Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans

Masahiro Fujita; Scott W. Woods; N. Paul L.G. Verhoeff; Anissa Abi-Dargham; Ronald M. Baldwin; Sami S. Zoghbi; Jair C. Soares; Peter A. Jatlow; John H. Krystal; Nallakkandi Rajeevan; Dennis S. Charney; John P. Seibyl; Robert B. Innis

doi:10.1016/S0014-2999(99)00013-8

Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans

Masahiro Fujita, Scott W. Woods, N. Paul L.G. Verhoeff, Anissa Abi-Dargham, Ronald M. Baldwin, Sami S. Zoghbi, Jair C. Soares, Peter A. Jatlow, John H. Krystal, Nallakkandi Rajeevan, Dennis S. Charney, John P. Seibyl, Robert B. Innis

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans. Copyright (C) 1999 Elsevier Science B.V.

Original language	English (US)
Pages (from-to)	161-172
Number of pages	12
Journal	European Journal of Pharmacology
Volume	368
Issue number	2-3
DOIs	https://doi.org/10.1016/S0014-2999(99)00013-8
State	Published - Mar 5 1999

Keywords

Benzodiazepine
Down regulation
GABA(A)/benzodiazepine receptor
Human
SPECT (single photon emission computed tomography)

ASJC Scopus subject areas

Pharmacology

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10.1016/S0014-2999(99)00013-8

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Fujita, M., Woods, S. W., Verhoeff, N. P. L. G., Abi-Dargham, A., Baldwin, R. M., Zoghbi, S. S., Soares, J. C., Jatlow, P. A., Krystal, J. H., Rajeevan, N., Charney, D. S., Seibyl, J. P., & Innis, R. B. (1999). Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. European Journal of Pharmacology, 368(2-3), 161-172. https://doi.org/10.1016/S0014-2999(99)00013-8

Fujita, M, Woods, SW, Verhoeff, NPLG, Abi-Dargham, A, Baldwin, RM, Zoghbi, SS, Soares, JC, Jatlow, PA, Krystal, JH, Rajeevan, N, Charney, DS, Seibyl, JP & Innis, RB 1999, 'Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans', European Journal of Pharmacology, vol. 368, no. 2-3, pp. 161-172. https://doi.org/10.1016/S0014-2999(99)00013-8

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abstract = "Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans. Copyright (C) 1999 Elsevier Science B.V.",

keywords = "Benzodiazepine, Down regulation, GABA(A)/benzodiazepine receptor, Human, SPECT (single photon emission computed tomography)",

author = "Masahiro Fujita and Woods, {Scott W.} and Verhoeff, {N. Paul L.G.} and Anissa Abi-Dargham and Baldwin, {Ronald M.} and Zoghbi, {Sami S.} and Soares, {Jair C.} and Jatlow, {Peter A.} and Krystal, {John H.} and Nallakkandi Rajeevan and Charney, {Dennis S.} and Seibyl, {John P.} and Innis, {Robert B.}",

note = "Funding Information: The authors thank staff of NeuroSPECT Center, L. Amici, B. Barnes, M. Sullivan, J. White, H. Nadim, S. Giddings, Q. Ramsby and R. Feinn for excellent technical assistance. The authors also thank Roy Money, MS and Marilyn Stolar, PhD for their help in statistical analyses. This work was supported by funds from the Department of Veterans Affairs (PTSD Center) and the Public Health Service (DA 10208).",

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doi = "10.1016/S0014-2999(99)00013-8",

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AU - Fujita, Masahiro

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AU - Verhoeff, N. Paul L.G.

AU - Abi-Dargham, Anissa

AU - Baldwin, Ronald M.

AU - Zoghbi, Sami S.

AU - Soares, Jair C.

AU - Jatlow, Peter A.

AU - Krystal, John H.

AU - Rajeevan, Nallakkandi

AU - Charney, Dennis S.

AU - Seibyl, John P.

AU - Innis, Robert B.

N1 - Funding Information: The authors thank staff of NeuroSPECT Center, L. Amici, B. Barnes, M. Sullivan, J. White, H. Nadim, S. Giddings, Q. Ramsby and R. Feinn for excellent technical assistance. The authors also thank Roy Money, MS and Marilyn Stolar, PhD for their help in statistical analyses. This work was supported by funds from the Department of Veterans Affairs (PTSD Center) and the Public Health Service (DA 10208).

PY - 1999/3/5

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N2 - Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans. Copyright (C) 1999 Elsevier Science B.V.

AB - Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans. Copyright (C) 1999 Elsevier Science B.V.

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Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans

Abstract

Keywords

ASJC Scopus subject areas

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