Adolescent nicotine administration alters serotonin receptors and cell signaling mediated through adenylyl cyclase.
Adolescent nicotine administration alters serotonin receptors and cell signaling mediated through adenylyl cyclase.
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青少年服用尼古丁会改变血清素受体和腺苷酸环化酶介导的细胞信号传导。
DOI：
10.1016/s0006-8993(02)03174-8
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发表时间：
2002
期刊：
影响因子：
2.9
通讯作者：
Slotkin,TA
中科院分区：
文献类型：
--
作者：
Xu,Z;Seidler,FJ;Cousins,MM;SlikkerJr,W;Slotkin,TA
尼古丁是一种神经致畸物，在关键的发育阶段针对突触功能，最近的研究表明，中枢神经系统的脆弱性延伸到青春期，这通常是吸烟开始的年龄。我们通过连续小泵输注尼古丁给青春期大鼠，剂量从PN30到PN47.5，剂量率为6mg /kg/天，与吸烟者的血浆尼古丁水平相同，并在尼古丁给药期间（PN45）和治疗后（PN50、60、75）检测5HT受体和相关细胞信号。青少年尼古丁降低5ht2受体在含有5HT投射的大脑区域（海马和大脑皮层）的结合，并在大脑皮层对女性有选择性；含有5HT细胞体的区域要么增加（雄性中脑），要么没有变化（脑干）。相比之下，5ht1a受体无明显变化；然而，受体通过腺苷酸环化酶（AC）发出信号的能力在治疗后的雌性中表现出从刺激到抑制的转变。AC对β-肾上腺素能受体刺激的反应也有短暂的改变，同时AC对非受体介导的兴奋剂forskolin的反应也有明显的诱导。我们的研究结果表明，青少年尼古丁暴露改变了突触后5HT受体的浓度和功能，其方式与受损的5HT突触功能相当。改变的方向、停止给药后缺陷的出现，以及女性对影响的性别偏好，都支持青少年吸烟者中5HT功能受损与抑郁症发病率较高的关系。
Nicotine is a neuroteratogen that targets synaptic function during critical developmental stages and recent studies indicate that CNS vulnerability extends into adolescence, the age at which smoking typically commences. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined 5HT receptors and related cell signaling during nicotine administration (PN45) and in the post-treatment period (PN50, 60, 75). Adolescent nicotine decreased 5HT2receptor binding in brain regions containing 5HT projections (hippocampus and cerebral cortex), with selectivity for females in the cerebral cortex; regions containing 5HT cell bodies showed either an increase (midbrain in males) or no change (brainstem). In contrast, there were no significant changes in 5HT1Areceptors; however, the ability of the receptors to signal through adenylyl cyclase (AC) showed a switch from stimulatory to inhibitory effects in females during the post-treatment period. There were also transient alterations in AC responses to β-adrenergic receptor stimulation, as well as pronounced induction of the AC response to the non-receptor-mediated stimulant, forskolin. Our results indicate that adolescent nicotine exposure alters the concentrations and functions of postsynaptic 5HT receptors in a manner commensurate with impaired 5HT synaptic function. The direction of change, emergence of defects after the cessation of nicotine administration, and sex-preference for effects in females, all support a relationship of impaired 5HT function to the higher incidence of depression seen in adolescent smokers.