Panagis G, Hildebrand B E, Svensson T H, Nomikos G G
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
Synapse. 2000 Jan;35(1):15-25. doi: 10.1002/(SICI)1098-2396(200001)35:1<15::AID-SYN3>3.0.CO;2-C.
In the present study the neuronal expression of Fos, the protein product of c-fos, was used to study changes in neuronal activity in nerve terminal regions of the ascending dopaminergic system during nicotine withdrawal. Rats were infused for 14 days with nicotine (9 mg/kg/day nicotine hydrogen tartrate) via minipumps, whereas control animals carried empty pumps. Withdrawal was induced by the nicotinic receptor (nAChR) antagonist mecamylamine (1 mg/kg, s.c.). The behavior of each animal was observed after mecamylamine injection and subsequently its brain was processed for Fos-like immunoreactivity. Following mecamylamine, the score of abstinence signs increased in the nicotine-treated rats as compared to controls. The number of Fos-positive nuclei was substantially increased in the central nucleus of amygdala (CNA) in animals undergoing mecamylamine-precipitated withdrawal, whereas no significant changes in c-fos expression were observed in the basolateral amygdaloid nucleus, the core and the shell of the nucleus accumbens, the dorsolateral striatum, or the medial prefrontal cortex. Since there are indications of involvement of amygdaloid dopaminergic neurotransmission in anxiety-a core symptom of withdrawal from dependence-producing drugs-in a second experiment utilizing microdialysis we examined whether nicotine withdrawal affects dopaminergic neurotransmission in the CNA. Following mecamylamine injection, dopamine (DA) significantly decreased in nicotine-treated animals compared with controls. These results indicate that the mecamylamine-precipitated nicotine withdrawal reaction is accompanied by a selective induction of c-fos and a concurrent decrease in DA release in the CNA, which may have a bearing on symptoms such as anxiety and distress, which frequently are associated with the nicotine abstinence reaction in humans.
在本研究中，c-fos的蛋白质产物Fos的神经元表达被用于研究尼古丁戒断期间多巴胺能上行系统神经末梢区域神经元活动的变化。通过微型泵给大鼠输注尼古丁（9毫克/千克/天酒石酸氢尼古丁），持续14天，而对照动物携带空泵。用烟碱型受体（nAChR）拮抗剂美加明（1毫克/千克，皮下注射）诱导戒断。注射美加明后观察每只动物的行为，随后对其大脑进行Fos样免疫反应处理。与对照组相比，尼古丁处理的大鼠在注射美加明后戒断症状评分增加。在经历美加明诱发戒断的动物中，杏仁核中央核（CNA）中Fos阳性核的数量显著增加，而在杏仁核基底外侧核、伏隔核的核心和壳、背外侧纹状体或内侧前额叶皮质中未观察到c-fos表达的显著变化。由于有迹象表明杏仁核多巴胺能神经传递参与焦虑——产生依赖性药物戒断的核心症状——在第二个使用微透析的实验中，我们研究了尼古丁戒断是否会影响CNA中的多巴胺能神经传递。与对照组相比，尼古丁处理的动物在注射美加明后多巴胺（DA）显著降低。这些结果表明，美加明诱发的尼古丁戒断反应伴随着c-fos的选择性诱导以及CNA中DA释放的同时减少，这可能与焦虑和痛苦等症状有关，而这些症状在人类尼古丁戒断反应中经常出现。
