beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy

E A Rabiner; R N Gunn; M E Castro; P A Sargent; P J Cowen; M J Koepp; J H Meyer; C J Bench; P J Harrison; A Pazos; T Sharp; P M Grasby

doi:10.1016/S0893-133X(00)00109-3

beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy

Neuropsychopharmacology. 2000 Sep;23(3):285-93. doi: 10.1016/S0893-133X(00)00109-3.

Authors

E A Rabiner¹, R N Gunn, M E Castro, P A Sargent, P J Cowen, M J Koepp, J H Meyer, C J Bench, P J Harrison, A Pazos, T Sharp, P M Grasby

Affiliation

¹ MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom. [email protected]

PMID: 10942852
DOI: 10.1016/S0893-133X(00)00109-3

Abstract

A novel strategy for improving the treatment of depressive illness is augmentation of antidepressants with a 5-HT1(1A) autoreceptor antagonist. However, trials using the 5-HT1(1A)/beta-blocker pindolol are proving inconsistent. We report how positron emission tomography (PET) and in vitro autoradiography can inform trials of antidepressant augmentation. We show that in healthy volunteers, in vivo, pindolol (n = 10) and penbutolol (n = 4), but not tertatolol (n = 4) occupy the human 5-HT(1A) receptors, at clinical doses. Pindolol, as well as the beta-blockers penbutolol and tertatolol, has high affinity for human 5-HT(1A) receptors in post-mortem brain slices (n = 4). Pindolol shows preference for 5-HT(1A) autoreceptors versus the post-synaptic receptors both in vitro and in vivo. Our data reveal that pindolol doses used in antidepressant trials so far are suboptimal for significant occupancy at the 5-HT(1A) autoreceptor. Penbutolol or higher doses of pindolol are candidates for testing as antidepressant augmenting regimes in future clinical trials.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-Antagonists / metabolism*
Adrenergic beta-Antagonists / pharmacology
Adult
Aged
Antidepressive Agents / metabolism*
Autoradiography
Autoreceptors / metabolism
Brain Chemistry / drug effects
Female
Humans
In Vitro Techniques
Male
Middle Aged
Penbutolol / metabolism
Penbutolol / pharmacology
Pindolol / metabolism
Pindolol / pharmacology
Piperazines / metabolism
Propanolamines / metabolism
Propanolamines / pharmacology
Pyridines / metabolism
Receptors, Neurotransmitter / drug effects
Receptors, Neurotransmitter / metabolism
Receptors, Serotonin / metabolism*
Receptors, Serotonin, 5-HT1
Serotonin Antagonists / metabolism
Thiophenes*
Tomography, Emission-Computed

Substances

Adrenergic beta-Antagonists
Antidepressive Agents
Autoreceptors
Piperazines
Propanolamines
Pyridines
Receptors, Neurotransmitter
Receptors, Serotonin
Receptors, Serotonin, 5-HT1
Serotonin Antagonists
Thiophenes
N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
Penbutolol
tertatolol
Pindolol