Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain.
The sustained administration of the 5-HT1A agonist gepirone (15 mg/kg/day, s.c.) in the rat produced an initial decrease of the firing activity of dorsal raphe 5-HT neurons which was followed by a progressive recovery to normal after 14 days of treatment. At this point in time, the effect of intravenous lysergic acid diethylamide (LSD) on the firing activity of 5-HT neurons was markedly reduced, whereas those of 8-hydroxy-2-N,N-propylamino-tetralin (8-OH-DPAT) and of gepirone were unchanged; however, the responsiveness of 5-HT neurons to direct microiontophoretic application of 5-HT, LSD, 8-OH-DPAT, and gepirone, but not of GABA, was reduced. The responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5-HT, 8-OH-DPAT, and gepirone was not altered by the 14-day gepirone treatment. The effectiveness of the electrical stimulation of the ascending 5-HT pathway in reducing pyramidal neuron firing activity was not significantly modified in rats treated with gepirone for 14 days. Furthermore, this treatment did not alter the function of the terminal 5-HT autoreceptor. It is concluded that the progressive restoration of the firing activity of 5-HT neurons, due to a desensitization of the somatodendritic 5-HT autoreceptor, combined with the direct activation of normosensitive postsynaptic 5-HT1A receptor by gepirone, should result in an augmented tonic activation of postsynaptic 5-HT1A receptors. The progressive appearance of this phenomenon would be consistent with the time course of the clinical anxiolytic, and possibly antidepressant, effects of gepirone.
Blier
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P
Neuroscience Research Center, Faculty of Medicine, University of Montreal, Quebec, Canada.
de Montigny
C
C
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001921:Brain / Q000502:physiology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012701:Serotonin / Q000502:physiology*
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012701:Serotonin; D008238:Lysergic Acid Diethylamide; C039979:gepirone