Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia.
Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia.
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DOI：
10.1038/npp.2011.299
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发表时间：
2012-04
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中科院分区：
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被诊断为精神分裂症的人有极高的烟草依赖风险。尸检研究表明，这些人在几个大脑区域的α7烟碱乙酰胆碱受体（nAChR）显着减少。α7介导的功能下降可能不仅与精神分裂症有关，而且与烟草消费增加有关。本研究的目的是确定α7 nAChR的药理学阻断是否会增加大鼠在渐进比例强化（PR）计划期间静脉内自我给予尼古丁（NIC）的动机。在PR之前，大鼠接受0、10或20 pmol的选择性α7 nAChR拮抗剂α-芋螺毒素ArIB [V11 L，V16 D]（ArIB）局部输注到延髓核（NAc）壳或前扣带皮层，这些脑区有助于药物奖励的动机。我们还试图确定在这些脑区局部输注0、10或40 nmol选择性α7 nAChR激动剂PNU 282987是否会降低NIC使用的动机。将ArIB注入NAc壳和前扣带皮层导致主动杠杆按压、断点和NIC摄入量显著增加，表明α7 nAChR功能降低增加了为NIC工作的动机。相比之下，PNU 282987输注导致NAc壳内给药时这些指标降低，但前扣带皮层给药后无影响。这些数据确定了α7 nAChR功能的降低是精神分裂症患者烟草使用增加的潜在机制，也确定了α7 nAChR的激活是戒烟治疗的潜在策略。
Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased α7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of α7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective α7 nAChR antagonist, α-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective α7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of α7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of α7 nAChRs as a potential strategy for tobacco cessation therapy.
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