GABA-benzodiazepine receptor function in alcohol dependence

a combined 11C-flumazenil PET and pharmacodynamic study

A R Lingford-Hughes, J. S. Wilson, Vincent Joseph Cunningham, Adrian Feeney, B Stevenson, D. J. Brooks, David J Nutt

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Rationale: Gamma-aminobutyric acid (GABA)benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. Objectives: We used positron emission tomography (PET) with [C-11]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Methods: Abstinent male alcohol dependent subjects underwent [C-11] flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [C-11]flumazenil between the plasma and brain compartments were derived from time activity curves. Results: A 50% reduction in electro- encephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG betal power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. Conclusions: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.
Original languageEnglish
Pages (from-to)595-606
Number of pages12
JournalPsychopharmacology
Volume180
Issue number4
DOIs
Publication statusPublished - Aug 2005

Fingerprint

Flumazenil
GABA Receptors
Midazolam
GABA-A Receptors
Positron-Emission Tomography
Alcoholism
Electroencephalography
Sleep
Alcohols
Saccades
Brain
Benzodiazepines
Control Groups

Keywords

  • adult
  • alcoholism
  • analysis of variance
  • blood pressure
  • brain
  • case-control studies
  • competitive bidding
  • electroencephalography
  • Flumazenil
  • GABA modulators
  • heart rate
  • humans
  • computer-assisted image processing
  • male
  • Midazolam
  • middle aged
  • pain measurement
  • positron emission tomography
  • GABA-A receptors
  • saccades
  • Severity of Illness Index
  • sleep
  • test anxiety scale
  • time factors
  • tritium

Cite this

Lingford-Hughes, A. R., Wilson, J. S., Cunningham, V. J., Feeney, A., Stevenson, B., Brooks, D. J., & Nutt, D. J. (2005). GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology, 180(4), 595-606. https://doi.org/10.1007/s00213-005-2271-x

GABA-benzodiazepine receptor function in alcohol dependence : a combined 11C-flumazenil PET and pharmacodynamic study. / Lingford-Hughes, A R; Wilson, J. S.; Cunningham, Vincent Joseph; Feeney, Adrian; Stevenson, B; Brooks, D. J.; Nutt, David J.

In: Psychopharmacology, Vol. 180, No. 4, 08.2005, p. 595-606.

Research output: Contribution to journalArticle

Lingford-Hughes, AR, Wilson, JS, Cunningham, VJ, Feeney, A, Stevenson, B, Brooks, DJ & Nutt, DJ 2005, 'GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study', Psychopharmacology, vol. 180, no. 4, pp. 595-606. https://doi.org/10.1007/s00213-005-2271-x
Lingford-Hughes, A R ; Wilson, J. S. ; Cunningham, Vincent Joseph ; Feeney, Adrian ; Stevenson, B ; Brooks, D. J. ; Nutt, David J. / GABA-benzodiazepine receptor function in alcohol dependence : a combined 11C-flumazenil PET and pharmacodynamic study. In: Psychopharmacology. 2005 ; Vol. 180, No. 4. pp. 595-606.
@article{811a9fceaa014114a0e77ac73c062911,
title = "GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study",
abstract = "Rationale: Gamma-aminobutyric acid (GABA)benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. Objectives: We used positron emission tomography (PET) with [C-11]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Methods: Abstinent male alcohol dependent subjects underwent [C-11] flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [C-11]flumazenil between the plasma and brain compartments were derived from time activity curves. Results: A 50{\%} reduction in electro- encephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG betal power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. Conclusions: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.",
keywords = "adult, alcoholism, analysis of variance, blood pressure, brain, case-control studies, competitive bidding, electroencephalography, Flumazenil, GABA modulators, heart rate, humans, computer-assisted image processing, male, Midazolam, middle aged, pain measurement, positron emission tomography, GABA-A receptors, saccades, Severity of Illness Index, sleep, test anxiety scale, time factors, tritium",
author = "Lingford-Hughes, {A R} and Wilson, {J. S.} and Cunningham, {Vincent Joseph} and Adrian Feeney and B Stevenson and Brooks, {D. J.} and Nutt, {David J}",
year = "2005",
month = "8",
doi = "10.1007/s00213-005-2271-x",
language = "English",
volume = "180",
pages = "595--606",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - GABA-benzodiazepine receptor function in alcohol dependence

T2 - a combined 11C-flumazenil PET and pharmacodynamic study

AU - Lingford-Hughes, A R

AU - Wilson, J. S.

AU - Cunningham, Vincent Joseph

AU - Feeney, Adrian

AU - Stevenson, B

AU - Brooks, D. J.

AU - Nutt, David J

PY - 2005/8

Y1 - 2005/8

N2 - Rationale: Gamma-aminobutyric acid (GABA)benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. Objectives: We used positron emission tomography (PET) with [C-11]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Methods: Abstinent male alcohol dependent subjects underwent [C-11] flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [C-11]flumazenil between the plasma and brain compartments were derived from time activity curves. Results: A 50% reduction in electro- encephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG betal power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. Conclusions: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

AB - Rationale: Gamma-aminobutyric acid (GABA)benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. Objectives: We used positron emission tomography (PET) with [C-11]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Methods: Abstinent male alcohol dependent subjects underwent [C-11] flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [C-11]flumazenil between the plasma and brain compartments were derived from time activity curves. Results: A 50% reduction in electro- encephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG betal power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. Conclusions: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

KW - adult

KW - alcoholism

KW - analysis of variance

KW - blood pressure

KW - brain

KW - case-control studies

KW - competitive bidding

KW - electroencephalography

KW - Flumazenil

KW - GABA modulators

KW - heart rate

KW - humans

KW - computer-assisted image processing

KW - male

KW - Midazolam

KW - middle aged

KW - pain measurement

KW - positron emission tomography

KW - GABA-A receptors

KW - saccades

KW - Severity of Illness Index

KW - sleep

KW - test anxiety scale

KW - time factors

KW - tritium

U2 - 10.1007/s00213-005-2271-x

DO - 10.1007/s00213-005-2271-x

M3 - Article

VL - 180

SP - 595

EP - 606

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 4

ER -