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

Lingford-Hughes, AR; Wilson, SJ; Cunningham, VJ; Feeney, Adrian; Stevenson, Brian J.; Brooks, David J.; Nutt, DJ

doi:10.1007/s00213-005-2271-x

Cited by 47 publications

(31 citation statements)

References 56 publications

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“…Furthermore, the GABA/benzodiazepine receptor availability in the cerebellum and occipital lobe at 1 week of abstinence was correlated with the severity of ethanol withdrawal determined in the subjects every 6 h immediately after admission to the clinic (Staley et al 2005). Using [ 11 C]-flumazenil PET to measure the pharmacokinetics and pharmacodynamics of midazolam, Lingford-Hughes et al (2005) showed that ethanol dependence was associated with decreased midazolam-induced time asleep in the absence of reduced benzodiazepine receptor occupancy in ethanol-dependent patients abstinent for at least 6 weeks. The authors hypothesized that this reduced sensitivity in ethanol dependence may reflect a difference in the subunit profile of the GABA A receptors, either as part of the vulnerability to, or as a consequence of their ethanol dependence.…”

Section: Human Alcoholicsmentioning

confidence: 99%

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

et al. 2009

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The past decade has brought many advances in our understanding of GABA A receptor-mediated ethanol action in the central nervous system. We now know that specific GABA A receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABA A receptors promoting increases in GABA sensitivity. Ethanol's effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABA A receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

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Section: Human Alcoholicsmentioning

confidence: 99%

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

et al. 2009

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“…When a saturation method or V T was used with [ 11 C]flumazenil or [ 123 I]iomazenil, group differences were either absent (Lingford-Hughes et al, 2000; Lingford-Hughes et al, 2005; Litton et al, 1993) or reversed (Jalan et al, 2000). However, recall that this latter study included alcohol-addicted individuals of older age and with liver disease, which may have affected findings.…”

Section: Gabaergic Changes In Drug Addiction (Table 2)mentioning

confidence: 99%

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity

Moeller

London

Northoff³

2016

Neuroscience & Biobehavioral Reviews

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Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications.

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“…For instance, GABA A receptor density can be inferred in PET using [11C]flumazenil, and more recently [18F]AH114726 (Rodnick, et al, 2013), GABA A benzodiazepine receptor antagonists, and [123l]iomazenil, a GABA A benzodiazepine receptor inverse agonist. Using these radiotracer methods, reduced GABA A receptor densities have been reported in 1-month, 3-month and 7-month abstinence alcohol dependent patients, and from brain regions that include the medial prefrontal cortex and cerebellum (Abi-Dargham, et al, 1998; Lingford-Hughes, et al, 2000; Lingford-Hughes, et al, 1998; Lingford-Hughes, et al, 2005). Conversely, elevated GABA A receptor density has been reported earlier during the course of abstinence, at 1-week, which normalized to control levels by 4-weeks (Staley, et al, 2005).…”

Section: Setting the Stagementioning

confidence: 99%

GABAergic contributions to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

Silveri

2014

Pharmacology & Therapeutics

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There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders.

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

Cited by 47 publications

References 56 publications

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity

GABAergic contributions to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

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