Pharmacokinetic and pharmacodynamic studies of ( R)-8-hydroxy-2-(di- n-propylamino)tetralin in the rat

Racemic 8-OH-DPAT, ( R,S)-8-hydroxy-2-(di- n-propylamino)tetralin, has become the prototype 5-HT 1A receptor agonist. The enantiomers of 8-OH-DPAT have similar affinities to the 5-HT 1A receptor, but the ( R)-enantiomer is a full agonist, whereas the ( S)-enantiomer is a partial agonist. This communication describes the dose- and time–response relationships of behavioural (5-HT behavioural syndrome, cage-leaving response), physiological (body temperature) and biochemical (5-HT turnover, 5-hydroxytryptophan accumulation) effects of ( R)-8-OH-DPAT in rats. A high-performance liquid chromatography (HPLC)–UV method for determination of plasma and brain concentrations of ( R)-8-OH-DPAT was developed, permitting studies of the pharmacokinetics of the drug. The concentrations of 8-OH-DPAT in brain were several fold higher than in plasma, and there were large variations in ( R)-8-OH-DPAT concentrations between brain regions (highest in the hippocampus). ( R)-8-OH-DPAT peaked in plasma at 5 min and in brain at 15 min after subcutaneous administration. The 5-HT 1A behavioural syndrome peaked within 5 min after administration and disappeared after 30 min, when brain concentrations were still high. The hypothermic and biochemical responses developed gradually and were maximal at 45–60 min post injection, when both plasma and brain concentrations were declining. Thus, there was not a simple relationship between the kinetics and the dynamics of ( R)-8-OH-DPAT. These results prompt further studies on the pharmacokinetics of 8-OH-DPAT within the central nervous system.