Serotonergic facilitation of acetylcholine release in vivo from rat dorsal hippocampus via serotonin 5-HT3 receptors.
The serotonin (5-HT) releaser d-fenfluramine and its active metabolite d-norfenfluramine, or the 5-HT-uptake inhibitor citalopram, by increasing synaptic 5-HT availability, facilitated in vivo release of acetylcholine (ACh) from dorsal hippocampi of freely moving rats as determined by the microdialysis technique. The effects of d-norfenfluramine (7.5 mg/kg i.p.) and citalopram (10 microM, applied by reverse dialysis) were prevented by a 14-day chemical lesion of the raphe nuclei, suggesting mediation by the 5-HT system in the cholinergic action of the drugs. The increase in extracellular ACh content induced by d-norfenfluramine (5 mg/kg i.p.) was antagonized by the 5-HT3 receptor antagonists tropisetron (0.5 mg/kg i.p.) and DAU 6215 (60 micrograms/kg i.p.), but not by the mixed 5-HT1 and 5-HT2 receptor antagonist metergoline (2 mg/kg s.c.). In accordance with an involvement of the 5-HT3 receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT3 receptor agonist 2-methylserotonin (250 micrograms i.c.v., or 10 microM applied by reverse dialysis) raised ACh release. The effect of the intracerebroventricular drug was prevented by the 5-HT3 antagonists DAU 6215 (60 micrograms/kg i.p.) and ondansetron (60 micrograms/kg s.c.). These antagonists by themselves did not modify the basal ACh release, indicating that 5-HT does not tonically activate the 5-HT3 receptors involved. In conclusion, the overall regulatory control exerted by 5-HT in vivo is to facilitate hippocampal ACh release. This is mediated by 5-HT3 receptors probably located in the dorsal hippocampi.
Consolo
S
S
Laboratory of Cholinergic Neuropharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Bertorelli
R
R
Russi
G
G
Zambelli
M
M
Ladinsky
H
H
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D017551:Microdialysis; D009642:Norfenfluramine / Q000494:pharmacology; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015283:Citalopram; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin; D000109:Acetylcholine