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 anx iolytic drug that acts by stimulation of 5-HT1A receptors. Some data s uggest that alnespirone might also be a weak dopamine D-2 receptor ago nist: it displays moderate affinity for dopamine D-2 receptors in vitr o and it inhibits prolactin release and induces yawning in rats. In or der to test for possible interactions of alnespirone with dopamine rec eptors in vivo, we studied the changes of in vivo striatal [H-3]SCH 23 390 thyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and [3H]raclopr ide binding following the injection of a tracer dose of either tritiat ed ligand (4 mu Ci) in mice treated with increasing doses of alnespiro ne (5, 10, 20 and 40 mg/kg, i.p.) and, in the same animals, the change s in the levels of dopamine, 5-hydroxytryptamine (5-HT) and their meta bolites 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 recept or 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 v ivo striatal [H-3]SCH 23390 specific binding was observed in mice trea ted with 5, 10 and 40 mg/kg alnespirone. Ln contrast, increased in viv o striatal [H-3]raclopride specific binding was observed in mice treat ed with 5 and 20 mg/kg alnespirone. In these animals, the striatal 5-H IAA/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 alnespiro ne. Similarly, 8-OH-DPAT decreased specific in vivo striatal [H-3]SCH 23390 binding at 0.25, 1 and 4 mg/kg, and increased in vivo specific s triatal [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 [H-3]raclopri de binding and increased the striatal HVA/DA ratio but did not modify the striatal 5-HIAA/5-HT ratio, whereas apomorphine (3 mg/kg) decrease d both in vivo specific striatal [H-3]SCH 23390 and [H-3]raclopride bi nding 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 groom ing induced by the dopamine D-1 receptor agonist SK&F 39393 yl-2,3,4,5 -tetrahydro-(1H)-3-benzazepine-7,8-diol, 1.87 mg/kg, s.c.), whereas bu spirone decreased both apomorphine-induced sniffing and SK&F 39393-ind uced grooming. These results indicate that alnespirone and 8-OH-DPAT h ave a similar profile and do not seem to interact directly with dopami ne receptors. The results also suggest that the stimulation of 5-HT1A receptors by either alnespirone or 8-OH-DPAT modulates the availabilit y of striatal [3H]SCH 23390 and [H-3]raclopride binding sites and poss ibly the functioning of striatal dopamine D-1 and D-2 receptors in opp osite directions. (C) 1998 Elsevier Science B.V. All rights reserved.