Similar pharmacological properties of 8-OH-DPAT and alnespirone (S 20499) at dopamine receptors: comparison with buspirone.
Alnespirone (S 20499) has previously been described as a potential anxiolytic drug that acts by stimulation of 5-HT1A receptors. Some data suggest that alnespirone might also be a weak dopamine D2 receptor agonist: it displays moderate affinity for dopamine D2 receptors in vitro and it inhibits prolactin release and induces yawning in rats. In order to test for possible interactions of alnespirone with dopamine receptors in vivo, we studied the changes of in vivo striatal [3H]SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine) and [3H]raclopride binding following the injection of a tracer dose of either tritiated ligand (4 microCi) in mice treated with increasing doses of alnespirone (5, 10, 20 and 40 mg/kg, i.p.) and, in the same animals, the changes in the levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). These changes were compared with those produced by increasing doses of the reference 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin, 0.25, 1 and 4 mg/kg, i.p.) or buspirone (5 and 20 mg/kg, i.p.). Decreased in vivo striatal [3H]SCH 23390 specific binding was observed in mice treated with 5, 10 and 40 mg/kg alnespirone. In contrast, increased in vivo striatal [3H]raclopride specific binding was observed in mice treated with 5 and 20 mg/kg alnespirone. In these animals, the striatal 5-HIAA/5-HT ratio was decreased by 5 to 40 mg/kg alnespirone, whereas the striatal HVA/DA ratio was unaffected at all tested doses of alnespirone. Similarly, 8-OH-DPAT decreased specific in vivo striatal [3H]SCH 23390 binding at 0.25, 1 and 4 mg/kg, and increased in vivo specific striatal [3H]raclopride binding at 1 and 4 mg/kg. In the same animals, all tested doses of 8-OH-DPAT decreased the striatal 5-HIAA/5-HT ratio but did not modify the striatal HVA/dopamine ratio. Buspirone (5 and 20 mg/kg) completely inhibited in vivo specific striatal [3H]raclopride binding and increased the striatal HVA/DA ratio but did not modify the striatal 5-HIAA/5-HT ratio, whereas apomorphine (3 mg/kg) decreased both in vivo specific striatal [3H]SCH 23390 and [3H]raclopride binding as well as the striatal HVA/DA and 5-HIAA/5-HT ratios. Finally, increasing doses of alnespirone or 8-OH-DPAT weakly increased sniffing induced by apomorphine (0.75 mg/kg, s.c.) in mice and decreased grooming induced by the dopamine D1 receptor agonist SK&F 39393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, 1.87 mg/kg, s.c.), whereas buspirone decreased both apomorphine-induced sniffing and SK&F 39393-induced grooming. These results indicate that alnespirone and 8-OH-DPAT have a similar profile and do not seem to interact directly with dopamine receptors. The results also suggest that the stimulation of 5-HT1A receptors by either alnespirone or 8-OH-DPAT modulates the availability of striatal [3H]SCH 23390 and [3H]raclopride binding sites and possibly the functioning of striatal dopamine D1 and D2 receptors in opposite directions.
Protais
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Laboratoire de Physiologie (VACOMED), U.F.R. de Médecine-Pharmacie de Rouen, Saint Etienne Rouvray, France. philippe.protais@univ-rouen.fr
Lesourd
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Comoy
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000378:metabolism; D002065:Buspirone / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D020891:Raclopride; D012457:Salicylamides / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D014316:Tritium
D014151:Anti-Anxiety Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D010879:Piperazines; D012457:Salicylamides; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D014316:Tritium; C081293:WAY 100135; D012701:Serotonin; C075319:alnespirone; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001058:Apomorphine; D002065:Buspirone; D004298:Dopamine