School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Psychopharmacology (Berl). 2019 Apr;236(4):1245-1253. doi: 10.1007/s00213-018-5130-2. Epub 2018 Dec 10.
Social withdrawal is a core feature of the negative symptoms of schizophrenia. Currently available pharmacotherapies have only limited efficacy towards the negative symptoms, i.e., there is a significant unmet medical need in the treatment of these symptoms.
We wanted to confirm whether selective adrenergic α receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an α AR antagonist to another putative therapeutic alternative, an α nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics.
Here, we used acute PCP administration and modified a protocol for testing social interaction deficits in male Wistar rats and then used this model to compare the effects of an α AR antagonist (ORM-13070 0.3 and 1.0 mg/kg s.c.) with an α nAChR partial agonist (EVP-6124 0.3 mg/kg s.c.) and three atypical antipsychotics (clozapine 2.5 mg/kg i.p., risperidone 0.04 and 0.08 mg/kg s.c., olanzapine 0.125 and 0.5 mg/kg s.c.) on social interaction behavior.
Acute PCP (1.5 mg/kg s.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective α AR antagonist significantly ameliorated PCP-induced social interaction deficits. In contrast, neither the partial α nAChR agonist nor any of the three atypical antipsychotics were able to reverse the behavioral deficits at the selected doses.
Our findings confirm that α AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia.
社会退缩是精神分裂症阴性症状的核心特征。目前可用的药物治疗对阴性症状的疗效有限，即这些症状的治疗存在显著未满足的医疗需求。
我们想确认选择性肾上腺素能 α 受体 (AR) 拮抗剂治疗是否能改善急性苯环己哌啶 (PCP) 诱导的大鼠类似精神分裂症的社交互动缺陷，并比较 α AR 拮抗剂与另一种潜在治疗选择，即 α 烟碱型乙酰胆碱受体 (nAChR) 部分激动剂的效果，以及与三种常用的非典型抗精神病药相比。
在这里，我们使用急性 PCP 给药并修改了一种用于测试雄性 Wistar 大鼠社交互动缺陷的方案，然后使用该模型比较 α AR 拮抗剂 (ORM-13070 0.3 和 1.0 mg/kg sc) 与 α nAChR 部分激动剂 (EVP-6124 0.3 mg/kg sc) 和三种非典型抗精神病药 (氯氮平 2.5 mg/kg ip、利培酮 0.04 和 0.08 mg/kg sc、奥氮平 0.125 和 0.5 mg/kg sc) 在社交互动行为上的效果。
急性 PCP (1.5 mg/kg sc) 产生了强大且可重复的社交互动行为缺陷，而不影响运动活动。选择性 α AR 拮抗剂显著改善了 PCP 引起的社交互动缺陷。相比之下，部分 α nAChR 激动剂或三种非典型抗精神病药在所选剂量下均不能逆转行为缺陷。
我们的发现证实，α AR 拮抗作用是治疗精神分裂症阴性症状的潜在机制。
