Publications
324 results found
Kalk NJ, Guo Q, Owen D, et al., 2017, Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [(11)C]PBR28 PET study, Translational Psychiatry, Vol: 7, ISSN: 2158-3188
Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [(11)C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [(11)C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [(11)C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [(11)C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [(11)C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.
Quelch D, Mick I, McGonigle J, et al., 2017, Nalmefene reduces reward anticipation in alcohol dependence: an experimental functional magnetic resonance imaging study, Biological Psychiatry, Vol: 81, Pages: 941-948, ISSN: 1873-2402
BackgroundNalmefene (Selincro®) is a µ- and δ- opioid receptor antagonist, κ-opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol dependent individuals with “high risk drinking levels” to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomised, double blind, placebo controlled within subject cross-over design we aimed to determine the effect of a single dose of nalmefene on striatal BOLD (blood oxygen level dependent) signal change during anticipation of monetary reward using the Monetary Incentive Delay Task following alcohol challenge.Methods and Materials22 currently heavy drinking, non-treatment seeking alcohol dependent males were recruited. The effect of single dose nalmefene (18mg; Selincro®) on changes in a priori defined striatal region of interest (ROI) BOLD signal change during reward anticipation compared with placebo were investigated using functional MRI (magnetic resonance imaging). Both conditions were performed under intravenous alcohol administration (6% v/v infusion to achieve a target level of 80mg%).ResultsDatasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal ROI compared with placebo. Nalmefene did not alter brain perfusion.DiscussionNalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene’s actions on opiate receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.
Limbrick-Oldfield E, Mick I, Cocks R, et al., 2017, Neural substrates of cue reactivity and craving in gambling disorder, Translational Psychiatry, Vol: 7, ISSN: 2158-3188
Cue reactivity is an established procedure in addictions research for examining the subjective experience and neural basis of craving. This experiment sought to quantify cue-related brain responses in Gambling Disorder using personally tailored cues in conjunction with subjective craving, as well as a comparison with appetitive non-gambling stimuli. Participants with Gambling Disorder (n=19) attending treatment and 19 controls viewed personally tailored blocks of gambling-related cues, as well as neutral cues and highly appetitive (food) images during a functional MRI scan performed ~2-3 hours after a usual meal. fMRI analysis examined cue-related brain activity, cue-related changes in connectivity, and associations with block-by-block craving ratings. Craving ratings in the participants with Gambling Disorder increased following gambling cues compared with non-gambling cues. fMRI analysis revealed group differences in left insula and anterior cingulate cortex, with the Gambling Disorder group showing greater reactivity to the gambling cues, but no differences to the food cues. In participants with Gambling Disorder, craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum, and negatively with functional connectivity between the ventral striatum and the medial PFC. Gambling cues, but not food cues, elicit increased brain responses in reward-related circuitry in individuals with Gambling Disorder (compared to controls), providing support for the incentive sensitisation theory of addiction. Activity in the insula co-varied with craving intensity, and may be a target for interventions.
Murphy A, Nestor LJ, McGonigle J, et al., 2017, Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence (vol 42, pg 1049, 2017), NEUROPSYCHOPHARMACOLOGY, Vol: 42, Pages: 1559-1559, ISSN: 0893-133X
Venkataraman A, Kalk N, Sewell G, et al., 2016, Alcohol and Alzheimer's Disease-Does Alcohol Dependence Contribute to Beta-Amyloid Deposition, Neuroinflammation and Neurodegeneration in Alzheimer's Disease?, Alcohol and Alcoholism, Vol: 52, Pages: 151-158, ISSN: 1464-3502
Aims:To investigate the underlying neurobiology between alcohol use, misuse and dependence and cognitive impairment, particularly Alzheimer's disease (AD).Methods:Review of the literature using searches of Medline, Pubmed, EMBASE, PsycInfo, and meeting abstracts and presentations.Results:The role of alcohol as a risk factor and contributor for cognitive decline associated with AD has received little attention. This is despite the high prevalence of alcohol use, the potential reversibility of a degree of cognitive impairment and the global burden of AD. Until now the focus has largely been on the toxic effects of alcohol, neuronal loss and the role of thiamine.Conclusion:We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance of AD pathology via neuroinflammation. We describe the common underlying neurobiology in alcohol and AD, and examine ways alcohol likely contributes to neuroinflammation directly via stimulation of Toll-like receptors and indirectly from small bowel changes, hepatic changes, withdrawal and traumatic brain injury to the pathogenesis of AD.
