Sparkman Nathan L, Li Ming
Department of Psychology, University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0308, USA.
Behav Pharmacol. 2012 Oct;23(7):658-68. doi: 10.1097/FBP.0b013e328358590d.
Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug-drug interactions. However, the pharmacological and behavioral mechanisms underlying drug-drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug-drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia.
精神分裂症患者常常伴有焦虑和抑郁症状，因此需要使用多种心理治疗药物进行治疗。这种联合用药的做法增加了药物相互作用的可能性。然而，精神分裂症中药物相互作用的药理和行为机制仍知之甚少。在本研究中，我们采用临床前研究方法，研究了一种鲜为人知的行为机制——氟哌啶醇（一种典型抗精神病药物）或奥氮平（非典型抗精神病药物）与西酞普兰（一种选择性5-羟色胺再摄取抑制剂）之间的药物-药物条件反射（DDC）。使用大鼠双向条件回避反应范式来测量抗精神病活性，并确定DDC如何改变该模型中的抗精神病疗效。在获得回避反应后，将大鼠随机分配接受溶剂、西酞普兰（10.0mg/kg，腹腔注射）、氟哌啶醇（0.05mg/kg，皮下注射）、奥氮平（1.0mg/kg，皮下注射）、氟哌啶醇与西酞普兰联合用药或奥氮平与西酞普兰联合用药治疗，共进行七次回避测试。与单独使用抗精神病药物治疗相比，在七次药物测试期间，西酞普兰联合治疗增强了奥氮平或氟哌啶醇（程度较轻）的抗回避作用。此外，西酞普兰与氟哌啶醇或奥氮平的重复配对导致西酞普兰表现出一种新获得的回避干扰效应。这种效应具有情境特异性，因为在回避测试情境（即饲养笼）之外，西酞普兰与氟哌啶醇或奥氮平配对不会出现这种效应。这些发现表明，同时进行抗抑郁和抗精神病治疗可能会引发一个遵循一般巴甫洛夫联想条件反射原则的DDC过程。它们还表明，辅助使用西酞普兰治疗可能会增强氟哌啶醇和奥氮平在治疗精神分裂症中的抗精神病疗效。
