Christensen Mark H, Ishibashi Masaru, Nielsen Michael L, Leonard Christopher S, Kohlmeier Kristi A
University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health Sciences, Universitetsparken 2, Copenhagen 2100, Denmark.
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Neuropharmacology. 2014 Oct;85:263-83. doi: 10.1016/j.neuropharm.2014.05.010. Epub 2014 May 24.
The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7-P15), nicotine induced larger intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15-P34). Nicotine increased neuronal firing of cholinergic cells to a greater degree in younger animals, possibly linked to development associated differences found in nicotinic effects on action potential shape and afterhyperpolarization. We conclude that in addition to age-associated alterations of several properties expected to affect resting cell excitability, parameters affecting cell excitability are altered by nicotine differentially across ontogeny. Taken together, our data suggest that nicotine induces a larger excitatory response in cholinergic LDT neurons from the youngest animals, which could result in a greater excitatory output from these cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across age.
一个人开始吸烟的年龄越小，对尼古丁上瘾的可能性就越大，这表明神经生物学反应在不同年龄对香烟成瘾成分的反应有所不同。外侧背盖核（LDT）的胆碱能神经元在成瘾发展中起着重要作用，然而，尼古丁在个体发育过程中对LDT神经元兴奋性的影响尚不清楚。使用钙成像和全细胞膜片钳技术研究了尼古丁对不同年龄组LDT细胞的影响。在最年轻的年龄组（P7 - P15）中，尼古丁诱导出更大的细胞内钙瞬变和内向电流。尼古丁在最年幼的动物中诱导出更多的兴奋性突触电流，而在最年长动物（P15 - P34）的细胞中诱导出更大幅度的抑制性突触事件。尼古丁在年幼动物中更大程度地增加了胆碱能细胞的神经元放电，这可能与尼古丁对动作电位形状和超极化后电位的影响在发育过程中发现的差异有关。我们得出结论，除了预期会影响静息细胞兴奋性的几种特性随年龄的变化外，影响细胞兴奋性的参数在个体发育过程中也会因尼古丁而有所不同。综上所述，我们的数据表明，尼古丁在最年幼动物的胆碱能LDT神经元中诱导出更大的兴奋性反应，这可能导致这些细胞向参与成瘾发展的靶区域输出更大的兴奋性信号。这种输出预计会促进成瘾；因此，尼古丁介导的LDT兴奋性增加在个体发育上的差异可能导致不同年龄对尼古丁成瘾的易感性差异。
