Effect of acute and repeated versus sustained administration of the 5-HT1A receptor agonist ipsapirone: electrophysiological studies in the rat hippocampus and dorsal raphe.
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 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. 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 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-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.
Dong
J
J
Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada.
de Montigny
C
C
Blier
P
P
D000818:Animals; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007279:Injections, Subcutaneous; D007478:Iontophoresis; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
D011743:Pyrimidines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C043077:ipsapirone