Interactions of (+)- and (-)-8- and 7-hydroxy-2-(di-n-propylamino)tetralin at human (h)D3, hD2 and h serotonin1A receptors and their modulation of the activity of serotoninergic and dopaminergic neurones in rats.
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-HT1A 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-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]-GTPgammaS) 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-HT1A 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-HT1A 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-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]-GTPgammaS 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-HT1A receptors 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 hD2 receptors.
Lejeune
F
F
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, France.
Newman-Tancredi
A
A
Audinot
V
V
Millan
M J
MJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000378:metabolism* / Q000494:pharmacology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C031349:7-hydroxy-2-N,N-dipropylaminotetralin