Effect of acute and repeated versus sustained administration of the 5-HT1A receptor agonist ipsapirone: electrophysiological studies in the rat hippocampus and dorsal raphe

被引:57
作者
Dong, JM
deMontigny, C
Blier, P
机构
[1] Neurobiological Psychiatry Unit, McGill University, Montréal, Que. H3A 1A1, 1033, Pine Avenue West
基金
英国医学研究理事会;
关键词
5-HT1A receptors; antidepressant; anxiolytic; affective disorders;
D O I
10.1007/PL00005055
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The present study was aimed at examining the adaptation of presynaptic 5-HT1A autoreceptors in the dorsal raphe and of postsynaptic 5-HT1A receptors in the dorsal hippocampus during long-term administration of the 5-HT1A receptor agonist ipsapirone given either repeatedly or in a sustained fashion. Concurrent microiontophoretic application of ipsapirone did not attentuate the suppressant effect of 5-hydroxytyptamine (5-HT) on 5-HT neurons, but markedly decreased it when co-applied on CA(3) pyramidal neurons in the dorsal hippocampus. Thus, ipsapirone acted as a full agonist in the dorsal raphe and as a partial agonist in the dorsal hippocampus. Ipsapirone (15 mg/kg/day, s.c. x 2 days) delivered by osmotic minipumps markedly decreased the firing activity of the dorsal raphe 5-HT neurons. After 14 days of treatment, there was a complete recovery of their firing activity and a desensitization of their somatodendritic 5-HT1A autoreceptors, as assessed using microiontophoretic applications of 5-HT and 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) onto 5-HT neurons. The same degree of desensitization was obtained when ipsapirone was administered with repeated injections (7.5 mg/kg b.i.d., s.c. x 14 days). In contrast, the two modalities of ipsapirone adminsitration left unaltered the responsiveness of CA(3) pyramidal neurons to microiontophoretic applications of 5-HT and 8-OH-DPAT. In conclusion, long-term administration of ipsapirone most likely increases 5-HT neurotransmission by enhancing the tonic activation of postsynaptic 5-HT1A receptors. Therefore, the use of sustained release preparation of 5-HT1A receptor agonists should not alter their therapeutic effectiveness in anxiety and affective disorders since the same effects on 5-HT1A receptor functions were produced in this rat model by the sustained and the repeated modes of administration of ipsapirone.
引用
收藏
页码:303 / 311
页数:9
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