title: beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy.
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.
authors.affiliation: MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom. ilan@cu.rpms.ac.uk
authors.forename: E A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: R N
authors.initials: RN
authors.lastname: Gunn
authors.forename: M E
authors.initials: ME
authors.lastname: Castro
authors.forename: P A
authors.initials: PA
authors.lastname: Sargent
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowen
authors.forename: M J
authors.initials: MJ
authors.lastname: Koepp
authors.forename: J H
authors.initials: JH
authors.lastname: Meyer
authors.forename: C J
authors.initials: CJ
authors.lastname: Bench
authors.forename: P J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: A
authors.initials: A
authors.lastname: Pazos
authors.forename: T
authors.initials: T
authors.lastname: Sharp
authors.forename: P M
authors.initials: PM
authors.lastname: Grasby
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000378:metabolism*; D001345:Autoradiography; D017660:Autoreceptors / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010394:Penbutolol / Q000378:metabolism / Q000494:pharmacology; D010869:Pindolol / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism; D013876:Thiophenes; D014055:Tomography, Emission-Computed
chemical_list: D000319:Adrenergic beta-Antagonists; D000928:Antidepressive Agents; D017660:Autoreceptors; D010879:Piperazines; D011412:Propanolamines; D011725:Pyridines; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D013876:Thiophenes; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010394:Penbutolol; C005632:tertatolol; D010869:Pindolol