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) antag onist pindolol, based on the concept that 5-HT1A receptor blockade would el iminate the need for desensitization of presynaptic 5-HT1A receptors and th erefore hasten the onset of action and improve the efficacy of SSRIs. Howev er, since pindolol plasma levels after 2.5 mg three times a day are about 6 0 nmol/L, and the K-i for the 5-HT1A receptor is 30 nmol/L, it is questiona ble whether pindolol levels in the brain would be sufficient to antagonize 5-HT1A receptors. Using microdialysis in the guinea pig, we correlated brai n and plasma levels of pindolol with its capability of augmenting paroxetin e-induced increases in brain 5-HT levels. In addition, central beta -recept or antagonism of pindolol was studied by investigating blockade of beta -ag onist-induced increases in brain cyclic adenosine monophosphate (cAMP) form ation. Methods: Using microdialysis and jugular vein catheterization, we studied t he ability of systemically administered pindolol to antagonize central 5-HT 1A 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 cont rast, antagonism of beta -agonist-induced increases of brain cAMP levels wa s already observed at pindolol plasma levels of 70 nmol/L (concurrent brain levels < 3 nmol/L) Conclusions: At plasma levels that are observed in patients after 2.5 mg th ree times a day (<similar to>60 nmol/L), pindolol produces only a partial b lockade of presynaptic 5-HT1A autoreceptors and does not augment the SSRI-i nduced 5-HT increase in the guinea pig brain. It is therefore very unlikely that the favorable effects of combining pindolol with SSRIs, as reported i n a number of clinical studies, are due to 5-HT1A antagonism. Since pindolo l completely blocks central beta -adrenoreceptors at clinically relevant pl asma levels, it is possible that beta -adrenoceptor antagonism is involved in mediating pindolol's beneficial effects. Biol Psychiatry 2001;50:13-21 ( C) 2001 Society of Biological Psychiatry.