Dooley D J, Bittiger H, Hauser K L, Bischoff S F, Waldmeier P C
Neuroscience. 1983 Aug;9(4):889-98. doi: 10.1016/0306-4522(83)90277-4.
A peripheral injection of DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] produced a marked, selective, and lasting depletion of norepinephrine in certain regions of the rat central nervous system. This depletion at 10 days after injection was associated with regional alterations in some, but not all, adrenergic binding sites (receptors) as determined by in vitro [3H]prazosin (alpha 1), [3H]p-aminoclonidine (alpha 2), and [3H]dihydroalprenolol (beta) binding. The neocortical alpha 1-receptor was not changed. The alpha 2-receptor in several regions was altered as indicated by an increase in ligand affinity; additionally, the density of this receptor was slightly decreased in some regions. Depending on the region, the beta-receptor either increased in density or was unchanged. The increased density of this receptor in neocortex corresponded to an increased activity of isoproterenol-sensitive adenylate cyclase. These two changes were not affected by subchronic treatment with desipramine, a norepinephrine uptake inhibitor. The changes were, however, partially or completely reversed by subchronic administration of clenbuterol, a centrally-acting beta-receptor agonist. The dopaminergic receptor in various regions was unaltered as assessed by in vivo and/or in vitro binding of [3H]spiperone. The in vivo binding of this ligand also indicated that the serotoninergic receptor in frontal neocortex was unchanged. Assessment of adrenergic receptors in neocortex at 50 days after injection indicated only the above affinity change of the (presumably postsynaptic) alpha 2-receptor. The alpha 1-receptor remained unaltered. The density of the beta-receptor had normalized, as had the activity of isoproterenol-sensitive adenylate cyclase. Implicit in these findings is the following rank order of receptor sensitivity to chronic norepinephrine depletion: alpha 2 greater than beta greater than alpha 1. The use of DSP-4 has clear advantages over other methods of depleting central norepinephrine. This neurotoxin can be administered by intraperitoneal injection, the depletion of norepinephrine can be readily checked by absence of the post-decapitation reflex, and the changes in other neurotransmitter concentrations are relatively minor or nonexistent. The alteration of alpha 2- and beta-receptors, as a consequence of DSP-4 treatment, may form the basis of a new animal model of adrenergic receptor supersensitivity. Such a model may clarify the importance of these central receptors to physiological and behavioral processes.
外周注射DSP-4 [N-(2-氯乙基)-N-乙基-2-溴苄胺] 可使大鼠中枢神经系统某些区域的去甲肾上腺素显著、选择性且持久地耗竭。注射后10天时的这种耗竭与部分（而非全部）肾上腺素能结合位点（受体）的区域改变有关，这些改变通过体外[3H]哌唑嗪（α1）、[3H]对氨基可乐定（α2）和[3H]二氢阿普洛尔（β）结合来确定。新皮质的α1受体未发生变化。几个区域的α2受体发生了改变，表现为配体亲和力增加；此外，该受体的密度在某些区域略有降低。根据区域不同，β受体密度要么增加，要么未变。新皮质中该受体密度的增加与异丙肾上腺素敏感的腺苷酸环化酶活性增加相对应。这两种变化不受去甲肾上腺素摄取抑制剂地昔帕明亚慢性治疗的影响。然而，通过亚慢性给予中枢作用的β受体激动剂克伦特罗，这些变化部分或完全得到逆转。通过[3H]螺哌隆的体内和/或体外结合评估，各区域的多巴胺能受体未发生改变。该配体的体内结合还表明额叶新皮质中的5-羟色胺能受体未发生变化。注射后50天时对新皮质中肾上腺素能受体的评估仅显示上述（可能是突触后）α2受体的亲和力变化。α1受体保持不变。β受体的密度已恢复正常，异丙肾上腺素敏感的腺苷酸环化酶活性也已恢复正常。这些发现暗示了受体对慢性去甲肾上腺素耗竭的敏感性存在以下排序：α2大于β大于α1。与其他耗竭中枢去甲肾上腺素的方法相比，使用DSP-4具有明显优势。这种神经毒素可通过腹腔注射给药，去甲肾上腺素的耗竭可通过断头后反射的缺失轻易检查，并且其他神经递质浓度的变化相对较小或不存在。DSP-4治疗导致的α2和β受体改变可能构成肾上腺素能受体超敏反应新动物模型的基础。这样的模型可能会阐明这些中枢受体对生理和行为过程的重要性。
