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利培酮对潜伏抑制的破坏与增强作用:非典型抗精神病药物作用的潜伏抑制模型

Disruption and potentiation of latent inhibition by risperidone: the latent inhibition model of atypical antipsychotic action.

作者信息

Weiner Ina, Schiller Daniela, Gaisler-Salomon Inna

机构信息

Department of Psychology, Tel Aviv University, Tel Aviv 69978, Israel.

出版信息

Neuropsychopharmacology. 2003 Mar;28(3):499-509. doi: 10.1038/sj.npp.1300069. Epub 2002 Sep 23.

Abstract

Latent inhibition (LI), that is, retarded conditioning to a stimulus following its nonreinforced pre-exposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Potentiation of LI by antipsychotic drugs (APDs) given in conditioning, under conditions that do not lead to LI in controls, is a well-established index of antipsychotic activity. Recently, we have shown that the atypical APD, clozapine, in addition disrupts LI if administered in pre-exposure, under conditions that lead to LI in controls. This study demonstrates the same behavioral profile for the atypical APD risperidone. LI was measured in a thirst-motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone previously paired with a foot shock in rats that received nonreinforced exposure to the tone prior to conditioning (pre-exposed (PE)) and rats for whom the tone was novel (non-pre-exposed (NPE)). We show that under conditions that did not yield LI in vehicle controls (40 pre-exposures and five conditioning trials), risperidone (0.25, 0.5, and 1.2 mg/kg) led to LI when administered in conditioning. Under conditions that led to LI in vehicle controls (40 pre-exposures and two conditioning trials), risperidone (0.25, 0.5, and 2.5 mg/kg) abolished LI when administered in pre-exposure; the latter effect was not evident with haloperidol. In addition, the effects of risperidone administered in both the pre-exposure and conditioning stages were dose-dependent so that the pre-exposure-based action was manifested at lower but not at higher doses. It is concluded that atypical APDs exert in the LI model a dual pattern of effects, which enables detection of their 'typical' action (conditioning-based LI potentiation) as well as a dissociation from typical APDs by their 'atypical' action (pre-exposure-based LI disruption). It is suggested that the former and latter effects are subserved by D2 and 5HT2A antagonism, respectively.

摘要

潜伏抑制(LI),即对刺激进行非强化性预暴露后,其条件反射形成受到延迟,在部分精神分裂症患者亚组以及苯丙胺处理的大鼠中会受损。在对照组不会产生潜伏抑制的条件下,在条件反射过程中给予抗精神病药物(APD)增强潜伏抑制,是抗精神病活性的一个公认指标。最近,我们发现,非典型抗精神病药物氯氮平在预暴露阶段给药时,在对照组会产生潜伏抑制的条件下,也会破坏潜伏抑制。本研究证明非典型抗精神病药物利培酮具有相同的行为特征。通过比较在条件反射前接受音调非强化暴露(预暴露(PE))的大鼠和对音调陌生(未预暴露(NPE))的大鼠对与足部电击配对的音调的饮水抑制情况,在口渴动机的条件性情绪反应程序中测量潜伏抑制。我们发现,在载体对照组中未产生潜伏抑制的条件下(40次预暴露和5次条件反射试验),利培酮(0.25、0.5和1.2mg/kg)在条件反射过程中给药时会导致潜伏抑制。在载体对照组中产生潜伏抑制的条件下(40次预暴露和2次条件反射试验),利培酮(0.25、0.5和2.5mg/kg)在预暴露阶段给药时会消除潜伏抑制;氟哌啶醇未出现后一种效应。此外,利培酮在预暴露和条件反射阶段给药的效应均呈剂量依赖性,因此基于预暴露的作用在较低而非较高剂量时表现出来。结论是非典型抗精神病药物在潜伏抑制模型中发挥双重效应模式,这使得能够检测其“典型”作用(基于条件反射的潜伏抑制增强)以及通过其“非典型”作用(基于预暴露的潜伏抑制破坏)与典型抗精神病药物相区分。提示前者和后者效应分别由D2和5HT2A拮抗作用介导。

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