim be havior, we found that the unilateral damaged animals still tend to use "mapping" strategies to solve the task as in the case of control groups but the accuracy is lower. The searching strategies used by the bilateral damaged animals showed complex patterns. The acquisition group with bilateral tend to use random and paratic strategies, however, the retention group with bilateral had a tendacy to use paratic and taxic strategies. The difference between searching strategies and its dynamic, change possibly suggest that other cognitive processing systems play an role in the processing of information about the task.

樟柳碱和石杉碱甲对学习和记忆的影响及其有关机制的研究

Two experiments were designed to examine the role of the cholinergic agents, anisodine and huperzine A, and related mechanisms. In experiment 1, the effects of anisodine and huperzine A on rat performance in Morris water maze were observed. It was found that the drugs injected before daily training had significant effect on performance of place navigation task and transfer test, while the drugs injected after daily training, before retest and overtraining had no such effect. the results indicated that the drugs, which only have effects on reference memory related to cognitive mapping strategy, may mediate the acquisition process of memory. In experiment 2, the spontaneous hippocampol neuronal activities and the effects of the drugs on them in awake rabbits were observed. The results showed that anisodine had significant inhibitory effect on the activities, the opposite effect was found in huperzine A. Furthermore, sensory stimulation and administration of huperzine A have similar effects. It was sujested that hipppocampus be directly relavent to transmission of information to memory storage system, in which the role of central cholinergic system is critical.