Scott G, Jolly A, Jenkins PO, et al., 2016, THE EFFECT OF MINOCYCLINE ON NEUROINFLAMMATION AFTER BRAIN TRAUMA, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Turton S, Lingford-Hughes A, 2016, Neurobiology and principles of addiction and tolerance, Medicine (United Kingdom), Vol: 44, Pages: 693-696, ISSN: 1357-3039
© 2016 Elsevier Ltd Substances of abuse dysregulate key brain systems involved in motivation, reward, decision-making and memory. As drug use evolves into a compulsive addiction, there are adaptations in these systems, mediated by a number of different neurotransmitters. The mesolimbic dopaminergic pathway plays a central role in the pleasurable and positive reinforcing effects of drugs. As an individual becomes addicted, there is a shift away from this positive reinforcement to the compulsive, habitual drug-seeking behaviours driven, for example, by cravings or withdrawal symptoms. Although the potential for addiction is common with all drugs of abuse, the underlying mechanisms, neurotransmission systems and adaptations vary between drugs. This review focuses on the neurobiology of addiction and tolerance for alcohol, benzodiazepines, opioids and stimulants.
Mick I, Ramos C, Myers J, et al., 2016, Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity., Addiction Biology, Vol: 22, Pages: 1601-1609, ISSN: 1369-1600
Background: As a behavioral 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. Methods: This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. Results: We found significantly higher [11C]Ro15-4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of The ‘Negative Urgency’ construct of impulsivity in GD and these were positively associated with higher [11C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. Conclusions: These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioral addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
McGonigle J, Murphy A, Paterson LM, et al., 2016, The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description, Journal of Psychopharmacology, Vol: 31, Pages: 3-16, ISSN: 1461-7285
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. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. PRINCIPLE OBSERVATIONS: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. CONCLUSIONS: In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres.
Turton S, Myers J, Mick I, et al., 2016, Alcohol dependent patients have blunted endogenous opioid release measured using [C-11] carfentanil PET and dexamphetamine challenge, 29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S676-S677, ISSN: 0924-977X
Lim TV, Ricceli R, Passamonti L, et al., 2016, Endogenous opioid blockade modulates neural networks implicated in attentional and behavioural control in individuals recovering from alcohol and drug dependence, 29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S696-S697, ISSN: 0924-977X
Lingford-Hughes AR, Patel Y, Bowden-Jones O, et al., 2016, Improving GHB withdrawal with baclofen: study protocol for a feasibility study for a randomised controlled trial, Trials, Vol: 17, ISSN: 1745-6215
BackgroundGHB (gamma-hydroxybutyrate) and its pro-drugs GBL (gamma-butyrolactone) 1,4-butanediol(1.4-BD) are central nervous system depressants whose street names include ‘G’ and ‘liquidecstasy’. They are used recreationally predominately for their stimulant and pro-sexual effectsor for sedation to help with sleep and/or to “come down” after stimulant recreational drugs.Although overall population prevalence is low (0.1%), in some groups such as men who havesex with men, GHB/GBL use may reach 20%. GHB/GBL dependence may be associated withsevere withdrawal with individuals presenting either acutely to Emergency Departments or toaddiction services for support. Benzodiazepines are currently prescribed for GHB/GBLdetoxification but do not prevent all complications such as behavioural disinhibition that mayrequire hospitalisation or admission to a High Dependency/Intensive Care Unit. The GABABreceptor mediates most effects of GHB/GBL and the GABAB agonist, baclofen, has shownpromise as an adjunct to benzodiazepines in reducing withdrawal severity when prescribedboth during withdrawal and as a 2 day ‘pre-load’ prior to detoxification.Methods / DesignThis is a randomised, double-blind, placebo-controlled feasibility study which will recruitparticipants (>18years) who are GHB/GBL dependent and wish to undergo planned GHB/GBLdetoxification or are at risk of acute withdrawal and are inpatients requiring unplannedwithdrawal. We aim to recruit 88 participants, 28 unplanned inpatients and 60 plannedoutpatients.During detoxification we will compare baclofen 10mg three times a day with placebo as anadjunct to usual benzodiazepine regimen. In the planned outpatient arm, we will alsocompare a 2-day preload of baclofen 10mg three times a day with placebo. Ratings ofGHB/GBL withdrawal, sleep, depression, anxiety as well as GHB/GBL use will be collected. Themain data analyses will be descriptive about recruitment and characterizing the
Nestor LJ, Murphy A, McGonigle J, et al., 2016, Acute naltrexone does not remediate fronto-striatal disturbances in alcoholic and alcoholic polysubstance-dependent populations during a monetary incentive delay task, Addiction Biology, Vol: 22, Pages: 1576-1589, ISSN: 1369-1600
There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.
