EFFECTS OF THE 5-HT1D RECEPTOR ANTAGONIST GR127935 ON EXTRACELLULAR LEVELS OF 5-HT IN THE GUINEA-PIG FRONTAL-CORTEX AS MEASURED BY MICRODIALYSIS

The involvement of 5-HT1D receptors in the regulation of 5-HT release in the guinea-pig brain was examined using the novel 5-HT1D receptor blocking drug GR127935. Levels of 5-HT were measured in frontal cortex of anaesthetized guinea-pigs using microdialysis. The infusion of GR127935 (100 nM) through the dialysis probe into frontal cortex caused a significant increase (61 +/- 8%)in cortical extracellular levels of 5-HT. The increase was transient ( similar or equal to 40 min) even in the continuous presence of GR127935. The transient increase was abolished by tetrodotoxin (1 mu M). The 5-HT1 receptor agonist GR46611 (10 mg/kg s.c.) caused a significant and sustained (> 100 min) reduction in extracellular levels of 5-HT (65 +/- 5%). This response was abolished in animals pre-treated with GR127935, 0.05 mg/kg i.p. Paradoxically, systemic administration of higher doses of GR127935 (0.1-1 mg/kg i.p.) in naive anaesthetized guinea-pigs caused significant and sustained (>120 min) decreases (>65%) in cortical levels of 5-HT. The increase in extracellular 5-HT seen following infusion of GR127935 into frontal cortex may be due to GR127935 blocking 5-HT terminal autoreceptors causing a subsequent increase in the outflow of 5-HT from pre-synaptic terminals. This conclusion is supported by the ability of GR127935 to block the decrease in 5-HT induced by the 5-HT1 receptor agonist GR46611. The paradoxical decrease in cortical levels of 5-HT following systemically-administered GR127935 may be explained if the antagonist blocks autoreceptors in the cell-body region; this would increase 5-HT levels in the raphe region and subsequently stimulate 5-HT1A receptors to inhibit serotonergic cell firing to reduce 5-HT release in the terminal-containing regions.