Yeghiayan S K, Kelley A E, Kula N S, Campbell A, Baldessarini R J
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Pharmacol Biochem Behav. 1997 Feb;56(2):251-9. doi: 10.1016/s0091-3057(96)00217-1.
Bilateral local microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventrolateral striatum (VLS) of the rat forebrain induces quantifiable stereotyped orofacial behaviors. The role of presynaptic dopamine (DA) and structural requirements of indoles for expression of this behavioral effect and for inhibition of neuronal transport of [3H]DA were examined. Bilateral local injection of 6-OHDA (8 micrograms/side) into VLS depleted DA and markedly diminished the behavioral effects of 5-HT. Intracerebral pretreatment with the potent DA transport inhibitors GBR-12909 (6 micrograms/side) or nomifensine (4 micrograms/side) also markedly decreased behavioral responses to 5-HT. A series of indoles and tyramine were examined for ability to induce stereotypy following infusion into the VLS. Of compounds tested, only p-tyramine, 5-HT, tryptamine and L-5-hydroxytryptophan (5-HTP) elicited strong orofacial behaviors; indoles lacking a free amino group or containing other substituents were virtually inactive in vivo, and the effect of 5-HTP was prevented by systemic pretreatment with the decarboxylase inhibitor NSD-1015, indicating its required conversion to 5-HT. Uptake of [3H]DA (0.1 microM) into rat striatal synaptosomes was inhibited in a concentration-dependent manner in the following apparent rank-order: p-tyramine, N-methyl-5-HT, tryptamine, 5-HT, N-methyltryptamine (IC50 = 44-718 nM), other indoles (IC50 = 10-100 microM). These results support the conclusion that oral stereotypy induced by microinjection of 5-HT or other aromatic amines into rat VLS is mediated by local release of endogenous DA. These results extend previous findings indicating that this effect of 5-HT was not blocked by 5-HT receptor antagonists, and suggest mediation by a neuronal transport process involved in the uptake or storage of DA.
将血清素（5-羟色胺；5-HT）双侧局部微量注入大鼠前脑腹外侧纹状体（VLS）会诱发可量化的刻板性口面部行为。研究了突触前多巴胺（DA）的作用以及吲哚的结构要求对这种行为效应的表达和对[3H]DA神经元转运抑制的影响。向VLS双侧局部注射6-OHDA（8微克/侧）可耗尽DA，并显著减弱5-HT的行为效应。用强效DA转运抑制剂GBR-12909（6微克/侧）或诺米芬辛（4微克/侧）进行脑内预处理也显著降低了对5-HT的行为反应。检测了一系列吲哚和酪胺注入VLS后诱导刻板行为的能力。在所测试的化合物中，只有对酪胺、5-HT、色胺和L-5-羟色氨酸（5-HTP）引发强烈的口面部行为；缺乏游离氨基或含有其他取代基的吲哚在体内几乎无活性，并且5-HTP的效应可通过用脱羧酶抑制剂NSD-1015进行全身预处理来阻断，这表明其需要转化为5-HT。[3H]DA（0.1微摩尔）进入大鼠纹状体突触体的摄取以浓度依赖性方式受到抑制，其明显的排序如下：对酪胺、N-甲基-5-HT、色胺、5-HT、N-甲基色胺（IC50 = 44 - 718纳摩尔），其他吲哚（IC50 = 10 - 100微摩尔）。这些结果支持以下结论：将5-HT或其他芳香胺微量注入大鼠VLS所诱导的口部刻板行为是由内源性DA的局部释放介导的。这些结果扩展了先前的发现，即5-HT的这种效应未被5-HT受体拮抗剂阻断，并提示其通过参与DA摄取或储存的神经元转运过程介导。
