Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA.
J Neurosci. 2013 Aug 21;33(34):13861-72. doi: 10.1523/JNEUROSCI.5099-12.2013.
Restriction of food intake increases the acquisition of drug abuse behavior and enhances the reinforcing efficacy of those drugs. However, the neurophysiological mechanisms responsible for the interactions between feeding state and drug use are largely unknown. Here we show that chronic mild food restriction increases the burst firing of dopamine neurons in the substantia nigra. Dopamine neurons from food-restricted mice exhibited increased burst firing in vivo, an effect that was enhanced by an injection of the psychomotor stimulant cocaine (10 mg/kg, i.p.). Food restriction also enhanced aspartic acid-induced burst firing of dopamine neurons in an ex vivo brain slice preparation, consistent with an adaptation occurring in the somatodendritic compartment and independent of a circuit mechanism. Enhanced burst firing persisted after 10 d of free feeding following chronic food restriction but was not observed following a single overnight fast. Whole-cell patch-clamp recordings indicated that food restriction also increased electrically evoked AMPAR/NMDAR ratios and increased D2 autoreceptor-mediated desensitization in dopamine neurons. These results identify dopamine neurons in the substantia nigra as a convergence point for the interactions between feeding state and drugs of abuse. Furthermore, increased glutamate transmission combined with decreased autoreceptor inhibition could work in concert to enhance drug efficacy in response to food restriction.
限制食物摄入会增加滥用药物行为的获得，并增强这些药物的强化效果。然而，负责进食状态和药物使用之间相互作用的神经生理机制在很大程度上是未知的。在这里，我们表明慢性轻度食物限制会增加黑质中多巴胺神经元的爆发放电。来自食物限制小鼠的多巴胺神经元在体内表现出爆发放电增加，这种效应被精神兴奋剂可卡因（10mg/kg，ip）注射增强。食物限制还增强了在体脑片制备中天门冬氨酸诱导的多巴胺神经元爆发放电，这与发生在体树突区的适应一致，且独立于电路机制。在慢性食物限制后 10 天的自由喂养后，爆发放电持续存在，但在单次过夜禁食后则观察不到。全细胞膜片钳记录表明，食物限制还增加了电诱发 AMPAR/NMDAR 比值，并增加了多巴胺神经元中 D2 自身受体介导的脱敏。这些结果表明，黑质中的多巴胺神经元是进食状态和滥用药物相互作用的交汇点。此外，谷氨酸传递的增加加上自身受体抑制的减少可能协同作用，以增强对食物限制的药物疗效。
