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Possible in vivo 5‐HT reuptake blocking properties of 8‐OH‐DPAT assessed by measuring hippocampal extracellular 5‐HT using microdialysis in rats
Author(s) -
Assié MarieBernadette,
Koek Wouter
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15749.x
Subject(s) - microdialysis , reuptake , chemistry , reuptake inhibitor , agonist , endocrinology , medicine , paroxetine , pharmacology , clomipramine , extracellular , serotonin , receptor , biochemistry
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‐HT 1A 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 [ 3 H]‐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 μ m ), paroxetine (0.1 μ m ) and clomipramine (1 μ m ), administered through the dialysis probe, significantly increased the hippocampal extracellular concentration of 5‐HT. In contrast, flesinoxan (100 μ m ) did not alter extracellular 5‐HT. Moreover, the effects of 100 μ m 8‐OH‐DPAT were not blocked by the 5‐HT 1A 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 μ m paroxetine, but also by 100 μ 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 5‐HT 1A receptor agonist properties, but may result, at least in part, from its 5‐HT reuptake blocking properties.