Secretin Effects on Cerebellar-Dependent Motor Learning in Schizophrenia
Secretin Effects on Cerebellar-Dependent Motor Learning in Schizophrenia
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DOI：
10.1176/appi.ajp.2008.08040597
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发表时间：
2009-04-01
影响因子：
17.7
通讯作者：
Shekhar, Anantha S.
中科院分区：
文献类型：
--
作者：
Bolbecker, Amanda R.;Hetrick, William P.;Shekhar, Anantha S.
目的：精神分裂症患者普遍存在的认知缺陷是导致该疾病患者残疾的主要原因。其中一项缺陷是有效联想学习的丧失，这可以通过眨眼调节程序轻松评估。作者检查了促胰液素（原型 B 族 G 蛋白偶联受体的激素激动剂）在改善精神分裂症患者眨眼调节缺陷方面的功效。方法：在预处理延迟眨眼调节记录会话后，25 名精神分裂症患者立即接受促胰液素（RG1068；20 μg/kg [N=15]）或盐水安慰剂（20μg/kg [N=10]）以双盲方式皮下注射。根据治疗前基线眨眼调节记录期间的表现，由成对的受试者组成比较组，因此 20 名受试者接受了进一步分析。选择促胰液素是因为眨眼调节取决于小脑深部核上浦肯野细胞抑制的释放，最近的研究表明促胰液素在小脑中内源性释放，在小脑中它充当篮子细胞和浦肯野细胞的逆行信使和神经调节剂。结果：在施用促胰液素后2和24小时，眨眼调节得到显着改善，但在安慰剂治疗后没有显着改善。这些结果与精神分裂症病理生理学中细胞内信号传导异常的证据一致，并表明促胰液素在调节小脑介导的经典条件学习中可能发挥作用。结论：如果如认知障碍模型所表明的，精神分裂症个体的小脑异常与该疾病的基本机制和症状相关，那么小脑靶向治疗可能为精神分裂症的治疗提供一种新方法。
Objective: Pervasive cognitive deficits in schizophrenia are a major cause of disability among individuals with the disorder. One such deficit is the loss of effective associative learning, which is readily assessed via eye-blink conditioning procedures. The authors examined the efficacy of secretin, a hormonal agonist for the prototype group B G-protein-coupled receptors, in ameliorating eye-blink conditioning deficits in schizophrenia patients.Method: Immediately following a pretreatment delay eye-blink conditioning recording session, 25 individuals with schizophrenia received either secretin (RG1068; 20 mu g/kg [N=15]) or a saline placebo (20 mu g/kg [N=10]) subcutaneously in a double-blind fashion. Comparison groups were formed by yoking pairs of subjects on the basis of performance during the pretreatment baseline eye-blink conditioning recording session, and thus 20 subjects underwent further analysis. Secretin was selected because eye-blink conditioning depends on the release of Purkinje cell inhibition on deep nuclei of the cerebellum and recent findings indicate that secretin is endogenously released in the cerebellum, where it acts as a retrograde messenger and neuromodulator on basket and Purkinje cells.Results: Eye-blink conditioning was significantly improved at 2 and 24 hours after secretin administration but not after treatment with placebo. These results are consistent with evidence of intracellular signaling abnormalities in the pathophysiology of schizophrenia and indicate a possible role for secretin in modulating cerebellar-mediated classically conditioned learning.Conclusion: If cerebellar abnormalities in individuals with schizophrenia are associated with fundamental mechanisms and symptoms of the disorder, as suggested by the cognitive dysmetria model, then cerebellar-targeted treatments may provide a novel approach to treatment for schizophrenia.