DIFFERENTIAL AGONIST PROFILE OF THE ENANTIOMERS OF 3-PPP AT STRIATAL DOPAMINE AUTORECEPTORS - DEPENDENCE ON EXTRACELLULAR DOPAMINE

The effects of the enantiomers of 3-hydroxyphenol-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)-and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0-mu-m, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15-mu-M). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors. The change in profile of (-)-3-PPP and TDHL is discussed in relation to their low intrinsic efficacy at synthesis modulating DA autoreceptors and to the variations in extracellular DA levels under different experimental conditions.