Narita Minoru, Nagumo Yasuyuki, Miyatake Mayumi, Ikegami Daigo, Kurahashi Kana, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Eur J Neurosci. 2007 Mar;25(5):1537-45. doi: 10.1111/j.1460-9568.2007.05403.x.
In the present study, we investigated the role of orexinergic systems in the activation of midbrain dopamine neurons. In an in vitro study, exposure to either orexin A or orexin B under superfusion conditions produced a transient increase in the intracellular Ca(2+) concentration through the phospholipase C (PLC)/protein kinase C (PKC) pathway via G(q11)alpha or Gbetagamma subunits in midbrain cultured neurons, which were shown to be tyrosine hydroxylase (TH)-positive cells, but not in purified midbrain astrocytes. Here we show that in vivo injection with a selective PKC inhibitor chelerythrine chloride or 2-{8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-1-methyl-1H-indol-3-ylmaleimide HCl (Ro-32-0432) into the ventral tegmental area (VTA) significantly suppressed the place preference and increased levels of dopamine in the nucleus accumbens (NAcc) induced by intra-VTA injection of orexins. These results strongly support the idea that activation of the orexin-containing neuron in the VTA leads to the direct activation of mesolimbic dopamine neurons through the activation of the PLC/PKC pathway via G(q11)alpha or Gbetagamma-subunit activation, which could be associated with the development of its rewarding effect.
在本研究中，我们调查了食欲素能系统在中脑多巴胺神经元激活中的作用。在一项体外研究中，在灌流条件下，中脑培养神经元暴露于食欲素A或食欲素B会通过磷脂酶C（PLC）/蛋白激酶C（PKC）途径，经G（q11）α或Gβγ亚基使细胞内Ca（2+）浓度短暂升高，这些神经元为酪氨酸羟化酶（TH）阳性细胞，而纯化的中脑星形胶质细胞则无此现象。在此我们表明，向腹侧被盖区（VTA）体内注射选择性PKC抑制剂氯化白屈菜红碱或2-{8-[(二甲氨基)甲基]-6,7,8,9-四氢吡啶并[1,2-a]吲哚-3-基}-3-1-甲基-1H-吲哚-3-基马来酰亚胺盐酸盐（Ro-32-0432）可显著抑制VTA内注射食欲素所诱导的位置偏爱，并降低伏隔核（NAcc）中的多巴胺水平。这些结果有力地支持了这样一种观点，即VTA中含食欲素神经元的激活通过经由G（q11）α或Gβγ亚基激活PLC/PKC途径导致中脑边缘多巴胺神经元的直接激活，这可能与其奖赏效应的产生有关。
