ENDOGENOUS SEROTONIN FACILITATES IN-VIVO ACETYLCHOLINE-RELEASE IN RATFRONTAL-CORTEX THROUGH 5-HT1B 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 (29 and 40 muM, reverse dialysis) administration of the 5-HT releaser and uptake inhibitor, d-norfenfluramine, dose-de pendently enhanced frontal cortex ACh output. The d-norfenfluramine-in duced increase in cortical ACh release was tetrodotoxin sinsitive and completely prevented by a 7-day chemical degeneration of the serotoner gic 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 antagon ists, at dosed effective in other in vivo tests, did not prevent the i ncrease in cortical ACh output induced by the maximal effective dose o f d-norfenfluramine. However, the 5-HT1A/1B receptor antagonists (-)-p indolol (8 mg/kg, s.c.) or (-)-propandolol (8.8 mg/kg, i.p.)antagonize d 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 facil itation induced by d-norfenfluramine is the finding that the selective 5-HT1B agonist, CP-93m 129, given locally (2,4 and 8 mug/side) dose d ependently raissed cortical ACh release. In conclusion, the overall re gulatory control exerted by endogenous 5-HT in vivo is to facilitate f rontal cortex ACh release through 5-HT1B receptors located in the fron tal cortex. The 5-HT1B receptors may act indirectly to facilitate ACh release probably by inhibiting cortical inhibitory inputs onto the cho linergic neurons.