Effects of chronic fluoxetine treatment in the presence and absence of (+/-)pindolol: a microdialysis study

1 Using in vivo microdialysis in the frontal cortex of the freely moving ra t we evaluated the effects of chronic treatment with the serotonin specific reuptake inhibitor (SSRI) fluoxetine in the presence and absence of the 5- HT1A/beta-adrenergic antagonist (+/-)pindolol. 2 Chronic vehicle treated animals produced no significant response to a cha llenge with fluoxetine (10 mg kg(-1)) on day 8 and 15. Alternatively, a sig nificant (P<0.05) decrease in extracellular 5-HT was observed in control an imals upon challenge with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.03 and 0.1 mg kg(-1)). 3 Conversely, animals treated with fluoxetine (10 mg kg(-1) o.d.) for 7 and 14 days produced a significant (P<0.05) 2 fold increase in extracellular 5 -HT when challenged with fluoxetine (10 mg kg(-1)) on day 8 and 15. Moreove r, no significant decrease in extracellular 5-HT was observed upon challeng e with either dose of 8-OH-DPAT. 4 Animals chronically treated with (+/-)pindolol (10 or 20 mg kg(-1) b.i.d. ) produced a significant dose-related increase in extracellular 5-HT upon c hallenge with fluoxetine on day 15 only. Furthermore, both doses produced a significantly blunted response to the low dose challenge of OH-DPAT (0.03 mg kg(-1)). In addition, 20 mg kg(-1) (+/-)pindolol treated animals also ha d no response to the higher 0.1 mg kg-l dose of 8-OH-DPAT. 5 Animals treated for 14 days with a combination of (+/-)pindolol (10 or 20 mg kg(-1)) and fluoxetine were not significantly different from vehicle tr eated animals when challenged with fluoxetine or 8-OH-DPAT. 6 Taken together it would therefore appear that although (+/-)pindolol alon e has sufficient intrinsic activity to produce a desensitization of the 5-H T1A receptor, when given in combination with fluoxetine it is able to preve nt the desensitization induced by not only fluoxetine but also itself. This may suggest that the clinical augmentation of antidepressant action by pin dolol, when coadministered with a SSRI, is via antagonism of the 5-HT1A rec eptor.