抗精神病药长期使用引起的敏化和耐受效果及其相关机制

Antipsychotic-induced behavioral sensitization and tolerance and the related neurobiological mechanisms

抗精神病药已经有60余年的使用历史,应用于治疗精神分裂症及其他精神疾病伴随的幻觉、妄想症等症状。临床和动物研究都提示抗精神病药的长期使用会导致个体对药物的敏感性发生变化,即产生敏化或耐受效果。在急性用药情况下,多种临床常用抗精神病药作用都可以抑制条件躲避反应和苯环利定诱发的运动增强。以这两个动物模型为基础,我们建立了研究抗精神病药敏化和耐受的行为学范式。以此为基础,我们一系列研究发现长期用药可导致药物敏感性加强或减弱,即敏化或耐受。并进一步考察了敏化和耐受的行为学特征及其神经生物学基础。结果表明大多数抗精神病药长期用药会导致敏化,这些药物包括:奥氮平、阿塞那平、阿立哌唑、利培酮、氟哌啶醇等,而只有氯氮平会导致耐受。在行为学层面,敏化和耐受在不同抗精神病药间存在迁移效应,并且可以长期保持。在受体机制方面,我们发现多巴胺D_2受体和五羟色胺2A(5-HT_(2A))受体参与调控敏化和耐受。在中枢机制方面,发现内侧前额叶以及中脑边缘系统核团参与调控敏化和耐受。

Antipsychotics are the medications that are used to treat schizophrenia.How they work to achieve their therapeutic effects has not been adequately addressed.Like other psychoactive drugs,repeated administration of these drugs can induce various clinically relevant sensitization and tolerance effects in many behavioral domains.In recent years,we have used the conditioned avoidance response（CAR） and phencyclidine（PCP）-induced hyperlocomotion,two models with high predictive validity for antipsychotic efficacy and examined the long-term treatment effects of antipsychotic drugs.In this paper,I discuss our animal work on the behavioral characteristics and neuroreceptor mechanisms of antipsychotic sensitization and tolerance,as well as their developmental impacts from adolescence into adulthood.I highlight our work on the roles of dopamine D2 receptors and serotonin 5-HT2 A receptors in the medial prefrontal cortex and nucleus accumbens in the induction and expression of antipsychotic sensitization and tolerance.