Rate-independent inhibition of 5-HT release by 5-HT in the somadendritic regions of raphe neurons

The somadendritic regions of raphe neurons respond to exogenous 5-hydroxytryptamine (5-HT) with an inhibition of spontaneous rate and a consequent reduction in local transmitter release, providing evidence for the operation of negative feedback regulation of spontaneous rate. Experiments were done to determine if a release process for 5-HT might also operate in the somadendritic regions that is independent of negative feedback and rate regulation. Slices of rabbit brain containing medullary or midbrain raphe nuclei, were stimulated in vitro at predetermined frequencies and the efflux of 3H-transmitter determined. The stimulation-induced pattern of transmitter release was independent of frequency, pointing to the absence of feedback. Further, exogenous 5-HT (1 x 10(-6)M) depressed the release of 3H-transmitter, but the inhibition, monitored over a range of frequencies, did not reflect competition with endogenous 5-HT for receptor sites. The antagonist methiothepin (3 x 10(-6)M) attenuated the inhibitions by 5-HT but did not by itself potentiate transmitter release, as expected if feedback inhibition were operative. Labeled transmitter release was antagonized by pretreatment with fluoxetine prior to 3H-HT incubation, and was severely curtailed in a calcium deficient medium, confirming that a neuronally relevant pool of transmitter was involved. It is concluded that serotonergic somadendritic sites contain inhibitory receptors for 5-HT release that operate independently of rate regulation and feedback. These findings could explain how other transmitters, and 5-HT itself (through dendritic release of transmitter), could exert synaptic effects on serotonergic and other neurons without being promptly countermanded by a somadendritic feedback-induced rate correction.