Department of Psychology and Neuroscience, The University of North Carolina, Chapel Hill, North Carolina.
Department of Psychology and Neuroscience, The University of North Carolina, Chapel Hill, North Carolina.
Biol Psychiatry. 2017 Dec 1;82(11):839-846. doi: 10.1016/j.biopsych.2017.05.009. Epub 2017 May 11.
Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in promoting opposing appetitive and aversive states, respectively. Here, we tested whether dopamine transmission along the rostral-caudal axis of the shell plays differential roles in the emergence of drug-induced negative affect.
In TH::Cre rats, the dopaminergic pathways from the ventral tegmental area to the rostral and caudal regions of the shell were optogenetically stimulated during intraoral delivery of a taste cue signaling delayed cocaine. Affective responses to the taste cue were measured using taste reactivity, and optical self-stimulation of the rostral and caudal shells was also examined.
Optical stimulation of the rostral shell during tastant infusion prevented the emergence of negative affect, but activation of the caudal shell exacerbated aversive responses. These effects endured in the absence of optical stimulation, and the degree of negative affect in our model predicted self-stimulation responding.
These findings reveal unprecedented, pronounced, and opposing roles of rapid dopamine signaling across the rostral-caudal axis of the nucleus accumbens in the control of drug-induced negative affect, a hallmark of continued drug seeking and use in human addicts.
成瘾的负强化理论假设，成瘾者使用药物来缓解负面情绪状态。在我们实验室开发的临床前模型中，当正常奖励性味觉提示预示即将到来但延迟的可卡因时，大鼠会表现出消极情绪。这种状态的出现伴随着伏隔核壳部多巴胺浓度的降低。然而，壳部的头端和尾端区域分别被认为促进了对立的食欲和厌恶状态。在这里，我们测试了壳部头端-尾端轴线上的多巴胺传递是否在药物引起的负面情绪的出现中发挥了不同的作用。
在 TH::Cre 大鼠中，在口腔内给予预示延迟可卡因的味觉提示时，通过光遗传学刺激腹侧被盖区到壳部头端和尾端的多巴胺能通路。使用味觉反应测量对味觉提示的情感反应，并且还检查了壳部头端和尾端的光自刺激。
在味觉提示输注期间刺激壳部头端可防止负面情绪的出现，但激活壳部尾端会加剧厌恶反应。这些效应在没有光刺激的情况下仍然存在，并且我们模型中的负面情绪程度预测了自我刺激反应。
这些发现揭示了伏隔核壳部头端-尾端轴线上快速多巴胺信号在控制药物引起的负面情绪方面前所未有的、显著的和对立的作用，这是人类成瘾者持续药物寻求和使用的标志。
