Neurochemical profile of the selective and silent 5-HT1A receptor antagonist WAY100135: an in vivo microdialysis study

Abstract The neurochemical profile of the selective 5- HT 1A receptor antagonist WAY 100135 [ N - tert - butyl 3-4-(2- methoxyphenyl ) piperazin -1- yl -2- phenylpropanamide dihydrochloride ] and its enantiomers at the somatodenditic 5- HT 1 A eceptor was determined by studying the effects of these compounds on 5-HT (5-hydroxytryptamine, serotonin) release in the rat hippocampus using in vivo microdialysis. (±)-WAY100135, (+)-WAY100135 and (−)-WAY100135 (all at 10 mg/kg s.c.) had no significant effect on extracellular levels of 5-HT in the hippocampus demonstrating that these compounds are devoid of 5-HT 1A receptor agonist properties. In contrast, the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1 mg/kg s.c.) and the partial agonists BMY 7378 (1.0 mg/kg s.c.) and buspirone (5 mg/kg s.c.) significantly decreased hippocampal 5-HT. Pretreatment with (±)-WAY100135 (at 10 mg/kg s.c.) and (+)-WAY100135 (at 1.0–10 mg/kg s.c.) completely blocked the 8-OH-DPAT-induced decrease in 5-HT release demonstrating that these compounds are antagonists at the somatodendritic 5- HT 1 A autoreceptor . (−)-WAY100135 at a dose of 10 mg / kg s . c . had no significant effect on the 8- OH - DPAT - induced inhibition of 5- HT release .(±)-WAY100135 had no significant effect on extracellular levels of dopamine in the rat hippocampus but significantly increased extracellular levels of noradrenaline. The mechanism underlying the increase in noradrenaline is unknown at present. These data suggest that WAY100135 is a silent and selective receptor antagonist at the somatodendritic 5-HT 1A receptor with activity residing in the (+)-enantiomer. In addition, these findings confirm that WAY100135 is likely to be a useful tool for further investigation of 5-HT 1A receptor function.