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Biomedical subjects

A R Lingford-Hughes

Publications and source records attributed to A R Lingford-Hughes.

5 recordsLinked to original sources
PubMed2005

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

RATIONALE: Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. OBJECTIVES: We used positron emission tomography (PET) with [11C]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 [11C]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 [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. RESULTS: A 50% reduction in electroencephalography (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 beta1 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.

Adult↗
PubMed2003

Addiction.

Alcohol and psycho-active substance misuse has far-reaching social, psychological and physical consequences. Advances in neuroimaging technology have allowed neurobiological theories of addiction to become better characterized. We describe the neurobiology of dependence, withdrawal, abstinence and craving states in alcohol, stimulant and opiate misuse. Structural neuroimaging techniques such as CT and MRI with new analytical approaches such as voxel-based morphometry have shown wide-spread changes in stimulant and opiate abuse and atrophy, particularly in the frontal lobes, in alcoholism. Functional neuroimaging techniques such as PET, SPECT and fMRI reveal altered regional cerebral activity by all drugs of abuse. The neurochemistry of addiction, particularly involving dopamine, serotonin, opiate and GABA, has been studied with PET and SPECT and similarities between all drugs of abuse have been found such as reduced dopaminergic markers. The evidence derived from these advances in neuroimaging is likely to herald the emergence of new biological treatments in this important field.

Brain↗
PubMed2000

Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study.

BACKGROUND: Although alcohol dependence in women is an increasing problem, little is known about the effects of alcohol on the female brain. Evidence from a few structural and functional neuroimaging studies suggests that the female brain may be more susceptible than the male brain to the harmful effects of alcohol. However, no in vivo studies of the neuropharmacology of alcohol dependence in women have been carried out. The aim of this preliminary study was to test the hypothesis that alcohol dependence in women is associated with greater reduction in gamma-aminobutyric acid (GABA)-benzodiazepine receptor levels than in men with an equivalent drinking history. METHODS: We used single photon emission tomography and 123I-iomazenil to label the central GABA-benzodiazepine receptor and to compare semiquantified levels in 9 abstinent alcohol-dependent and 13 control women. These groups were further compared with equivalent male groups from a previous study. RESULTS: There was a trend toward a reduction in GABA-benzodiazepine receptor levels in alcohol-dependent women, but this did not reach significance. These lower levels were seen primarily in the cerebellum, occipital lobes, and parietal cortex (left > right). This was in marked contrast with the pattern of reduction seen in the previous study of male dependence, where significant reductions were seen primarily in the frontal cortex. CONCLUSIONS: Due to the semiquantitative analysis performed and the relatively small number of subjects in this study, which resulted in a nonsignificant trend, we can only comment on the differences in the pattern of lower levels of GABA-benzodiazepine receptors seen in alcohol dependence in men and women. Although we are not able to ascertain whether the female brain is more susceptible to the effects of alcohol, it appears that alcohol has a differential effect on the central GABA-benzodiazepine receptors in men and women. Recent animal evidence supports this hypothesis. Future studies should explore whether other neuropharmacological differences exist between men and women in alcohol dependence that could have implications for pharmacotherapy.

Adult↗
PubMed1998

Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy.

BACKGROUND: We tested the hypothesis that reduced levels of the GABA-benzodiazepine receptor occur in alcohol dependency using single photon emission tomography (SPET) and the specific GABA-benzodiazepine ligand, 123I-iomazenil. METHOD: Neurologically and cognitively unimpaired abstinent alcohol-dependent (n = 12) and non-alcohol-dependent male subject (n = 14) underwent a 123I-iomazenil SPET scan. SPET and magnetic resonance images were co-registered and voxel-based statistical tests performed. Subjects' clinical and alcohol history were obtained with standard questionnaires. The relationships between clinical and alcohol variables and the regional level of GABA-benzodiazepine receptors were investigated using multiple regression analysis. RESULTS: Abstinent alcohol-dependent subjects had decreased levels of GABA-benzodiazepine receptor compared with non-alcohol-dependent subjects within the frontal, parietal and temporal cortices, including regions in which grey matter atrophy was absent. CONCLUSIONS: Alcohol dependency is associated with reduced GABA-benzodiazepine receptor levels in the absence of grey matter atrophy in some cortical regions, such as within the parietal lobe. Regional variability of reduction in GABA-benzodiazepine receptors demonstrates that alcohol does not have a global, toxic effect on the brain.

Adult↗