A [¹¹C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions

Abstract

Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [(11)C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [(11)C]Ro15 4513 PET scan. We report [(11)C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [(11)C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [(11)C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.

Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

“…Notably, our finding of higher [ 11 C]Ro15‐4513 V T is in contrast to our previous finding of lower levels of [ 11 C]Ro15‐4513 binding in the NAc in alcohol and in opiate dependence and lower levels in the hippocampus in alcohol dependence (Lingford‐Hughes et al 2016; Lingford‐Hughes et al 2012a). Higher [ 11 C]Ro15‐4513 binding reflects greater GABA A receptor availability, which may be due to increased receptor expression or, as a consequence of Ro15‐4513 being an inverse agonist, lower endogenous GABA levels (Stokes et al 2014).…”

“…This is different to substance dependence where we have shown reduced [ 11 C]Ro15‐4513 V T in the NAc (Lingford‐Hughes et al 2016; Lingford‐Hughes et al 2012a). As described, GD was categorized in DSM‐IV as an impulse control disorder but based on shared clinical and aetiological features is now classified as a behavioural addiction in DSM‐5.…”

“…We are unable to separate these two mechanisms within our study. Nevertheless, our [ 11 C]Ro15‐4513 PET studies show clear differences in GABA A receptor availability between substance addictions and a behavioural addiction with lower levels of [ 11 C]Ro15‐4513 binding in both alcohol and opiate addiction not apparent in GD (Lingford‐Hughes et al 2016; Lingford‐Hughes et al 2012a). …”

“…With the [ 11 C]Ro15‐4513 PET radiotracer, which is relatively selective for the α5 subtype of the benzodiazepine receptor, we observed in alcohol and in heroin addiction lower levels of limbic [ 11 C]Ro15 4513 binding, particularly in the nucleus accumbens (NAc) and right hippocampus (Lingford‐Hughes et al 2016; Lingford‐Hughes et al 2012a). We have also shown that [ 11 C]Ro15 4513 binding was higher in participants with a history of tobacco smoking (Stokes et al 2013) .…”

“…For the [ 11 C]Ro15‐4513 PET scan, we followed our previous protocol (Lingford‐Hughes et al 2012a). Briefly, each participant underwent a 90‐minute [ 11 C]Ro15‐4513 PET acquisition.…”