Endogenous serotonin facilitates in vivo acetylcholine release in rat frontal cortex through 5-HT 1B receptors.
We characterized the role of endogenous serotonin (5-HT) in regulating in vivo acetylcholine (ACh) output in frontal cortex of freely moving rats using the microdialysis technique. Systemic (0.63, 1.25 and 2.5 mg/kg, i.p.) or local (20 and 40 microM, reverse dialysis) administration of the 5-HT releaser and uptake inhibitor, d-norfenfluramine, dose-dependently enhanced frontal cortex ACh output. The d-norfenfluramine-induced increase in cortical ACh release was tetrodotoxin sensitive and completely prevented by a 7-day chemical degeneration of the serotonergic afferents to the frontal cortex. Investigating the 5-HT receptors that might mediate the d-norfenfluramine cholinergic effect, we found that the 5-HT4 (GR 125487) and 5-HT2A/2C (ritanserin) receptor antagonists, at doses effective in other in vivo tests, did not prevent the increase in cortical ACh output induced by the maximal effective does of d-norfenfluramine. However, the 5-HT1A/1B receptor antagonists (-)-pindolol (8 mg/kg, s.c.) or (-)-propanolol (8.8 mg/kg, i.p.) antagonized the increasing effect of d-norfenfluramine although the selective 5-HT1A receptor antagonist WAY-100635 (1 and 2 mg/kg, s.c.) did not. In accordance with an involvement of the 5-HT1B receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT1B agonist, CP-93,129, given locally (2, 4 and 8 micrograms/side) does-dependently raised cortical ACh release. In conclusion, the overall regulatory control exerted by endogenous 5-HT in vivo is to facilitate frontal cortex ACh release through 5-HT1B receptors located in the frontal cortex. The 5-HT1B receptors may act indirectly to facilitate ACh release probably by inhibiting cortical inhibitory inputs onto the cholinergic neurons.
Consolo
S
S
Laboratory of Cholinergic Neuropharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Arnaboldi
S
S
Ramponi
S
S
Nannini
L
L
Ladinsky
H
H
Baldi
G
G
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D009642:Norfenfluramine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D016713:Ritanserin; D009642:Norfenfluramine; D012701:Serotonin; D013779:Tetrodotoxin; D000109:Acetylcholine; C082871:GR 113808