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-HT(1A)) antagonist pindolol, based on the concept that 5-HT(1A) receptor blockade would eliminate the need for desensitization of presynaptic 5-HT(1A) 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-HT(1A) receptor is 30 nmol/L, it is questionable whether pindolol levels in the brain would be sufficient to antagonize 5-HT(1A) 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-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 state 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 < 3 nmol/L).


CONCLUSIONS
At plasma levels that are observed in patients after 2.5 mg three times a day ( approximately 60 nmol/L), pindolol produces only a partial blockade of presynaptic 5-HT(1A) autoreceptors and does not augment the SSRI-induced 5-HT increase in the guinea pig brain. It is therefore very unlikely that the favorable effects of combining pindolol with SSRIs, as reported in a number of clinical studies, are due to 5-HT(1A) antagonism. Since pindolol completely blocks central beta-adrenoreceptors at clinically relevant plasma levels, it is possible that beta-adrenoceptor antagonism is involved in mediating pindolol's beneficial effects.
Cremers
T I
TI
Department of Medicinal Chemistry, University of Groningen, Groningen, The Netherlands.
Wiersma
L J
LJ
Bosker
F J
FJ
den Boer
J A
JA
Westerink
B H
BH
Wikström
H V
HV
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017660:Autoreceptors / Q000037:antagonists & inhibitors*; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D017374:Paroxetine / Q000378:metabolism / Q000493:pharmacokinetics; D010869:Pindolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D014055:Tomography, Emission-Computed
D000928:Antidepressive Agents; D017660:Autoreceptors; D000242:Cyclic AMP; D017374:Paroxetine; D010869:Pindolol; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors