PT - JOURNAL ARTICLE AU - F. Lejeune AU - A. Newman-Tancredi AU - V. Audinot AU - M. J. Millan TI - Interactions of (+)- and (−)-8- and 7-Hydroxy-2-(Di-n-Propylamino)tetralin at Human (h)D<sub>3</sub>, hD<sub>2 </sub>and h Serotonin<sub>1A </sub>Receptors and Their Modulation of the Activity of Serotoninergic and Dopaminergic Neurones in Rats DP - 1997 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1241--1249 VI - 280 IP - 3 4099 - http://jpet.aspetjournals.org/content/280/3/1241.short 4100 - http://jpet.aspetjournals.org/content/280/3/1241.full SO - J Pharmacol Exp Ther1997 Mar 01; 280 AB - 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 D2receptors, 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-HT1A autoreceptors, and of dopaminergic neurones of the ventral tegmental area (VTA), which possess inhibitory D3and D2 receptors. These actions were compared to theirin vitro interactions with cloned, human (h)5-HT1A, hD3 and hD2 receptors. In binding studies, racemic 8-OH-DPAT showed 100-fold selectivity for h5-HT1A vs. hD2 and hD3 receptors and there was little difference between its (+)- and (-)-isomers either in terms of their potency at 5-HT1A receptors or of their selectivity at 5-HT1A 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]-GTPγS) at h5-HT1A 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-HT1Aantagonist, (-)-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, hD2receptors. Correspondingly, (+)-7-OH-DPAT was 20-fold more potent than (-)-7-OH-DPAT in reducing VTA firing. Concerning 5-HT1Areceptors, 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-HT1A 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]-GTPγS binding, 76 and 53%, respectively) at h5-HT1A receptors. In conclusion, for these substituted aminotetralins, stereospecificity is a more marked feature of interactions at hD3 (and hD2) than at h5-HT1A 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-HT1Areceptors and their inhibition of the firing of VTA as compared to DRN neurones is mediated by hD3/hD2 and 5-HT1A receptors, respectively. Finally, VTA neurones are stimulated by (+)-8-OH-DPAT via 5-HT1A receptors and inhibited by (-)-8-OH-DPAT via hD3 and/or hD2receptors. The American Society for Pharmacology and Experimental Therapeutics