Vol. 280, Issue 3, 1241-1249, 1997

Interactions of (+)- and ()-8- and 7-Hydroxy-2-(Di-n-Propylamino)tetralin at Human (h)D₃, hD₂ and h Serotonin_1A Receptors and Their Modulation of the Activity of Serotoninergic and Dopaminergic Neurones in Rats

F. Lejeune, A. Newman-Tancredi, V. Audinot and M. J. Millan

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 78290, Croissy-sur-Seine, France

The aminotetralins, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 7-OH-DPAT behave as preferential agonists at serotonin (5-HT)_1A and dopamine D₃ and D₂ receptors, respectively. In our study, we evaluated the influence of their (+)- and (-) isomers on the electrical activity of serotoninergic neurones of the dorsal raphe nucleus (DRN), which bear 5-HT_1A autoreceptors, and of dopaminergic neurones of the ventral tegmental area (VTA), which possess inhibitory D₃ and D₂ receptors. These actions were compared to their in vitro interactions with cloned, human (h)5-HT_1A, hD₃ and hD₂ receptors. In binding studies, racemic 8-OH-DPAT showed 100-fold selectivity for h5-HT_1A vs. hD₂ and hD₃ receptors and there was little difference between its (+)- and (-)-isomers either in terms of their potency at 5-HT_1A receptors or of their selectivity at 5-HT_1A vs hD₂/hD₃ sites. Nevertheless, the (+)-isomer was markedly more efficacious than its (-)-counterpart in stimulating the binding of guanosine 5-O-(3-[³⁵S]thiotriphosphate) ([³⁵S]-GTPS) at h5-HT_1A receptors, a measure of coupling to G-proteins; 90 vs. 57% maximal stimulation respectively, relative to 5-HT = 100%. Also the (+)-isomer was ca. 3-fold more potent than the (-)-isomer in inhibiting the firing rate of DRN neurones. These actions were abolished by the 5-HT_1A antagonist, (-)-tertatolol, but unaffected by the hD₂/hD₃ antagonist, haloperidol. Whereas (+)-8-OH-DPAT stimulated VTA neurone firing with a bell-shaped dose response curve, the (-)-isomer only inhibited VTA firing. The (+)-isomer-induced stimulation was blocked by (-)-tertatolol but not haloperidol, whereas the (-)-isomer-induced inhibition was abolished by haloperidol and unaffected by (-)-tertatolol. In contrast to 8-OH-DPAT, the (+)- and (-)-isomers of 7-OH-DPAT showed marked stereoselectivity inasmuch as the latter bound with 20-fold less potency than the former at hD₃ and, at higher concentrations, hD₂ receptors. Correspondingly, (+)-7-OH-DPAT was 20-fold more potent than (-)-7-OH-DPAT in reducing VTA firing. Concerning 5-HT_1A receptors, the (+)-isomer showed 20-fold lower affinity than at hD₃ receptors and, accordingly, it inhibited DRN firing at 20-fold higher doses than for inhibition of VTA firing. (-)-7-OH-DPAT showed even less (5-fold) selectivity for hD₃ vs. 5-HT_1A sites and for inhibition of VTA vs. DRN firing. The inhibition of VTA and DRN neurone firing by (+)-7-OH-DPAT was abolished by haloperidol and (-)-tertatolol, respectively. Finally, in line with this inhibition of DRN firing, both (+)- and (-)-7-OH-DPAT showed substantial efficacy ([³⁵S]-GTPS binding, 76 and 53%, respectively) at h5-HT_1A receptors. In conclusion, for these substituted aminotetralins, stereospecificity is a more marked feature of interactions at hD₃ (and hD₂) than at h5-HT_1A receptors and is more pronounced for 7- as compared to 8-OH-DPAT. Neither (+)- nor (-)-7-OH-DPAT show substantial selectivity for hD₃ vs. 5-HT_1A receptors and their inhibition of the firing of VTA as compared to DRN neurones is mediated by hD₃/hD₂ and 5-HT_1A receptors, respectively. Finally, VTA neurones are stimulated by (+)-8-OH-DPAT via 5-HT_1A receptors and inhibited by (-)-8-OH-DPAT via hD₃ and/or hD₂ receptors.