THE ROLE OF 5-HT1B 1D RECEPTORS IN THE MODULATION OF 5-HYDROXYTRYPTAMINE LEVELS IN THE FRONTAL-CORTEX OF THE CONSCIOUS GUINEA-PIG/

The role of 5-HT1B/1D receptors in modulating extracellular 5-hydroxyt ryptamine (5-HT) levels in the guinea pig was investigated with the no n-selective 5-HT1B/1D receptor inverse agonist, methiothepin, and the selective 5-HT1B/1D receptor partial agonists, GR 2,4-oxadiazole-3-yl) [1,1'-biphenyl]-4-carboxamide) and GR 125743 (n-[4-methoxy-3-(4-methyl -1-piperizinyl) Extracellular 5-HT levels were measured using the tech nique of brain microdialysis, in the frontal cortex of the freely movi ng guinea-pig. Extracellular 5-HT was tetrodotoxin sensitive and calci um dependent, and increased when perfused with a high concentration of K+. In addition, extracellular 5-HT levels were lowered by the 5-HT1B /1D receptor agonist, sumatriptan, and the 5-HT1A receptor agonist, 8- hydroxy-2-(di-n-propylamino)tetralin, while perfusion of the selective serotonin re-uptake inhibitor, paroxetine, increased 5-HT in a concen tration-dependent manner. Perfusion of methiothepin, GR 127935 and GR 125743 into the frontal cortex caused significant but transient increa ses of extracellular 5-HT. However, systemic administration of methiot hepin, GR 127935 and GR 125743, at 0.3 mg/kg i.p., produced significan t decreases in extracellular 5-HT, to minima of 27+/-3%, 31+/-12% and 27+/-13% of basal, respectively. The increase of extracellular 5-HT, f ollowing 5-HT1B/1D receptor inverse and partial agonist perfusion into the frontal cortex, was probably a consequence of attenuation of an e ndogenous 5-HT tone at terminal 5-HT autoreceptors. The unexpected dec rease in 5-HT levels following systemic administration may be a result of additional attenuation of endogenous 5-HT tone at cell body autore ceptors in the raphe. Such an increase in local 5-HT levels could then stimulate 5-HT1A receptors to inhibit cell firing and hence decrease 5-HT levels in the terminal regions. This was confirmed when co-admini stration of the 5-HT1A receptor antagonist, WAY 100635, significantly attenuated the GR 127935 decrease in 5-HT.