Differential agonist profile of the enantiomers of 3‐PPP at striatal dopamine autoreceptors: Dependence on extracellular dopamine

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Abstract
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 μm, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 μM). 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.

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