Walker Q David, Kuhn Cynthia M
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, United States.
Neurotoxicol Teratol. 2008 Sep-Oct;30(5):412-8. doi: 10.1016/j.ntt.2008.04.002. Epub 2008 Apr 22.
The neural mechanisms responsible for the enhanced adolescent vulnerability for initiating drug abuse are unclear. We investigated whether age differences in dopamine neurotransmission could explain cocaine's enhanced psychomotor effects in the periadolescent rat. Electrical stimulation of the medial forebrain bundle of anesthetized post-natal age 28 days (PN28) and PN65 rats elicited dopamine release in caudate nucleus and nucleus accumbens core before and after 15 mg/kg cocaine i.p. Extracellular dopamine concentrations were greater in PN65 than PN28 caudate following 20 and 60 Hz stimulations and in the PN65 nucleus accumbens following 60 Hz stimulations. Cocaine increased dopamine concentrations elicited by 20 Hz stimulations 3-fold in the adult, but almost 9-fold in periadolescent caudate. Dopamine release rate was lower in the periadolescent caudate although total dopamine clearance was similar to that of adults. The periadolescent caudate achieved adult levels of clearance by compensating for a lower V(max) with higher uptake affinity. Tighter regulation of extracellular dopamine by the higher uptake/release ratio in periadolescents led to greater increases after cocaine. In nucleus accumbens, dopamine release and V(max) were lower in periadolescents than adults, but uptake affinity and cocaine effects were similar. Immaturity of dopamine neurotransmission in dorsal striatum may underlie enhanced acute responses to psychostimulants in adolescent rats and suggests a mechanism for the greater vulnerability of adolescent humans to drug addiction.
导致青少年更容易开始滥用药物的神经机制尚不清楚。我们研究了多巴胺神经传递的年龄差异是否可以解释可卡因对围青春期大鼠增强的精神运动效应。对出生后28天（PN28）和PN65天的麻醉大鼠的内侧前脑束进行电刺激，在腹腔注射15mg/kg可卡因前后，检测尾状核和伏隔核核心中的多巴胺释放。在20Hz和60Hz刺激后，PN65大鼠尾状核中的细胞外多巴胺浓度高于PN28大鼠；在60Hz刺激后，PN65大鼠伏隔核中的细胞外多巴胺浓度也更高。可卡因使20Hz刺激引起的成年大鼠多巴胺浓度增加3倍，但使围青春期大鼠尾状核中的多巴胺浓度增加近9倍。尽管围青春期大鼠尾状核的多巴胺总清除率与成年大鼠相似，但其多巴胺释放速率较低。围青春期大鼠尾状核通过以更高的摄取亲和力补偿较低的V(max)，从而达到成年水平的清除率。围青春期大鼠较高的摄取/释放比导致对细胞外多巴胺的更严格调节，从而在使用可卡因后产生更大的增加。在伏隔核中，围青春期大鼠的多巴胺释放和V(max)低于成年大鼠，但摄取亲和力和可卡因效应相似。背侧纹状体中多巴胺神经传递的不成熟可能是青少年大鼠对精神兴奋剂急性反应增强的基础，并提示了青少年人类更容易成瘾的一种机制。
