The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors
The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors
复制标题
DOI：
10.1038/npp.2015.220
复制
发表时间：
2016-02-01
影响因子：
7.6
通讯作者：
Roitman, Mitchell F.
中科院分区：
文献类型：
--
作者：
Fortin, Samantha M.;Chartoff, Elena H.;Roitman, Mitchell F.
无条件的奖励刺激引起阶段性增加多巴胺浓度在延髓核（NAc），而离散的厌恶刺激引起暂停多巴胺神经元放电和减少NAc多巴胺浓度。更长时间的厌恶状态对多巴胺释放动力学的无条件影响还没有得到很好的理解，并在这里使用不适诱导剂氯化锂（LiCl）进行了研究。我们使用快速扫描循环伏安法来测量电刺激腹侧被盖区（VTA）的多巴胺细胞体导致的NAc多巴胺的阶段性增加。全身注射氯化锂减少电诱发的多巴胺释放在NAC的麻醉和清醒的大鼠。由于LiCl的一些行为效应似乎是通过胰高血糖素样肽-1受体（GLP-1 R）激活介导的，因此我们假设LiCl对阶段性多巴胺的抑制是GLP-1 R依赖性的。事实上，用GLP-1 R拮抗剂exendin-9（Ex-9）进行外周预处理可有效减弱LiCl诱导的多巴胺抑制。然而，用Ex-9预处理不影响κ-阿片样物质受体激动剂鼠尾草素A对阶段性多巴胺释放的抑制，支持GLP-1 R刺激在LiCl诱导的多巴胺抑制中的选择性作用。通过将Ex-9递送至侧脑室或第四脑室，我们突出了后脑嘴侧的中枢GLP-1受体群体，其参与了LiCl介导的NAc多巴胺释放抑制。
Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.