Wadenberg Marie-Louise G, Manetti Dina, Romanelli Maria Novella, Arias Hugo R
Linnaeus University, Kalmar, Sweden.
Department of Neurosciences, Psychology, Drug Research and Child Health Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Italy.
Behav Brain Res. 2017 Aug 30;333:129-134. doi: 10.1016/j.bbr.2017.07.001. Epub 2017 Jul 3.
Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer's drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity. Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective α7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that α7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, α7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the antipsychotic efficacy of atypical antipsychotics.
精神分裂症（SCH）患者在注意力表现方面存在认知障碍。已证明，阿尔茨海默病药物加兰他敏（GAL）和PAM - 2等α7烟碱型乙酰胆碱受体（nAChRs）的正变构调节剂具有促认知特性。然而，当作为治疗精神病症状所需的抗精神病药物的辅助用药时，这些特性是否会丧失或可能妨碍抗精神病疗效，目前尚不清楚。我们在此使用成年雄性Wistar大鼠，研究了以下影响：a）单独使用GAL或与抗精神病药物利培酮（RISP）联合使用，对急性苯环己哌啶（PCP）诱导的注意力转换（ASST）测试中的缺陷的影响；b）单独使用PAM - 2以及与RISP联合使用，在条件性回避反应（CAR）测试中的抗精神病活性。急性PCP在维度外转换（EDS）表现中产生了选择性且显著的类似SCH的损伤，而GAL可使其完全逆转。当与RISP联合使用时，GAL逆转PCP诱导的EDS损伤的能力并未受到阻碍，这表明GAL与低剂量RISP的组合可用于改善SCH中的认知障碍。用选择性α7 nAChR拮抗剂甲基lycaconitine（MLA）预处理可完全阻止GAL引起的逆转，支持α7 nAChRs参与此过程的概念。另一方面，单独使用PAM - 2对CAR没有影响，但与RISP一起给药时，虽未显著增强，但增强了RISP的抗精神病样作用。总之，α7正变构调节剂除了可减轻SCH患者中观察到的认知障碍外，还可能增强非典型抗精神病药物的抗精神病疗效。
