Possible in vivo 5-HT reuptake blocking properties of 8-OH-DPAT assessed by measuring hippocampal extracellular 5-HT using microdialysis in rats

1 The 5-hydroxytryptamine (5-HT)(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), has been shown to label 5-HT reuptake sites. 2 To study the functional consequences of this property, the effects of 8-OH-DPAT were compared with those of the 5-HT reuptake inhibitors, paroxetine and clomipramine, and of the 5-HT1A receptor agonist flesinoxan, in vitro on 5-HT reuptake, and in vivo on the extracellular concentration of 5-HT by use of microdialysis, in rat hippocampus. Because 5-HT reuptake inhibitors reportedly attenuate the ability of (+)-fenfluramine to increase the extracellular concentration of 5-HT, the possible reversal of these effects by 8-OH-DPAT and by paroxetine were examined. 3 8-OH-DPAT, paroxetine and clomipramine inhibited [H-3]-5-HT reuptake in rat hippocampal synaptosomes (pIC(50): 6.00, 8.41 and 7.00, respectively). In contrast, flesinoxan did not alter 5-HT reuptake (pIC(50) < 5); 4 8-OH-DPAT (10 and 100 mu M), paroxetine (0.1 mu M) and clomipramine (1 mu M), administered through the dialysis probe, significantly increased the hippocampal extracellular concentration of 5-HT. In contrast, flesinoxan (100 mu M) did not alter extracellular 5-HT. Moreover, the effects of 100 mu M 8-OH-DPAT were not blocked by the 5-HT1A receptor antagonist, WAY-100635 (0.16 mg kg(-1), s.c.). 5 The increase in extracellular 5-HT induced by 10 mg kg(-1), i.p., (+)-fenfluramine was prevented not only by 0.1 mu M paroxetine, but also by 100 mu M 8-OH-DPAT. In addition, systemic administration of 10 mg kg(-1), but not 2.5 mg kg(-1), i.p. 8-OH-DPAT attenuated the increase in extracellular 5-HT induced by 2.5 mg kg(-1), i.p., (+)-fenfluramine. 6 These findings suggest that the increase in extracellular 5-HT produced by local administration of 8-OH-DPAT does not involve its S-HT1A receptor agonist properties, but may result, at least in part, from its 5-HT reuptake blocking properties.