|Alternative Title||Factors that influence clozapine tolerance and its central mechanism|
|Place of Conferral||北京|
|Keyword||氯氮平 耐受 用药环境 尼古丁滥用 条件回避反应 内侧前额叶 5-羟色胺|
|Abstract||精神分裂症是一种病因未明的严重精神疾病，目前应用抗精神分裂药物改善症状是治疗精神分裂症的主要手段。氯氮平是国内目前临床使用最多的抗精神分裂症药物，并以其独特的疗效被誉为治疗精神分裂症的“金标准”，但其作用机制尚不清楚。在条件回避反应（conditioned avoidance response，CAR）模型中，有假设认为抗精神分裂药物通过抑制条件刺激（声音）的动机突显，而产生对大鼠条件回避反应的抑制作用。本论文首先通过改变大鼠在CAR 模型中的测试次数，对氯氮平及奥氮平治疗精神分裂症的行为机制进行研究。我们推测越多的条件刺激呈现次数使得氯氮平或奥氮平有更多机会抑制条件刺激的动机突显，从而使大鼠的条件回避反应下降更快。给予三组大鼠相同剂量的氯氮平（或奥氮平），分别在3、10 和40-trial 条件下测试，连续6 天。结果发现40 和10-trial 组大鼠条件回避反应比3 -trial 组下降更快。表明氯氮平和奥氮平通过抑制条件刺激的动机突显而降低大鼠条件回避反应，验证了抗精神分裂药物可能通过降低某些刺激（如，异常的想法和感觉）的动机突显起效。|
同时，我们还观察到在CAR 模型中重复氯氮平给药后出现耐受。此耐受现象的产生不仅源于药物本身的药理作用，还受到用药环境、用药后的行为反应（测试）、联合用药等因素影响。对氯氮平耐受的深入研究有利于阐明氯氮平抗精神分裂的作用机制，提高临床疗效。因此，我们采用CAR 模型和phencyclidine 诱导的快速运动行为模型（简称PCP 模型），重点研究了用药环境、行为反应和尼古丁滥用对氯氮平耐受的影响，以及氯氮平耐受的中枢神经受体机制。
采用在两个模型中相互转移的实验范式，研究了用药环境对氯氮平耐受的调控作用。大鼠先在CAR（或PCP）模型中连续5 天给予氯氮平（2.5-10.0 mg/kg），后转移到PCP（或CAR）模型中进行另外5 天的氯氮平耐受表达测试，再回到最初的模型中进行氯氮平耐受表达测试。结果发现当大鼠从CAR 模型转移到PCP 模型时，逐渐出现氯氮平耐受；相反，当大鼠从PCP 模型转移到CAR 模型时，氯氮平耐受逐渐消失。表明用药环境可以调控氯氮平耐受的产生和表达。
采用药物-药物条件化范式，在CAR 模型中研究了尼古丁与氯氮平相互作用的行为机制。结果表明尼古丁（0.4 mg/kg）与氯氮平（5.0 和10.0 mg/kg）联用在一定程度上加强了氯氮平对条件回避反应的抑制；前期尼古丁（0.4 mg/kg）联合氯氮平（10.0 mg/kg）药物处理显著减弱氯氮平耐受的表达。
运用脑微量注射技术结合行为药理学的方法，在CAR 模型中考察了伏隔核壳部和内侧前额叶多巴胺和5-羟色胺（5-HT）系统对氯氮平耐受的调控。急性或慢性条件下，向大鼠伏隔核壳部或内侧前额叶内分别注射D2 受体激动剂quinpirloe （ 0.0, 1.0, 10.0 μg/side ） 或5-HT2A 受体激动剂2,5-dimethoxy-4-iodo-amphetamine（DOI，0.0、5.0、25.0 μg/side），同时外周给予氯氮平（10.0 mg/kg）。结果发现，慢性条件下内侧前额叶内注射高剂量DOI可消除氯氮平耐受。另外，急性内侧前额叶内注射quinpirloe 能加强氯氮平对条件回避反应的抑制；伏隔核壳部注射DOI 和quinpirloe 对氯氮平的作用均无影响。
|Other Abstract||Schizophrenia is an etiology unknown mental disorder, and antipsychotic drugsare the main medications used to treat schizophrenia. Clozapine is referred to as thegold standard for the treatment of schizophrenia and its use is much higher than other antipsychotics in China. How clozapine works in the brain and changes the psychological processing to achieve its therapeutic effect is still unknown. Our preliminary work shows that antipsychotic drugs suppress animals' ability to avoid an aversive stimulus in the conditioned avoidance response (CAR) model. This behavioral effect is thought to reflect antipsychotic activity and is suggested to be mediated by a drug's action in attenuating the motivational salience of a conditioned stimulus (CS). In this thesis, we tested whether clozapine and olanzapine act through this behavioral mechanism by manipulating the number of avoidance test trials. We reasoned that more CS trials in the presence of clozapine or olanzapine would afford the drug more opportunities to decrease the motivational salience of the CS, thus avoidance decline would be greater with the increase of CS trials in each test session.|
