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

Abstract

The present study was aimed at examining the adaptation of presynaptic 5-HT_1A autoreceptors in the dorsal raphe and of postsynaptic 5-HT_1A receptors in the dorsal hippocampus during long-term administration of the 5-HT_1A 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 CA₃ 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. × 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-HT_1A 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. × 14 days). In contrast, the two modalities of ipsapirone adminsitration left unaltered the responsiveness of CA₃ 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-HT_1A receptors. Therefore, the use of sustained release preparation of 5-HT_1A receptor agonists should not alter their therapeutic effectiveness in anxiety and affective disorders since the same effects on 5-HT_1A receptor functions were produced in this rat model by the sustained and the repeated modes of administration of ipsapirone.