Neurotrophic effects of ipsapirone and other 5-HT1A receptor agonists on septal cholinergic neurons in culture.
Repeated treatment of primary cultures of fetal rat septal neurons with 5-HT1A receptor agonists (8-OH-DPAT, ipsapirone, gepirone and buspirone) increased choline acetyltransferase activity after 6-7 days in culture. This effect was optimal with ipsapirone (+ 50-80% at 1 microM of the agonist), and could be prevented by potent 5-HT1A receptor antagonists such as (-)-tertatolol and (+)-WAY 100135. Under conditions where they completely suppressed the stimulatory effect of NGF on choline acetyltransferase in these cultures, specific anti-NGF antibodies did not alter the stimulatory effect of ipsapirone, suggesting that a possible release of NGF from some septal cells did not account for the effect of 5-HT1A receptor stimulation. Autoradiographic investigations with [3H]8-OH-DPAT as radioligand and immunocytochemistry with specific anti-choline acetyltransferase antibodies and anti-rat 5-HT1A receptor antibodies showed that 5-HT1A receptors were expressed on septal neurons in culture, notably on the cholinergic neurons identified by their positive staining with anti-choline acetyltransferase antibodies. Detailed morphometrical analysis by computer-assisted imaging revealed that repeated exposure to ipsapirone (1 microM for 7 days) did not influence the survival of cholinergic as well as non-cholinergic neurons, but specifically altered the neuritic tree (i.e. the total length of neurites and the number of branching points) of cholinergic neurons only. These data suggest that under in vitro conditions ipsapirone and other 5-HT1A receptor agonists may exert a direct trophic action on septal cholinergic neurons.
INSERM U288, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D007150:Immunohistochemistry; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D011412:Propanolamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013876:Thiophenes; D014316:Tritium
D009414:Nerve Growth Factors; D010879:Piperazines; D011412:Propanolamines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; D014316:Tritium; C081293:WAY 100135; D012701:Serotonin; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C005632:tertatolol; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine