Background

Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M₁ receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M_1/4 receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M₁ receptor signaling in psychotic disorders.

Methods

Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M₁ antagonist biperiden, while performing the paired associated learning task. M₁ binding potentials (BP_ND) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using ¹²³I-IDEX single photon emission computed tomography.

Results

In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M₁ antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M₁ receptor binding during learning, with no association found with M₁ receptor binding in the DLPFC. M₁ receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.

Conclusion

The current study is the first to show differences in M₁ receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M₁ receptor reserve in temporal-limbic areas.

中文翻译：

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毒蕈碱M1受体调节精神病性疾病的联想学习和记忆。

背景

精神病性障碍的特征在于联想学习和记忆的明显缺陷，目前尚无有效的治疗方法。在精神病性疾病中的功能磁共振成像（fMRI）研究已经确定了在联想学习和记忆过程中额颞激活的缺陷。这些发现的病理基础尚不清楚。验尸数据表明，这些缺陷可能与毒蕈碱M ₁受体介导的信号传导丢失有关。一项体内研究表明，用实验性M _1/4受体激动剂Xanomeline治疗后，这些症状得到改善，这得到了支持。当前的研究测试是否可以通过丢失M ₁来介导额颞激活的缺陷 精神病性疾病中的受体信号传导。

方法

26名被诊断患有精神病的无药受试者和29名年龄，性别和智商匹配的健康对照者接受了两次功能性磁共振成像（fMRI），一次在安慰剂治疗下，另一次在选择性M ₁拮抗剂双哌啶下接受治疗，而执行配对的关联学习任务。使用¹²³ I-IDEX单光子发射计算机断层扫描技术测量背外侧前额叶皮层（DLPFC）和海马中的M ₁结合电位（BP _ND）。

结果

In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M₁ antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M₁ receptor binding during learning, with no association found with M₁ receptor binding in the DLPFC. M₁ receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.

Conclusion

当前的研究是第一个显示在配对的联想学习和记忆任务期间，患有精神病的受试者与对照之间的M ₁受体介导的功能敏感性差异的研究。结果表明患有精神病的受试者在颞缘区域失去了M ₁受体储备。