Mansvelder Huibert D, Keath J Russel, McGehee Daniel S
Department of Anesthesia, University of Chicago, Chicago, IL 60637, USA.
Neuron. 2002 Mar 14;33(6):905-19. doi: 10.1016/s0896-6273(02)00625-6.
A single nicotine exposure increases dopamine levels in the mesolimbic reward system for hours, but nicotine concentrations experienced by smokers desensitize nAChRs on dopamine neurons in seconds to minutes. Here, we show that persistent modulation of both GABAergic and glutamatergic synaptic transmission by nicotine can contribute to the sustained increase in dopamine neuron excitability. Nicotine enhances GABAergic transmission transiently, which is followed by a persistent depression of these inhibitory inputs due to nAChR desensitization. Simultaneously, nicotine enhances glutamatergic transmission through nAChRs that desensitize less than those on GABA neurons. The net effect is a shift toward excitation of the dopamine reward system. These results suggest that spatial and temporal differences in nicotinic receptor activity on both excitatory and inhibitory neurons in reward areas coordinate to reinforce nicotine self-administration.
单次接触尼古丁会使中脑边缘奖赏系统中的多巴胺水平在数小时内升高，但吸烟者所经历的尼古丁浓度会在数秒到数分钟内使多巴胺神经元上的烟碱型乙酰胆碱受体（nAChRs）脱敏。在此，我们表明尼古丁对γ-氨基丁酸能（GABAergic）和谷氨酸能突触传递的持续调节可导致多巴胺神经元兴奋性的持续增加。尼古丁会短暂增强GABA能传递，随后由于nAChR脱敏，这些抑制性输入会持续受到抑制。同时，尼古丁通过nAChRs增强谷氨酸能传递，这些nAChRs的脱敏程度小于GABA神经元上的nAChRs。最终结果是多巴胺奖赏系统向兴奋状态转变。这些结果表明，奖赏区域中兴奋性和抑制性神经元上烟碱型受体活性的时空差异协同作用，以强化尼古丁的自我给药行为。
