Exploratory study of associations between monetary reward anticipation brain responses and mu-opioid signalling in alcohol dependence, gambling disorder and healthy controls.

Alcohol dependence (AD) and gambling disorder (GD) are common addiction disorders with significant physical and mental health consequences. AD and GD are associated with dysregulated responses to reward which could be due to a common mechanism of dysregulated endogenous opioid signalling. We explored associations between reward anticipation responses, using the Monetary Incentive Delay (MID) functional magnetic resonance imaging (fMRI) task, and mu-opioid receptor (MOR) availability and endogenous opioid release capacity using [C]carfentanil positron emission tomography (PET), in 13 AD, 15 GD and 14 heathy control (HC) participants.

Selective D3 receptor antagonism modulates neural response during negative emotional processing in substance dependence.

Introduction: Negative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target.

COVID-19 and substance use disorders: a review of international guidelines for frontline healthcare workers of addiction services.

Background: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety.

Cerebral blood flow predicts differential neurotransmitter activity.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action.

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects.

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

As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity.

The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description.

Objectives: We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction - reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants.

Experimental Design: Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity.

γ-aminobutyric acid as a metabolite: Interpreting magnetic resonance spectroscopy experiments.

The current rise in the prevalence of magnetic resonance spectroscopy experiments to measure γ-aminobutyric acid in the living human brain is an exciting and productive area of research. As research spreads into clinical populations and cognitive research, it is important to fully understand the source of the magnetic resonance spectroscopy signal and apply appropriate interpretation to the results of the experiments. γ-aminobutyric acid is present in the brain not only as a neurotransmitter, but also in high intracellular concentrations, both as a transmitter precursor and a metabolite.

Impulsivity in abstinent alcohol and polydrug dependence: a multidimensional approach.

Rationale: Dependence on drugs and alcohol is associated with impaired impulse control, but deficits are rarely compared across individuals dependent on different substances using several measures within a single study.

Objectives: We investigated impulsivity in abstinent substance-dependent individuals (AbD) using three complementary techniques: self-report, neuropsychological and neuroimaging. We hypothesised that AbDs would show increased impulsivity across modalities, and that this would depend on length of abstinence.

Antidepressant treatment response: 'I want it all, and I want it now!'†.

The treatment of depression remains suboptimal, highlighting the need for more effective antidepressants. Traditional drug discovery and development is time-consuming and costly, prompting the need for faster translation of novel therapies into practice. But clinical expediency comes at a cost against which potential benefits need to be considered judiciously.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers.

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability.

The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description.

Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513.

Amphetamine induced endogenous opioid release in the human brain detected with [¹¹C]carfentanil PET: replication in an independent cohort.

This study aimed to replicate a previous study which showed that endogenous opioid release, following an oral dose of amphetamine, can be detected in the living human brain using [11C]carfentanil positron emission tomography (PET) imaging. Nine healthy volunteers underwent two [11C]carfentanil PET scans, one before and one 3 h following oral amphetamine administration (0.5 mg/kg).

Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations.

Does human presynaptic striatal dopamine function predict social conformity?

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two.

Resting state synchrony in anxiety-related circuits of abstinent alcohol-dependent patients.

Background: Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiological models of anxiety have proposed important roles for amygdala-insula and amygdala-medial prefrontal cortex interactions in the generation and regulation of anxiety states, respectively.

Objectives: This study tested the hypotheses that abstinent alcohol-dependent patients would show a disruption of synchrony in these circuits as measured by resting state functional MRI.

Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized.

The clinical pharmacology of acamprosate.

Acamprosate is one of the few medications licensed for prevention of relapse in alcohol dependence, and over time it has proved to be significantly, if moderately, effective, safe and tolerable. Its use is now being extended into other addictions and neurodevelopmental disorders. The mechanism of action of acamprosate has been less clear, but in the decade or more that has elapsed since its licensing, a body of translational evidence has accumulated, in which preclinical findings are replicated in clinical populations.

History of cigarette smoking is associated with higher limbic GABAA receptor availability.

Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction.

Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study.

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins.

Striatal dopamine D₂/D₃ receptor binding in pathological gambling is correlated with mood-related impulsivity.

Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D(2)/D(3) receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D(2)/D(3) receptor availability in PG, and its association with trait impulsivity.