Jonsson G, Hallman H, Ponzio F, Ross S
Eur J Pharmacol. 1981 Jun 19;72(2-3):173-88. doi: 10.1016/0014-2999(81)90272-7.
The effect of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on monoamine neurons was studied in mice and rats. In mice DSP4 produced acutely a marked reduction of endogenous noradrenaline (NA), [3H]NA uptake and nerve density of the adrenergic nerves in the iris and atrium. Pronounced accumulations of NA were observed in non-terminal axons, which is a degenerative sign, while no changes were found in the NA cell bodies. A marked recovery of all parameters analysed was found as soon as 1 week after DSP4. In the mouse CNS, however, there was a marked and long-lasting NA reduction, especially in the cerebral and cerebellar cortex and spinal cord, leaving dopamine (DA) and serotonin (5-HT) neurons apparently unaffected. Administration of DSP4 to adult rats produced regional changes in the NA levels of the CNS were similar to those observed in the mouse. There were no indications of DSP4 affecting dopamine and adrenaline neurons in rat CNS, although a minor 5-HT depleting effect was noted. DSP4 treatment resulted in an increase in beta-adrenoceptor binding in vitro to homogenates from the cerebral cortex, using [3H]dihydroalprenolol as radioligand. Treatment of newborn rats with DSP4 caused permanent NA disappearance in the cerebral cortex and spinal cord, whereas marked NA increases were found in the pons-medulla and cerebellum. Administration of DSP4 to pregnant rats (gestation day 15) led to a marked and permanent NA depletion in the cerebral cortex and spinal cord in the offspring. The results support the view that DSP4 can produce an acute and relatively selective degeneration of NA nerve terminals in the rat and mouse. The results furthermore indicate that DSP4 (systemically administered) causes a preferential degeneration of NA nerve terminal projections originating from the locus coeruleus in the CNS. Since DSP4 can pass both the blood-brain and blood-placenta barrier and appears to have potent neurotoxic actions on NA neurons, DSP4 may serve as a useful denervation tool for the analysis of NA transmitter functions, particularly in the CNS of both adult and developing animals.
研究了N-(2-氯乙基)-N-乙基-2-溴苄胺（DSP4）对小鼠和大鼠单胺能神经元的影响。在小鼠中，DSP4急性导致内源性去甲肾上腺素（NA）显著减少、[3H]NA摄取以及虹膜和心房中肾上腺素能神经的神经密度降低。在非终末轴突中观察到NA明显蓄积，这是一种退行性标志，而NA细胞体未发现变化。在DSP4处理后1周，所有分析参数均显著恢复。然而，在小鼠中枢神经系统中，NA显著且持久减少，尤其是在大脑和小脑皮质以及脊髓，而多巴胺（DA）和5-羟色胺（5-HT）神经元明显未受影响。给成年大鼠施用DSP4后，中枢神经系统中NA水平的区域变化与在小鼠中观察到的相似。没有迹象表明DSP4会影响大鼠中枢神经系统中的多巴胺和肾上腺素能神经元，尽管注意到有轻微的5-HT耗竭作用。使用[3H]二氢心得舒作为放射性配体，DSP4处理导致体外大脑皮质匀浆中β-肾上腺素能受体结合增加。用DSP4处理新生大鼠导致大脑皮质和脊髓中NA永久性消失，而在脑桥-延髓和小脑中发现NA显著增加。给妊娠大鼠（妊娠第15天）施用DSP4导致后代大脑皮质和脊髓中NA显著且永久性耗竭。这些结果支持这样的观点，即DSP4可在大鼠和小鼠中产生NA神经末梢的急性和相对选择性变性。此外，结果表明DSP4（全身给药）导致源自中枢神经系统蓝斑的NA神经末梢投射优先变性。由于DSP4可穿过血脑屏障和血胎盘屏障，并且似乎对NA神经元具有强大的神经毒性作用，DSP4可作为一种有用的去神经工具，用于分析NA递质功能，特别是在成年和发育中动物的中枢神经系统中。
