MODULATION OF CORTICAL ACETYLCHOLINE-RELEASE BY SEROTONIN - THE ROLE OF SUBSTANCE-P INTERNEURONS

The cholinergic system exerts an important modulatory effect on hippoc ampal functions. Presynaptic inhibition of hippocampal and neocortical acetylcholine (ACh) release by serotonin (5-HT) has been reported in both rat and human brain. There is some controversy, however, concerni ng the 5-HT receptor which mediates the inhibitory effects of 5-HT. Us ing slices of the hippocampal formation of rat prelabelled with [H-3]- choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 2 4 mA) or by K+ (20 mM) we observed that 5-HT inhibits hippocampal and entorhinal [H-3]-overflow ([H-3]-ACh release) by 5-HT1B receptors loca ted on cholinergic terminals. However, this inhibition requires the fu nctional elimination of substance P/gamma-aminobutyric acid (SP/GABA) interneurons which express 5-HT2A receptors as shown by in situ hybrid isation histochemistry. Activation of these somadendritically located 5-HT2A receptors facilitates SP release. SP, in turn, stimulates hippo campal [H-3]-ACh release through NK1 receptors present on cholinergic terminals. These findings suggest close links between cholinergic affe rents, SP interneurons and 5-HT2 receptors. A loss of cholinergic affe rents and 5-HT2 receptors, along with a reduction in substance P-immun oreactive neurons, have been observed in the brains of patients suffer ing from Alzheimer's disease, suggesting the concept that these three alterations reflect a disruption of a functional unit. The present fin dings might help to explain early pathological changes in Alzheimer's disease.