Differential effect of gepirone on presynaptic and postsynaptic serotonin receptors: single-cell recording studies.
The sustained administration of the serotonin (5-hydroxytryptamine1A, 5-HT1A) agonist gepirone (15 mg/kg/day subcutaneously) 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, the somatodendritic 5-HT1A autoreceptor had desensitized, as indicated by the reduced effectiveness of intravenous lysergic acid diethylamide (LSD) and of microiontophoretic applications of 5-HT, LSD, 8-hydroxy-2-(N,N-propylamino) tetralin (8-OH-DPAT), and gepirone, but not of gamma-aminobutyric acid in depressing the firing activity of 5-HT neurons. In contrast, 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. In an attempt to unravel the differential effect of sustained gepirone administration on presynaptic and postsynaptic 5-HT1A receptors, the properties of gepirone at these two receptors were assessed. The concurrent microiontophoretic application of gepirone readily blocked the effect of 5-HT on dorsal hippocampus pyramidal neurons, but not on dorsal raphe 5-HT neurons, thus indicating that gepirone is a partial agonist at postsynaptic 5-HT1A receptors and a full agonist at somatodendritic 5-HT1A receptors. It is proposed that gepirone, being a partial agonist at postsynaptic 5-HT1A receptors, fails to desensitize them; whereas, because of its full agonistic activity at the somatodendritic 5-HT1A receptor, it desensitizes this autoreceptor with long-term administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Blier
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P
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
de Montigny
C
C
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D014151:Anti-Anxiety Agents; D001143:Arousal / Q000187:drug effects*; D003712:Dendrites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / 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 / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D008238:Lysergic Acid Diethylamide; C039979:gepirone