Asanuma M, Ogawa N, Haba K, Hirata H, Mori A
Department of Neurochemistry, Okayama University Medical School, Japan.
J Neurol Sci. 1992 Jul;110(1-2):205-14. doi: 10.1016/0022-510x(92)90029-k.
In order to compare the effects of total catecholamine (CA) or noradrenaline (NA) depletions on cholinergic systems, and the mechanisms of receptor regulation in various brain regions, the regional changes in the levels of acetylcholine (ACh), M1-receptor (M1-R) binding, and M1-R messenger RNA (mRNA) were mainly examined in rats which had received either repeated reserpine treatment or a single injection of the selective noradrenergic neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP-4). The levels of dopamine (DA), its metabolites, NA, binding to both D1 and D2 sites, and the mRNA encoding the D2 receptor were also measured. Administration of reserpine (0.5 mg/kg/day, s.c.) for 2, 7 and 14 days depleted DA and NA in virtually all brain regions, while the short-term treatment increased DA metabolites in the striatum (at 2 days) and basal forebrain (at both 2 and 7 days). Administration of DSP-4 (50 mg/kg, i.p.) resulted in a specific loss of NA in the brain 10 days after the injection. These DSP-4 treated rats showed no change in the levels of ACh or M1-R except for an increase in ACh in the frontal cortex. In contrast, numerous changes in cholinergic indices were seen in the reserpine treated groups, and these changes varied from region to region of brain and with the length of drug treatment. In the striatum, ACh levels were increased in rats treated for 2 or 7 days but were normal after 14 days. M1-Rs were decreased at 14 days. These changes suggest that striatal DA, initially released by reserpine, inhibits the release of ACh from striatal cholinergic interneurons, while prolonged depletion of DA relieves this inhibition, leading to a subsequent down-regulation of M1-Rs. In the frontal cortex, ACh and M1-R levels were all decreased by reserpine treatment for 2 or 7 days, and the M1-Rs remained depressed at 14 days. In the basal forebrain, which contains the cholinergic cells that project to the cortex, DA metabolism was increased by 2 or 7 day reserpine treatment. This increased DAergic activity in the basal forebrain may facilitate cholinergic neurons, causing increased release of ACh in the frontal cortex. This, in turn, may lead to a down-regulation of the M1-Rs in that region. The levels of mRNAs encoding M1-Rs were increased in the striatum and frontal cortex by reserpine treatment, despite the decreases in the M1-Rs themselves.(ABSTRACT TRUNCATED AT 400 WORDS)
为了比较总儿茶酚胺（CA）或去甲肾上腺素（NA）耗竭对胆碱能系统的影响，以及不同脑区受体调节的机制，主要检测了反复给予利血平治疗或单次注射选择性去甲肾上腺素能神经毒素N-2-氯乙基-N-乙基-2-溴苄胺（DSP-4）的大鼠中乙酰胆碱（ACh）水平、M1受体（M1-R）结合及M1-R信使核糖核酸（mRNA）的区域变化。还测定了多巴胺（DA）及其代谢产物、NA、与D1和D2位点的结合以及编码D2受体的mRNA水平。皮下注射利血平（0.5mg/kg/天）2天、7天和14天，几乎使所有脑区的DA和NA耗竭，而短期治疗使纹状体（2天时）和基底前脑（2天和7天时）的DA代谢产物增加。腹腔注射DSP-4（50mg/kg）导致注射后10天脑内NA特异性缺失。这些经DSP-4处理的大鼠除额叶皮质ACh增加外，ACh或M1-R水平无变化。相比之下，利血平处理组出现了许多胆碱能指标的变化，且这些变化因脑区不同以及药物治疗时间长短而异。在纹状体中，利血平处理2天或7天的大鼠ACh水平升高，但14天后恢复正常。14天时M1-Rs减少。这些变化表明，最初由利血平释放的纹状体DA抑制纹状体胆碱能中间神经元释放ACh，而DA的长期耗竭解除了这种抑制，导致随后M1-Rs下调。在额叶皮质，利血平处理2天或7天使ACh和M1-R水平均降低，且14天时M1-Rs仍处于抑制状态。在含有投射到皮质的胆碱能细胞的基底前脑，利血平处理2天或7天使DA代谢增加。基底前脑这种增加的多巴胺能活性可能促进胆碱能神经元，导致额叶皮质ACh释放增加。这反过来可能导致该区域M1-Rs下调。尽管M1-Rs本身减少，但利血平处理使纹状体和额叶皮质中编码M1-Rs的mRNA水平增加。（摘要截于400字）