Datta G, Colasanti A, Kalk NJ, et al., 2016, <i>In vivo</i> translocator protein positron emission tomography imaging detects a heterogeneity of lesion inflammatory activity in multiple sclerosis not evident by MRI., 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 36-37, ISSN: 1352-4585
Taylor M, Lees R, Henderson G, et al., 2016, Comparison of cannabinoids in hair with self-reported cannabis consumption in heavy, light and non-cannabis users, Drug and Alcohol Review, Vol: 36, Pages: 220-226, ISSN: 1465-3362
INTRODUCTION: Biological tests of drug use can be used to inform clinical and legal decisions and hold potential to provide evidence for epidemiological studies where self-reported behaviour may be unavailable or unreliable. We test whether hair can be considered as a reliable marker of cannabis exposure. METHODS: Hair samples were collected from 136 subjects who were self-reported heavy, light or non-users of cannabis and tested using GC-MS/MS. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for five cannabinoids (tetrahydrocannabinol [THC], THC-OH, THC-COOH, cannabinol and cannabidiol). Samples also were segmented in 1 cm sections representing 1 month exposure and the correlation between amount of cannabinoid detected and self-reported cannabis consumption tested. RESULTS: All five cannabinoids were detected. Seventy-seven percent of heavy users, 39% of light users and 0% of non-users tested positive for THC. The sensitivity of detection of THC was 0.77 (0.56-0.91) comparing heavy cannabis smokers with light and non-users, whereas the sensitivity of other cannabinoids generally was considerably lower. The positive and negative predictive value of detection of THC were 0.57 (0.39-0.74) and 0.91 (0.82-0.97), respectively. A correlation of 0.52 (P < 0.001) was observed between self-reported monthly cannabis use and THC. DISCUSSION: Hair analysis can be used as a qualitative indicator of heavy (daily or near daily) cannabis consumption within the past 3 months. However, this approach is unable to reliably detect light cannabis consumption or determine the quantity of cannabis used by the individual. [Taylor M, Lees R, Henderson G, Lingford-Hughes A, Macleod J, Sullivan J, Hickman M. Comparison of cannabinoids in hair with self-reported cannabis consumption in heavy, light and non-cannabis users. Drug Alcohol Rev 2016;00:000-000].
Magazzini L, Muthukumaraswamy SD, Campbell AE, et al., 2016, Significant reductions in human visual gamma frequency by the gaba reuptake inhibitor tiagabine revealed by robust peak frequency estimation, Human Brain Mapping, Vol: 37, Pages: 3882-3896, ISSN: 1097-0193
The frequency of visual gamma oscillations is determined by both the neuronal excitation-inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [] (Neuropsychopharmacology 38(6):1105-1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Georgiou P, Sklirou M, Kalk N, et al., 2016, CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL UPREGULATES TSPO, A MARKER OF NEUROINFLAMMATION, 27th International Symposium on Cerebral Blood Flow, Metabolism and Function / 12th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 658-658, ISSN: 0271-678X
Cooper SJ, Reynolds GP, Barnes T, et al., 2016, BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment, Journal of Psychopharmacology, Vol: 30, Pages: 717-748, ISSN: 1461-7285
Excess deaths from cardiovascular disease are a major contributor to the significant reduction in life expectancy experienced by people with schizophrenia. Important risk factors in this are smoking, alcohol misuse, excessive weight gain and diabetes. Weight gain also reinforces service users' negative views of themselves and is a factor in poor adherence with treatment. Monitoring of relevant physical health risk factors is frequently inadequate, as is provision of interventions to modify these. These guidelines review issues surrounding monitoring of physical health risk factors and make recommendations about an appropriate approach. Overweight and obesity, partly driven by antipsychotic drug treatment, are important factors contributing to the development of diabetes and cardiovascular disease in people with schizophrenia. There have been clinical trials of many interventions for people experiencing weight gain when taking antipsychotic medications but there is a lack of clear consensus regarding which may be appropriate in usual clinical practice. These guidelines review these trials and make recommendations regarding appropriate interventions. Interventions for smoking and alcohol misuse are reviewed, but more briefly as these are similar to those recommended for the general population. The management of impaired fasting glycaemia and impaired glucose tolerance ('pre-diabetes'), diabetes and other cardiovascular risks, such as dyslipidaemia, are also reviewed with respect to other currently available guidelines.These guidelines were compiled following a consensus meeting of experts involved in various aspects of these problems. They reviewed key areas of evidence and their clinical implications. Wider issues relating to primary care/secondary care interfaces are discussed but cannot be resolved within guidelines such as these.
