Noah B. Walker, Brenton R. Tucker, Leanne N. Thomas, Andrew E. Tapp, Dylan R. Drenan, Ryan M. Drenan
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引用次数: 0
摘要
腹侧被盖区(VTA)的烟碱乙酰胆碱受体(nAChRs)对尼古丁强化很重要。为了确定这些受体对尼古丁强化是否足够以及在多大程度上足够,我们在成年雄性大鼠的 VTA 中表达了 β2Leu9′Ser(即敏化)nAChR 亚基,并评估了静脉自我给药(SA)中尼古丁的剂量-反应关系。WT β2亚基的表达证实,这种对尼古丁敏感性的增强是由于β2中的Leu9′Ser突变造成的。在 17 个固定比率疗程中,β2Leu9′Ser 大鼠的单位剂量越大,尼古丁的敏感性就越高。在相同单位剂量下,对照组大鼠的剂量升级很小或没有。在渐进比例 SA 中,当尼古丁单位剂量为 1.5 μg/kg/inf 或更高时,β2Leu9′Ser 大鼠的断点高于对照组大鼠。在间歇性接触 SA 中,β2Leu9′Ser 大鼠的反应模式与对照组大鼠非常相似。通过添加尼古丁剂量-反应数据、渐进比试验以及排除刻板印象的间歇性接触结果,这些数据大大扩展了我们之前的发现,即尼古丁激活间叶多巴胺通路足以实现尼古丁强化。
Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats
Ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) are important for nicotine reinforcement. To determine whether and to what extent these receptors are sufficient for nicotine reinforcement, we expressed β2Leu9′Ser (i.e. sensitized) nAChR subunits in the VTA of adult male rats and assessed the nicotine dose-response relationship in intravenous self-administration (SA). β2Leu9′Ser rats self-administered nicotine doses 50–100 fold lower than the lowest doses that control rats would respond for. Expression of WT β2 subunits confirmed that this enhanced sensitivity to nicotine was due to the Leu9′Ser mutation in β2. Higher unit doses were associated with strong escalation in β2Leu9′Ser rats over 17 fixed ratio sessions. Escalation was minimal or absent in control rats at the same unit doses. In progressive ratio SA, β2Leu9′Ser rats exhibited higher breakpoints than control rats when the nicotine unit dose was 1.5 μg/kg/inf or higher. In intermittent access SA, β2Leu9′Ser rats exhibited response patterns very similar to control rats. By adding nicotine dose-response data, progressive ratio assays, and intermittent access results that rule out stereotypy, these data significantly extend our previous finding that nicotine activation of the mesolimbic dopamine pathway is sufficient for nicotine reinforcement.
期刊介绍:
Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).