Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: An animal model

被引：61

作者：

Hahn, Margaret ^{[1
,2
]}

Chintoh, Araba ^{[1
,2
]}

Giacca, Adria ^{[2
,3
]}

Xu, Li ^{[3
]}

Lam, Loretta ^{[3
]}

Mann, Steve ^{[1
,2
]}

Fletcher, Paul ^{[1
,4
]}

Guenette, Melanie ^{[1
,2
]}

Cohn, Tony ^{[1
,5
]}

Wolever, Tom ^{[6
]}

Arenovich, Tamara ^{[1
]}

Remington, Gary ^{[1
,2
,5
]}

机构：

[1] Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada

[2] Univ Toronto, Inst Med Sci, Kings Coll Circle 1, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Physiol, Kings Coll Circle 1, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Dept Psychol, Toronto, ON M5S 3G3, Canada

[5] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada

[6] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada

来源：

SCHIZOPHRENIA RESEARCH | 2011年 / 131卷 / 1-3期

关键词：

Atypical antipsychotics; Metabolic; Insulin secretion; Diabetes; Receptor binding; Serotonergic; Histaminergic; Dopaminergic; Muscarinic; PANCREATIC BETA-CELLS; PLASMA-GLUCOSE; RESISTANCE; ACETYLCHOLINE; OLANZAPINE; AGONISTS; SENSITIVITY; RISPERIDONE; ANTAGONISM; OCCUPANCY;

D O I：

10.1016/j.schres.2011.06.004

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n = 10), a selective M-3 muscarinic antagonist; ketanserin 2 mg/kg (n = 10), a 5HT(2A) antagonist; raclopride 0.3 mg/kg (n = 11) a selective D-2/D-3 antagonist; terfenadine 20 mg/kg (n = 9) a selective H-1 antagonist; or, vehicle (n = 11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic beta-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H-1 blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M-3) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D-2-like receptors in beta-cells, which mediate inhibition of insulin secretion, we propose that prolonged D-2 blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.

引用

页码：90 / 95

页数：6

共 46 条

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