Is the beneficial antidepressant effect of coadministration of pindolol really due to somatodendritic autoreceptor antagonism?

Background: We investigated the combination of selective serotonin reuptake inhibitors (SSRIs) with the beta -adrenoceptor/serotonin 1A (5-HT1A) antagonist pindolol, based on the concept that 5-HT1A receptor blockade would eliminate the need for desensitization of presynaptic 5-HT1A receptors and therefore hasten the onset of action and improve the efficacy of SSRIs. However, since pindolol plasma levels after 2.5 mg three times a day are about 60 nmol/L, and the K-i for the 5-HT1A receptor is 30 nmol/L, it is questionable whether pindolol levels in the brain would be sufficient to antagonize 5-HT1A receptors. Using microdialysis in the guinea pig, we correlated brain and plasma levels of pindolol with its capability of augmenting paroxetine-induced increases in brain 5-HT levels. In addition, central beta -receptor antagonism of pindolol was studied by investigating blockade of beta -agonist-induced increases in brain cyclic adenosine monophosphate (cAMP) formation. Methods: Using microdialysis and jugular vein catheterization, we studied the ability of systemically administered pindolol to antagonize central 5-HT1A and beta -adrenoceptors, while simultaneously monitoring pindolol plasma and brain concentrations. Results: Augmentation of paroxetine-induced increases in extracellular 5-HT levels in the ventral hippocampus was only observed at steady stare plasma levels exceeding 7000 nmol/L (concurrent brain levels 600 nmol/L). In contrast, antagonism of beta -agonist-induced increases of brain cAMP levels was already observed at pindolol plasma levels of 70 nmol/L (concurrent brain levels