The role of 5-HT1A and 5-HT1B/1D receptors on the modulation of acute fluoxetine-induced changes in extracellular 5-HT:: the mechanism of action of (±)pindolol

Some clinical evidence has suggested that (+/-)pindolol can be effective at producing a shortened time to onset of antidepressant activity when co-administered with a Serotonin specific reuptake inhibitor (SSRI). This effect has been attributed to the antagonist effects of pindolol at the 5-HT1A receptor. In the present study, we compared the pharmacology of (+/-)pindolol, WAY-100635 (a 5-HT1A antagonist), GR127935 (a 5-HT1B/1D antagonist), and isamoltane (a 5-HT1B antagonist), when given acutely in combination with fluoxetine. using in vivo microdialysis in the frontal cortex of the freely moving rat. We have determined that the acute fluoxetine-induced increases in extracellular 5-HT can be augmented by (+/-)pindolol. WAY100635, GR127935 and isamoltane with maximum increases of 216+/-32%. 235+/-49%, 240+/-18% and 171+/-47% of preinjection control levels, respectively. Combination of both 5-HT1A and 5-HT1B/1D autoreceptor antagonists with fluoxetine produced additive increases in extracellular 5-HT (i.e. WAY100635+GR127935+fluoxetine and WAY100635+isamoltane+fluoxetine produced a four- and five-fold potentiation, respectively), suggesting that this strategy may be useful in further augmenting the action of a SSRI in the. treatment of depression In addition, by comparing the combined administration of(+/-)pindolol with tither WAY100635, GR127935 or isamoltane, we have determined that (+/-)pindolol produces much of its acute potentiation of fluoxetine-induced increases in extracellular 5-HT via its action at the 5-HT1B/D receptor in addition to any activity it has at the presynaptic 5-HT1A receptor. (C) 2000 Elsevier Science Ltd. All rights reserved.