Neurobiology, Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany.
Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany.
J Comp Neurol. 2018 Sep 1;526(13):2019-2031. doi: 10.1002/cne.24471. Epub 2018 Aug 2.
Despite the reduced life expectancy and staggering financial burden of medical treatment associated with tobacco smoking, the molecular, cellular, and ensemble adaptations associated with chronic nicotine consumption remain poorly understood. Complex circuitry interconnecting dopaminergic and cholinergic regions of the midbrain and mesopontine tegmentum are critical for nicotine associated reward. Yet our knowledge of the nicotine activation of these regions is incomplete, in part due to their cell type diversity. We performed double immunohistochemistry for the immediate early gene and surrogate activity sensor, c-Fos, and markers for either cholinergic, dopaminergic or GABAergic cell types in mice treated with nicotine. Both acute (0.5 mg/kg) and chronic (0.5 mg/kg/day for 7 days) nicotine strongly activated GABAergic neurons of the interpeduncular nucleus and medial terminal nucleus of the accessory optic tract (MT). Acute but not chronic nicotine also activated small percentages of dopaminergic and other neurons in the ventral tegmental area (VTA) as well as noncholinergic neurons in the pedunculotegmental and laterodorsal tegmental nuclei (PTg/LDTg). Twenty four hours of nicotine withdrawal after chronic nicotine treatment suppressed c-Fos activation in the MT. In comparison to nicotine, a single dose of cocaine caused a similar activation in the PTg/LDTg but not the VTA where GABAergic cells were strongly activated but dopaminergic neurons were not affected. These results indicate the existence of drug of abuse specific ensembles. The loss of ensemble activation in the VTA and PTg/LDTg after chronic nicotine represents a molecular and cellular tolerance which may have implications for the mechanisms underlying nicotine dependence.
尽管与吸烟相关的医学治疗费用高昂且预期寿命缩短，但与慢性尼古丁消费相关的分子、细胞和整体适应仍未得到充分理解。连接中脑和中脑被盖腹侧部多巴胺能和胆碱能区域的复杂电路对于尼古丁相关的奖励至关重要。然而，由于它们的细胞类型多样性，我们对这些区域的尼古丁激活的了解并不完整。我们对用尼古丁处理的小鼠进行了双重免疫组织化学染色，用于检测即刻早期基因和替代活性传感器 c-Fos 以及用于胆碱能、多巴胺能或 GABA 能细胞类型的标志物。急性（0.5mg/kg）和慢性（0.5mg/kg/天，持续 7 天）尼古丁均强烈激活了脚间核和副视束内侧终核的 GABA 能神经元。急性尼古丁但不是慢性尼古丁也激活了腹侧被盖区（VTA）中的一小部分多巴胺能和其他神经元以及脚桥被盖核和外侧背侧被盖核（PTg/LDTg）中的非胆碱能神经元。慢性尼古丁治疗后 24 小时的尼古丁戒断抑制了 MT 中的 c-Fos 激活。与尼古丁相比，单次可卡因剂量引起了类似的 PTg/LDTg 激活，但 VTA 中没有激活，VTA 中 GABA 能细胞强烈激活，但多巴胺能神经元不受影响。这些结果表明存在滥用药物的特定集合。慢性尼古丁后 VTA 和 PTg/LDTg 中的集合激活丧失代表了分子和细胞耐受性，这可能对尼古丁依赖的机制产生影响。