Limbrick-Oldfield E, Mick I, Cocks R, et al., 2016, Neural Substrates of Cue Reactivity and Craving in Gambling Disorder, Publisher: ELSEVIER SCIENCE INC, Pages: 341S-341S, ISSN: 0006-3223
Myers JF, Nutt DJ, Lingford-Hughes AR, 2016, γ-aminobutyric acid as a metabolite: Interpreting magnetic resonance spectroscopy experiments., Journal of Psychopharmacology, Vol: 30, Pages: 422-427, ISSN: 1461-7285
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. γ-aminobutyric acid concentrations measured by magnetic resonance spectroscopy are not necessarily implicated in neurotransmission and therefore may reflect a very different brain activity to that commonly suggested. In this perspective, we examine some of the considerations to be taken in the interpretation of any γ-aminobutyric acid signal measured by magnetic resonance spectroscopy.
Mick I, Myers J, Ramos AC, et al., 2016, Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers, 3rd International Conference on Behavioral Addictions, Publisher: Akadémiai Kiadó, Pages: 30-30, ISSN: 2063-5303
Goodwin GM, Haddad PM, Ferrier IN, et al., 2016, Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology, Journal of Psychopharmacology, Vol: 30, Pages: 495-553, ISSN: 1461-7285
The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.
Nahar LK, Cordero R, Nutt D, et al., 2016, Validated method for the quantification of baclofen in human plasma using solid-phase extraction and liquid chromatography–tandem mass spectrometry, Journal of Analytical Toxicology, Vol: 40, Pages: 117-123, ISSN: 0146-4760
A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupoleliquid chromatography–tandem mass spectrometry (LC–MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r2 > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthymale volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.
Taylor EM, Murphy A, Boyapati V, et al., 2016, Impulsivity in abstinent alcohol and polydrug dependence: a multidimensional approach, Psychopharmacology, Vol: 233, Pages: 1487-1499, ISSN: 1432-2072
Lingford-Hughes A, 2016, Substitution treatment in addiction: there is more than one way…, Addiction, Vol: 111, Pages: 776-777, ISSN: 1360-0443
Lingford-Hughes A, Myers J, Watson B, et al., 2016, Using [11C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism, Neuroimage, Vol: 132, Pages: 1-7, ISSN: 1095-9572
The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised inaddiction. Using the α1/α5 benzodiazepine receptor PET radioligand [ 23 11C]Ro15 4513, we previously showed reducedbinding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that 24reduced [ 25 11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampusand positive relationship with memory was a consequence of chronic alcohol abuse. To examine this 26further we assessed [ 27 11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysisto estimate contributions of α1 and α5 subtypes to [ 28 11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependentgroups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [ 29 11C]Ro154513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in 30[ 31 11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy controlgroup. There was no relationship between [ 32 11C]Ro15 4513 binding in the hippocampus with memory. Wefound that reduced [ 33 11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependentgroup. This was also seen in an alcohol-dependent group where an association between memory 34performance and [ 35 11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reducedα5 levels in the nucleus accumbens are associated with addiction since we have now shown this in depen- 36dence to two pharmacologically different substances, alcohol and opiates.
Malhi GS, Lingford-Hughes AR, Young AH, 2016, Antidepressant treatment response: 'I want it all, and I want it now!', BRITISH JOURNAL OF PSYCHIATRY, Vol: 208, Pages: 101-103, ISSN: 0007-1250
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Lingford-Hughes AR, Mick I, Myers J, et al., 2015, Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers, Neuropsychopharmacology, Vol: 41, Pages: 1742-1750, ISSN: 1740-634X
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 aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [¹¹C]carfentanil PET with an oral amphetamine challenge. 14 PG and 15 healthy volunteers (HV) underwent two [¹¹C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [¹¹C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [¹¹C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may play an important role in the pathophysiology of addictions.
Hill R, Lyndon A, Withey S, et al., 2015, Ethanol reversal of tolerance to the respiratory depressant effects of morphine, Neuropsychopharmacology, Vol: 41, Pages: 762-773, ISSN: 1740-634X
Lingford-Hughes A, McGonigle J, