Stiedl O, Misane I, Spiess J, Ogren S O
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, D-37075 Goettingen, Germany.
J Neurosci. 2000 Nov 15;20(22):8515-27. doi: 10.1523/JNEUROSCI.20-22-08515.2000.
The present study examined the involvement of the 5-HT(1A) receptors in classical fear conditioning using the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) and the selective "silent" 5-HT(1A) receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo- hexane carboxamide trihydrochloride (WAY 100635). The drugs were administered both subcutaneously and bilaterally into the dorsal hippocampus of male C57BL/6J mice. The training was performed in a single trial in which a tone was followed by a footshock. The retention of context- and tone-dependent fear was examined in separate tests conducted either 1 or 24 hr after training. Subcutaneous 8-OH-DPAT (0.1-1.0 mg/kg), when injected before but not after training, caused a dose-dependent impairment of contextual fear in both 1 and 24 hr tests, whereas tone-dependent fear was less affected. Pretraining intrahippocampal injections of 5.0 microg but not 1.0 microg 8-OH-DPAT caused a severe deficit in contextual fear when tested 24 hr after training. When injected both subcutaneously and intrahippocampally, 8-OH-DPAT induced the 5-HT syndrome, indicative of postsynaptic 5-HT(1A) receptor activation at the dose ranges that impaired fear conditioning. However, the behavioral changes induced by 8-OH-DPAT at the time of training could not account for inhibitory effects of 8-OH-DPAT on fear conditioning. Neither subcutaneous (0.03 mg/kg) nor intrahippocampal (0.5 microg per mouse) WAY 100635 altered context- or tone-dependent fear. However, subcutaneous WAY 100635 blocked both the 5-HT syndrome and the impairment of fear conditioning induced by subcutaneous or intrahippocampal 8-OH-DPAT. In contrast, intrahippocampal WAY 100635 blocked the impairment caused by intrahippocampal but not subcutaneous 8-OH-DPAT, indicating the involvement of extrahippocampal 5-HT(1A) receptors in fear conditioning. It is concluded that the deficits in fear conditioning induced by 8-OH-DPAT are a result of postsynaptic 5-HT(1A) receptor activation that interferes with learning processes operating at acquisition but not consolidation. Furthermore, the dorsohippocampal 5-HT(1A) receptors play an important but not exclusive role in the limbic circuitry subserving contextual fear conditioning.
本研究使用5-羟色胺（5-HT）1A受体激动剂氢溴酸8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）和选择性“沉默”5-HT1A受体拮抗剂N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-N-（2-吡啶基）环己烷甲酰胺三盐酸盐（WAY 100635），研究了5-HT1A受体在经典恐惧条件反射中的作用。将这些药物皮下注射和双侧注射到雄性C57BL/6J小鼠的背侧海马体中。训练在单次试验中进行，先给予一个音调，随后施加足部电击。在训练后1小时或24小时进行的单独测试中，检测对情境和音调依赖性恐惧的记忆保持情况。皮下注射8-OH-DPAT（0.1 - 1.0毫克/千克），在训练前而非训练后注射时，在1小时和24小时测试中均导致情境恐惧出现剂量依赖性损伤，而音调依赖性恐惧受影响较小。训练前海马内注射5.0微克而非1.0微克的8-OH-DPAT，在训练后24小时进行测试时，导致情境恐惧严重缺失。当皮下和海马内同时注射时，8-OH-DPAT诱发5-HT综合征，表明在损害恐惧条件反射的剂量范围内，突触后5-HT1A受体被激活。然而，8-OH-DPAT在训练时引起的行为变化并不能解释其对恐惧条件反射的抑制作用。皮下注射（0.03毫克/千克）或海马内注射（每只小鼠0.5微克）WAY 100635均未改变情境或音调依赖性恐惧。然而，皮下注射WAY 100635可阻断皮下或海马内注射8-OH-DPAT所诱发的5-HT综合征和恐惧条件反射损伤。相反，海马内注射WAY 100635可阻断海马内注射而非皮下注射8-OH-DPAT所导致的损伤，表明海马外5-HT1A受体参与了恐惧条件反射。研究得出结论，8-OH-DPAT诱发的恐惧条件反射缺陷是突触后5-HT1A受体激活的结果，该激活干扰了习得时而非巩固时的学习过程。此外，背侧海马体5-HT1A受体在支持情境恐惧条件反射的边缘回路中起重要但非唯一的作用。
