Yoshitake T, Yoshitake S, Yamaguchi M, Ogren S O, Kehr J
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
Neuropharmacology. 2003 Feb;44(2):206-13. doi: 10.1016/s0028-3908(02)00373-8.
The microdialysis technique was used to examine interactions between 5-HT(1A) and galanin receptors in the dorsal raphe nucleus (DRN), by measuring the extracellular levels of 5-HT in the ventral hippocampus of awake rats. The rats were pretreated with the 5-HT(1A) receptor agonist (R,S)-8-OH-DPAT (0.3 mg/kg, s.c.) or saline. 8-OH-DPAT caused a time-dependent reduction of basal 5-HT levels down to 43-48% at 40 min while at 140 min, the hippocampal 5-HT had returned to control values. At that time point, the rats received a second injection of 8-OH-DPAT or galanin (0.15, 0.5 and 1.5 nmol/0.5 microl) infused into the lateral ventricle. The second injection of 8-OH-DPAT caused a significantly smaller reduction of hippocampal 5-HT levels. In contrast, galanin at all three doses in the 8-OH-DPAT-pretreated groups, was significantly more potent in reducing 5-HT levels (maximal reduction to 74%, 52% and 49%, respectively) than it was in saline-pretreated rats (maximal reduction to 96%, 85% and 69%, respectively). The inhibitory effect of galanin (1.5 nmol) on extracellular 5-HT levels in the rat hippocampus was significantly attenuated by co-administration of the 5-HT(1A) receptor antagonists WAY-100635 (0.3 and 0.6 mg/kg s.c.) and, to a lesser extent, with pindolol (20 mg/kg s.c.). These data provide direct in vivo evidence of agonistic 5-HT(1A)-galanin receptor interaction at the presynaptic level. Furthermore, the findings indicate that a down-regulation of the somato-dendritic 5-HT(1A) autoreceptors, following their stimulation with 8-OH-DPAT and possibly also indirectly with 5-HT reuptake inhibitors, may be compensated by a subsequent 'sensitization' of the inhibitory galanin receptors in the DRN. Thus, the enhanced galanin receptor-mediated inhibition of 5-HT neurotransmission may contribute to the pathophysiology of depression or to the reduced and delayed efficacy of antidepressant therapies.
采用微透析技术，通过测量清醒大鼠腹侧海马中5-羟色胺（5-HT）的细胞外水平，研究中缝背核（DRN）中5-HT（1A）与甘丙肽受体之间的相互作用。大鼠预先接受5-HT（1A）受体激动剂（R,S）-8-羟基二丙胺四乙酸（8-OH-DPAT，0.3mg/kg，皮下注射）或生理盐水处理。8-OH-DPAT导致基础5-HT水平随时间依赖性降低，40分钟时降至43%-48%，而140分钟时，海马5-HT已恢复至对照值。在该时间点，大鼠接受第二次注射8-OH-DPAT或甘丙肽（0.15、0.5和1.5nmol/0.5μl），注入侧脑室。第二次注射8-OH-DPAT导致海马5-HT水平的降低明显较小。相比之下，在8-OH-DPAT预处理组中，所有三种剂量的甘丙肽在降低5-HT水平方面（最大降低分别至74%、52%和49%）比在生理盐水预处理的大鼠中（最大降低分别至96%、85%和69%）显著更有效。甘丙肽（1.5nmol）对大鼠海马细胞外5-HT水平的抑制作用通过共同给予5-HT（1A）受体拮抗剂WAY-100635（0.3和0.6mg/kg，皮下注射）而显著减弱，并且在较小程度上与吲哚洛尔（20mg/kg，皮下注射）共同给药也有减弱作用。这些数据提供了在突触前水平上5-HT（1A）-甘丙肽受体激动性相互作用的直接体内证据。此外，研究结果表明，在用8-OH-DPAT刺激后，以及可能也间接用5-羟色胺再摄取抑制剂刺激后，躯体树突状5-HT（1A）自身受体的下调可能通过随后DRN中抑制性甘丙肽受体的“致敏”得到补偿。因此，甘丙肽受体介导的对5-羟色胺神经传递的增强抑制可能导致抑郁症的病理生理学，或导致抗抑郁治疗效果降低和延迟。
