DIFFERENTIAL SEROTONINERGIC AND DOPAMINERGIC ACTIVITIES OF THE (R)-ENANTIOMER AND THE (S)-ENANTIOMER OF 2-(DI-N-PROPYLAMINO) TETRALIN

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenoli c or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat bo dy posture) behavioural responses. The present study shows that s.c. a dministration of(R)-DPAT induces typical 5-HT1A receptor agonist behav iours. These effects are blocked by the 5-HT1A receptor antagonist S)- 5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administ ration of (S)-DPAT induces dopaminergic behaviours, which are fully an tagonised by raclopride, a dopamine D-2 receptor antagonist. Both enan tiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-h ydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxy lase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytr yptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT 1A receptor agonist and (S)-DPAT as a dopamine D-2 receptor agonist. P resynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S )-DPAT for dopamine D-2 receptors. Receptor binding studies, utilizing [H-3]8-hydroxy-2-(di-n-propylamino)tetralin and [H-3]quinpirole as ra dioligands for 5-HT1A and dopamine D-2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A re ceptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT f or dopamine D-2 receptors. Thus, the results from receptor binding stu dies support the conclusion that (R)- and (S)-DPAT are agonists showin g selectivity for 5-HT1A and dopamine D-2 receptors, respectively. Tak en together, these findings may explain previous controversies with re gard to the pharmacology of racemic DPAT and re-emphasise the necessit y to study pure enantiomers of chiral compounds.