Table_2_The Appetite Suppressant D-norpseudoephedrine (Cathine) Acts via D1/D2-Like Dopamine Receptors in the Nucleus Accumbens Shell.DOCX

D-norpseudoephedrine (NPE), also known as cathine, is found naturally in the shrub Catha edulis “Khat.” NPE has been widely used as an appetite suppressant for the treatment of obesity. Although it is known that NPE acts on α1-adrenergic receptors, there is little information about the role of dopamine receptors on NPE’s induced anorectic and weight loss effects. Equally untouched is the question of how NPE modulates neuronal activity in the nucleus accumbens shell (NAcSh), a brain reward center, and a pharmacological target for many appetite suppressants. To do this, in rats, we characterized the pharmacological effects induced by NPE on weight loss, food intake, and locomotion. We also determined the involvement of dopamine D1- and D2-like receptors using systemic and intra-NAcSh antagonists, and finally, we recorded single-unit activity in the NAcSh in freely moving rats. We found that NPE decreased 24-h food intake, induced weight loss, and as side effects increased locomotor activity and wakefulness. Also, intraperitoneal and intra-NAcSh administration of D1 and D2 dopamine antagonists partially reversed NPE’s induced weight loss and food intake suppression. Furthermore, the D1 antagonist, SCH-23390, eliminated NPE-induced locomotion, whereas the D2 antagonist, raclopride, only delayed its onset. We also found that NPE evoked a net activation imbalance in NAcSh that propelled the population activity trajectories into a dynamic pharmacological brain state, which correlated with the onset of NPE-induced wakefulness. Together, our data demonstrate that NPE modulates NAcSh spiking activity and that both dopamine D1 and D2 receptors are necessary for NPE’s induced food intake suppression and weight loss.

D-去甲伪麻黄碱（D-norpseudoephedrine，简称NPE），又名卡西酮（cathine），天然存在于巧茶（Catha edulis，俗称“卡特茶”）灌木中。NPE曾被广泛用作食欲抑制剂，用于肥胖症的治疗。尽管已知NPE可作用于α1肾上腺素能受体（α1-adrenergic receptors），但关于多巴胺受体（dopamine receptors）在NPE诱导的厌食与减重效应中所发挥的作用，目前相关研究仍较为匮乏。同样尚未得到阐明的问题是，NPE如何调控伏隔核壳区（nucleus accumbens shell，简称NAcSh）的神经元活动——该脑区既是大脑奖赏中枢，也是多款食欲抑制剂的药理学靶点。为探究上述问题，本研究以大鼠为模型，表征了NPE诱导的减重、摄食及运动相关药理学效应。我们还通过全身给药及伏隔核壳区局部给药的拮抗剂（antagonists），明确了多巴胺D1样与D2样受体的参与作用；最终，我们在自由活动大鼠的伏隔核壳区记录了单神经元单位活动（single-unit activity）。研究结果显示，NPE可降低大鼠24小时摄食量并诱导体重减轻，同时会产生运动活性增加与觉醒度升高的副作用。此外，腹腔内（intraperitoneal）及伏隔核壳区局部给予D1和D2型多巴胺拮抗剂，可部分逆转NPE诱导的体重减轻与摄食抑制现象。进一步研究发现，D1受体拮抗剂SCH-23390可完全消除NPE诱导的运动活性升高，而D2受体拮抗剂雷氯必利（raclopride）仅能延缓该效应的发作。我们还观察到，NPE会在伏隔核壳区引发净激活失衡（net activation imbalance），使群体活动轨迹（population activity trajectories）推进至一种动态药理学脑状态（dynamic pharmacological brain state），该状态与NPE诱导的觉醒发作存在相关性。综上，本研究数据表明，NPE可调控伏隔核壳区的锋电位活动（spiking activity），且多巴胺D1与D2受体均为NPE诱导的摄食抑制与减重效应所必需。