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

Eur Neuropsychopharmacol. 1997 Aug;7(3):165-72. doi: 10.1016/s0924-977x(96)00395-1.

Abstract

Racemic 8-OH-DPAT, (R,S)-8-hydroxy-2-(di-n-propylamino)tetralin, has become the prototype 5-HT1A receptor agonist. The enantiomers of 8-OH-DPAT have similar affinities to the 5-HT1A 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-HT1A 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacokinetics*
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Body Temperature / drug effects
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Injections, Subcutaneous
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / biosynthesis
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / pharmacokinetics*
  • Serotonin Receptor Agonists / pharmacology*
  • Spectrophotometry, Ultraviolet
  • Tissue Distribution

Substances

  • Serotonin Receptor Agonists
  • Serotonin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin