[123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain

E. Sybirska, J. P. Seibyl, J. D. Bremner, R. M. Baldwin, M. S. Al-Tikriti, C. Bradberry, R. T. Malison, Y. Zea-Ponce, S. Zoghbi, M. During, A. W. Goddard, S. W. woods, P. B. Hoffer, D. S. Charney, R. B. Innis

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 ± 0.01 mg/kg (mean ± SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with <3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. <3%) of BZ receptors and that BZ binding sites have a significant (i.e. 97%) receptor reserve.

Original languageEnglish (US)
Pages (from-to)671-680
Number of pages10
JournalNeuropharmacology
Volume32
Issue number7
DOIs
StatePublished - 1993
Externally publishedYes

Fingerprint

Lorazepam
GABA-A Receptors
Primates
Brain
Benzodiazepines
gamma-Aminobutyric Acid
GABA Uptake Inhibitors
GABA Agonists
iomazenil
Papio
Microdialysis
Sensory Receptor Cells
Single-Photon Emission-Computed Tomography
Haplorhini
Binding Sites
Injections
Therapeutics

Keywords

  • benzodiazepine
  • GABA shift
  • lorazepam
  • SPECT

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Sybirska, E., Seibyl, J. P., Bremner, J. D., Baldwin, R. M., Al-Tikriti, M. S., Bradberry, C., ... Innis, R. B. (1993). [123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain. Neuropharmacology, 32(7), 671-680. https://doi.org/10.1016/0028-3908(93)90080-M

[123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain. / Sybirska, E.; Seibyl, J. P.; Bremner, J. D.; Baldwin, R. M.; Al-Tikriti, M. S.; Bradberry, C.; Malison, R. T.; Zea-Ponce, Y.; Zoghbi, S.; During, M.; Goddard, A. W.; woods, S. W.; Hoffer, P. B.; Charney, D. S.; Innis, R. B.

In: Neuropharmacology, Vol. 32, No. 7, 1993, p. 671-680.

Research output: Contribution to journalArticle

Sybirska, E, Seibyl, JP, Bremner, JD, Baldwin, RM, Al-Tikriti, MS, Bradberry, C, Malison, RT, Zea-Ponce, Y, Zoghbi, S, During, M, Goddard, AW, woods, SW, Hoffer, PB, Charney, DS & Innis, RB 1993, '[123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain', Neuropharmacology, vol. 32, no. 7, pp. 671-680. https://doi.org/10.1016/0028-3908(93)90080-M
Sybirska, E. ; Seibyl, J. P. ; Bremner, J. D. ; Baldwin, R. M. ; Al-Tikriti, M. S. ; Bradberry, C. ; Malison, R. T. ; Zea-Ponce, Y. ; Zoghbi, S. ; During, M. ; Goddard, A. W. ; woods, S. W. ; Hoffer, P. B. ; Charney, D. S. ; Innis, R. B. / [123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain. In: Neuropharmacology. 1993 ; Vol. 32, No. 7. pp. 671-680.
@article{e9f494576e9a416fa8607c8b1ecb531a,
title = "[123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain",
abstract = "SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50{\%} of receptor bound activity) and was equal to 0.34 ± 0.01 mg/kg (mean ± SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with <3{\%} BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200{\%} of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. <3{\%}) of BZ receptors and that BZ binding sites have a significant (i.e. 97{\%}) receptor reserve.",
keywords = "benzodiazepine, GABA shift, lorazepam, SPECT",
author = "E. Sybirska and Seibyl, {J. P.} and Bremner, {J. D.} and Baldwin, {R. M.} and Al-Tikriti, {M. S.} and C. Bradberry and Malison, {R. T.} and Y. Zea-Ponce and S. Zoghbi and M. During and Goddard, {A. W.} and woods, {S. W.} and Hoffer, {P. B.} and Charney, {D. S.} and Innis, {R. B.}",
year = "1993",
doi = "10.1016/0028-3908(93)90080-M",
language = "English (US)",
volume = "32",
pages = "671--680",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "7",

}

TY - JOUR

T1 - [123I]Iomazenil spect imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain

AU - Sybirska, E.

AU - Seibyl, J. P.

AU - Bremner, J. D.

AU - Baldwin, R. M.

AU - Al-Tikriti, M. S.

AU - Bradberry, C.

AU - Malison, R. T.

AU - Zea-Ponce, Y.

AU - Zoghbi, S.

AU - During, M.

AU - Goddard, A. W.

AU - woods, S. W.

AU - Hoffer, P. B.

AU - Charney, D. S.

AU - Innis, R. B.

PY - 1993

Y1 - 1993

N2 - SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 ± 0.01 mg/kg (mean ± SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with <3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. <3%) of BZ receptors and that BZ binding sites have a significant (i.e. 97%) receptor reserve.

AB - SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 ± 0.01 mg/kg (mean ± SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with <3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. <3%) of BZ receptors and that BZ binding sites have a significant (i.e. 97%) receptor reserve.

KW - benzodiazepine

KW - GABA shift

KW - lorazepam

KW - SPECT

UR - http://www.scopus.com/inward/record.url?scp=0027336439&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027336439&partnerID=8YFLogxK

U2 - 10.1016/0028-3908(93)90080-M

DO - 10.1016/0028-3908(93)90080-M

M3 - Article

VL - 32

SP - 671

EP - 680

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 7

ER -