The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT1A receptor

The present study was undertaken to determine whether d-threo-(R,R)-methylphenidate (MPH) was exerting binding activity as an agonist or antagonist of 5.HT 1A and 5-HT 2B receptors. [ 35 S]guanosine5'[gamma-thio]triphosphate ([ 35 5]GTPγS) binding assay and field-stimulated Guinea pig ileum assay were used to determine 5-HT 1A receptor agonism and antagonism activity of d-threo-(R,R)-MPH. The results suggested d-threo-(R,R)-MPH induced 5-HT 1A receptor agonist activity at 100 μM. The Guinea pig ileum functional assay showed that d-threo-(R,R)-MPH produced agonist-like reduction of neurogenic twitch with an EC 50 5.65 ± 0.36 μM. At 30 μM concentrations, d-threo-(R,R)-MPH produced 171 ± 4.24% of the relaxation relative to that caused by 0.12 μM 8-OH-DPAT. However, d-threo-(R,R)-MPH exhibited no significant pharmacological activity in rat stomach fundus 5-HT 2B receptor functional assay. Thus, d-threo-(R,R)-MPH appears to act as a selective 5-HT 1A receptor agonist in vitro. It is speculated that the activation of 5-HT 1A receptor might play a partial role in d-threo-(R,R)-MPH mediated dopamine (DA) release in the brain.