SPECIES-DIFFERENCES IN 5-HT AUTORECEPTORS

Release of 5-HT in the CNS is under the control of autoreceptors. Thes e autoreceptors fall into two categories: cell body autoreceptors and terminal autoreceptors. The former inhibit 5-HT release through inhibi tion of cell firing; the latter through direct inhibition of release a t the terminal. Cell body (or somatodendritic) autoreceptors belong to the 5-HT1A receptor subtype in all species studied so far. In the rat and mouse, the terminal autoreceptor is known to be a 5-HT1B receptor , whereas in human, pig, rabbit, and guinea pig, the terminal autorece ptor is thought to belong to the 5-HT1D receptor subtype. Until recent ly, the absence of a potent and selective 5-HT1D receptor antagonist h as hindered this classification. We now present data with the novel 5- HT1D receptor antagonist, GR 127935, which demonstrates that in guinea pig cerebral cortex the terminal autoreceptor is a 5-HT1D receptor. I n vitro [H-3]5-HT release studies demonstrate that 5-HT inhibition of [H-3]5-HT release is attenuated by GR 127935. In vivo, using the techn ique of microdialysis, GR 127935 and the non-selective antagonist meth iothepin, when administered down the dialysis probe, potentiate extrac ellular levels of 5-HT. Both the in vitro and in vivo effects of these compounds are consistent with terminal autoreceptor blockade. However , when GR 127935 and methiothepin were administered systemically, both compounds inhibit extracellular levels of 5-HT. The most plausible ex planations for this effect, such as partial agonism or activation of s omatodendritic 5-HT1A receptors, are discussed.