In two separate experiments, rats were tested under clozapine (5.0 mg/kg, sc), olanzapine (0.5 mg/kg, sc) or vehicle (sterile water) for 6 consecutive days in three CS trial conditions (i.e. 3, 10, and 40 CS trials per session). Results show that the anti-avoidance effect of clozapine and olanzapine were potentiated by the increase of number of CS trials in the test sessions, as the clozapine-treated or olanzapine-treated rats tested under the 40-trial or 10-trial condition had significantly lower avoidance and faster decline across-sessions than those tested under the 3-trial condition. These findings suggest that the clinical efficacy of a drug can be enhanced by increasing the exposure of symptoms in the presence of the drug.
We also observed that clozapine can be singled out based on its tolerance effect (other drugs cause a sensitization) in the CAR model. The main part of the present study investigated the factors (contextual control, nicotine abuse) affecting clozapine tolerance and its central mechanisms in the CAR and phencyclidine (PCP)-induced hyperlocomotion models.
By using a validated across-model transfer paradigm, rats were first repeatedly treated with clozapine (2.5-10.0 mg/kg, sc) in the CAR model or PCP (1.6 mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another 5 days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response.
Next, we used a drug-drug conditioning paradigm to examine the interaction between nicotine and clozapine in the CAR model. During the 7 drug test days, combined treatment with nicotine potentiated (to a lesser extent) the anti-avoidance effect of clozapine. In the clozapine challenge test, prior combined treatment of nicotine 0.04 mg/kg with clozapine 10 mg/kg attenuated clozapine-induced tolerance. These findings suggest that the interaction between nicotine and clozapine is dose-dependent and needs a long-term to manifest.
Third, we microinjected 2,5-dimethoxy-4-iodo-amphetamine (DOI, a 5-HT2A agonist, 5.0 or 25.0 μg/side) or quinpirole (a dopamine D2receptor agonist, 1.0 or 10.0 μg/side) into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs) and tested their impacts on the acute and repeated effects of clozapine (10 mg/kg, sc ) in the CAR model. Microinjection of DOI at 25.0 μg/side into the mPFC did not affect the acute avoidance suppressive effect of clozapine or its tolerance development, but completely abolished the expression of clozapine tolerance as assessed in a subsequent challenge test. Conversely, microinjection of quinpirole into the mPFC enhanced the acute avoidance suppressive effect of clozapine. Neither microinjection of quinpirole or DOI into the NAs had any effect.
In conclusion, clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response, as well as combined nicotine used. The expression of clozapine tolerance is primarily mediated by clozapine’s antagonist action on 5-HT2A in the mPFC. The therapeutic effects of clozapine may be subject to the modulation by various environmental and behavioral factors, as well as polypharmacy with other drugs which act on 5-HT systems.
|冯 敏. 抗精神分裂药氯氮平耐受的影响因素及中枢神经机制[D]. 北京. 中国科学院研究生院,2013.|
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