Electrophysiological investigation of the adaptive response of the 5-HT system to the administration of 5-HT1A receptor agonists.
The effects of acute and long-term administration of 5-HT1A agonists were studied in vivo in the rat brain. Unitary extracellular recordings were obtained from dorsal raphe 5-HT neurons and dorsal hippocampus pyramidal neurons. Gepirone and 8-OH-DPAT, two 5-HT1A agonists, when administered intravenously or applied by microiontophoresis, dose-dependently decreased the firing rate of these 5-HT neurons. Gepirone acted as a full agonist at the somatodendritic 5-HT autoreceptor, which is of the 5-HT1A subtype. Microiontophoretic application of gepirone also decreased the firing activity of postsynaptic hippocampus pyramidal neurons. At these postsynaptic 5-HT1A receptors, however, gepirone acted as a partial agonist. A 2-day treatment with gepirone markedly reduced the firing rate of 5-HT neurons; this was followed by a partial recovery after 7 days of treatment and a complete one after 14 days of treatment. This adaptation of 5-HT neurons was attributable to a desensitization of their somatodendritic 5-HT autoreceptors. The 14-day treatment with gepirone did not induce a desensitization of 5-HT1A receptors on postsynaptic pyramidal neurons. It is concluded that the sustained administration of a 5-HT1A agonist results in an enhanced tonic activation of postsynaptic 5-HT1A receptors in the forebrain. It can be presumed that the recovery of the firing activity of 5-HT neurons restores a normal release of endogenous 5-HT, upon which the agonistic action of the 5-HT1A agonist on normosensitive postsynaptic 5-HT receptors is superimposed.
Neurobiological Psychiatry Unit, Faculty of Medicine, McGill University, Montreal, Canada.
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Blier
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de Montigny
D000222:Adaptation, Physiological; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007478:Iontophoresis; D054833:Isoindoles; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011712:Pyramidal Tracts / Q000166:cytology / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
D014151:Anti-Anxiety Agents; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; C055267:tandospirone; D012701:Serotonin; C039979:gepirone