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

• Published in: Biological psychiatry (1969) Vol. 50; no. 1; pp. 13 - 21
• Main Authors: Cremers, Thomas I.F.H, Wiersma, Loes J, Bosker, Fokko J, den Boer, Johan A, Westerink, Ben H.C, Wikström, Håkan V
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-07-2001; Elsevier Science
• Subjects: 5-HT1A; Animals; Antidepressive Agents - pharmacology; Autoreceptors - antagonists & inhibitors; Biological and medical sciences; Brain - drug effects; Brain - pathology; Cyclic AMP - metabolism; guinea pig; Guinea Pigs; Hippocampus - drug effects; Magnetic Resonance Imaging; Male; Medical sciences; microdialysis; Neuropharmacology; paroxetine; Paroxetine - metabolism; Paroxetine - pharmacokinetics; Pharmacology. Drug treatments; Pindolol; Pindolol - blood; Pindolol - pharmacokinetics; Pindolol - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - pharmacokinetics; Serotonin Antagonists - pharmacology; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacokinetics; SSRI; Synaptic Transmission - drug effects; Time Factors; Tomography, Emission-Computed; 5-HT1A; guinea pig; SSRI; paroxetine; microdialysis; Pindolol; Performance evaluation; Isoprenaline; Reuptake inhibitor; β-Adrenergic receptor; Guinea pig; Piperidine derivatives; Antidepressant agent; Antagonist; Quantitative analysis; Paroxetine; Drug combination; Serotonin; Rodentia; Cyclic AMP; Exploration; Pharmacology; Experimental study; Vertebrata; Chemotherapy; Mammalia; Microdialysis; Treatment; Animal; Pharmacokinetics; Comparative study
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/S0006-3223(00)01093-3

Background: We investigated the combination of selective serotonin reuptake inhibitors (SSRIs) with the β-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 Ki 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 β-receptor antagonism of pindolol was studied by investigating blockade of β-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 β-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 β-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 (∼60 nmol/L), pindolol produces only a partial blockade of presynaptic 5-HT1A 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-HT1A antagonism. Since pindolol completely blocks central β-adrenoreceptors at clinically relevant plasma levels, it is possible that β-adrenoceptor antagonism is involved in mediating pindolol’s beneficial effects.