Chronic underactivity of medial frontal cortical beta2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats.
Chronic underactivity of medial frontal cortical beta2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats.
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DOI：
10.1016/j.pnpbp.2008.12.003
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发表时间：
2009-03-17
影响因子：
5.6
通讯作者：
Christopher, N. Channelle
中科院分区：
文献类型：
--
作者：
Levin, Edward D.;Perkins, Abigail;Brotherton, Terrell;Qazi, Melissa;Berez, Chantal;Montalvo-Ortiz, Janitza;Davis, Kasey;Williams, Paul;Christopher, N. Channelle
额叶皮层和海马体中烟碱受体的减少是精神分裂症和阿尔茨海默病认知障碍的重要介质。这些疾病的药物治疗应考虑大脑功能受损对药物反应的影响。这项研究调查了大鼠额叶皮层烟碱受体活性受损对记忆功能的影响。由于阿尔茨海默病和精神分裂症都可能涉及精神病，因此通常会给予抗精神病药物。研究发现抗精神病药物对认知功能的影响差异很大。本研究和之前的研究假设抗精神病药物对认知功能的认知作用取决于参与认知的大脑系统的完整性。之前在海马体的研究中，我们发现用二氢-β-赤碱（DHβE）长期抑制含β2烟碱受体会损害工作记忆，并且抗精神病药物氯氮平可以减弱这种影响。相比之下，用甲基乌头碱 (MLA) 慢性海马 α7 烟碱受体阻断会增强氯氮平诱导的记忆损伤，这种情况在烟碱受体活性未受损的大鼠中可见。目前的研究确定了内侧额皮质 α7 和 β2 烟碱受体参与记忆以及与氯氮平抗精神病药物治疗的相互作用。在放射臂迷宫中测试记忆的雌性大鼠中评估了慢性 DHβE 和 MLA 输注效果以及与全身氯氮平的相互作用。由于已提出烟碱促认知治疗，因此研究了抗精神病药物与慢性全身性尼古丁的相互作用。与海马输注损害记忆的局部输注 DHβE 剂量相同，当输注到内侧额叶皮层时，不会损害记忆。额叶 DHβE 输注增强了氯氮平引起的记忆损伤，而之前海马 DHβE 输注引起的记忆损伤则被氯氮平减弱。先前发现额叶皮质 MLA 输注剂量可增强氯氮平诱导的海马输注记忆障碍，但输注至内侧额叶皮质时却没有显着效果。烟碱受体活性低下的位置和亚型是氯氮平对记忆影响的关键决定因素。海马β2烟碱受体缺失的患者可以用氯氮平治疗得到很好的治疗，而额叶皮质β2受体缺失的患者可能会加剧氯氮平引起的记忆障碍。
Nicotinic receptor decreases in the frontal cortex and hippocampus are important mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. Drug treatments for these diseases should take into account the impacts of compromised brain function on drug response. This study investigated the impact of compromised nicotinic receptor activity in the frontal cortex in rats on memory function. Since both Alzheimer's disease and schizophrenia can involve psychosis, antipsychotic drugs are often given. The impacts of antipsychotic drugs on cognitive function have been found to be quite variable. It is the hypothesis of this and previous studies that the cognitive effects of antispychotic drugs on cognitive function depend on the integrity of brain systems involved in cognition. Previously in studies of the hippocampus, we found that chronic inhibition of β2-containing nicotinic receptors with dihydro-β-erythrodine (DHβE) impaired working memory and that this effect was attenuated by the antipsychotic drug clozapine. In contrast, chronic hippocampal α7 nicotinic receptor blockade with methyllycaconitine (MLA) potentiated the clozapine-induced memory impairment which is seen in rats without compromised nicotinic receptor activity. The current study determined medial frontal cortical α7 and β2-containing nicotinic receptor involvement in memory and the interactions with antipsychotic drug therapy with clozapine. Chronic DHβE and MLA infusion effects and interactions with systemic clozapine were assessed in female rats tested for memory on the radial-arm maze. Antipsychotic drug interactions with chronic systemic nicotine were investigated because nicotinic procognitive treatment has been proposed. The same local infusion DHβE dose that impaired memory with hippocampal infusion did not impair memory when infused in the medial frontal cortex. Frontal DHβE infusion potentiated clozapine-induced memory impairment, whereas previously the memory impairment caused by hippocampal DHβE infusion was attenuated by clozapine. Frontal cortical MLA infusions at a dose that previously was found to potentiate the clozapine-induced memory impairment with hippocampal infusion had no significant effect when infused into the medial frontal cortex. The location and subtype of nicotinic receptor underactivity are critical determinates for clozapine effects on memory. Patients with hippocampal β2-containing nicotinic receptor loss may be well treated with clozapine therapy, while those with frontal cortical β2-containing receptor loss may potentiate the memory impairment caused by clozapine.
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影响因子：
--
作者：
Leonard, S;Gault, J;Freedman, R
通讯作者：
Freedman, R
影响因子：
3.4
作者：
Arthur, D;Levin, ED
通讯作者：
Levin, ED
影响因子：
14.5
作者：
BADDELEY, AD;BRESSI, S;SPINNLER, H
通讯作者：
SPINNLER, H
影响因子：
2.9
作者：
Nott, A;Levin, ED
通讯作者：
Levin, ED
影响因子：
4.7
作者：
Bancroft, A;Levin, ED
通讯作者：
Levin, ED