Bubser Michael, Fadel Jim R, Jackson Lela L, Meador-Woodruff James H, Jing Deqiang, Deutch Ariel Y
Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Eur J Neurosci. 2005 Jun;21(11):2993-3001. doi: 10.1111/j.1460-9568.2005.04121.x.
Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA) innervate midbrain dopamine (DA) neurons that project to corticolimbic sites and subserve psychostimulant-induced locomotor activity. However, it is not known whether dopamine neurons in turn regulate the activity of orexin cells. We examined the ability of dopamine agonists to activate orexin neurons in the rat, as reflected by induction of Fos. The mixed dopamine agonist apomorphine increased Fos expression in orexin cells, with a greater effect on orexin neurons located medial to the fornix. Both the selective D1-like agonist, A-77636, and the D2-like agonist, quinpirole, also induced Fos in orexin cells, suggesting that stimulation of either receptor subtype is sufficient to activate orexin neurons. Consistent with this finding, combined SCH 23390 (D1 antagonist)-haloperidol (D2 antagonist) pretreatment blocked apomorphine-induced activation of medial as well as lateral orexin neurons; in contrast, pretreatment with either the D1-like or D2-like antagonists alone did not attenuate apomorphine-induced activation of medial orexin cells. In situ hybridization histochemistry revealed that LH/PFA cells rarely express mRNAs encoding dopamine receptors, suggesting that orexin cells are transsynaptically activated by apomorphine. We therefore lesioned the nucleus accumbens, a site known to regulate orexin cells, but this treatment did not alter apomorphine-elicited activation of medial or lateral orexin neurons. Interestingly, apomorphine failed to activate orexin cells in isoflurane-anaesthetized animals. These data suggest that apomorphine-induced arousal but not accumbens-mediated hyperactivity is required for dopamine to transsynaptically activate orexin neurons.
下丘脑外侧区及相邻的穹窿周区（LH/PFA）的食欲素/下丘脑泌素神经元支配着投射至皮质边缘位点并参与精神兴奋药诱导的运动活动的中脑多巴胺（DA）神经元。然而，多巴胺神经元是否反过来调节食欲素细胞的活动尚不清楚。我们研究了多巴胺激动剂激活大鼠食欲素神经元的能力，以Fos的诱导作为反映指标。混合多巴胺激动剂阿扑吗啡增加了食欲素细胞中Fos的表达，对穹窿内侧的食欲素神经元影响更大。选择性D1样激动剂A-77636和D2样激动剂喹吡罗也诱导了食欲素细胞中的Fos，表明刺激任一受体亚型都足以激活食欲素神经元。与这一发现一致，联合使用SCH 23390（D1拮抗剂）-氟哌啶醇（D2拮抗剂）预处理可阻断阿扑吗啡诱导的内侧和外侧食欲素神经元的激活；相反，单独使用D1样或D2样拮抗剂预处理并未减弱阿扑吗啡诱导的内侧食欲素细胞的激活。原位杂交组织化学显示，LH/PFA细胞很少表达编码多巴胺受体的mRNA，提示食欲素细胞是由阿扑吗啡经突触激活的。因此，我们损毁了已知调节食欲素细胞的伏隔核，但这种处理并未改变阿扑吗啡引起的内侧或外侧食欲素神经元的激活。有趣的是，阿扑吗啡未能激活异氟烷麻醉动物的食欲素细胞。这些数据表明，多巴胺经突触激活食欲素神经元需要阿扑吗啡诱导的觉醒而非伏隔核介导的多动。
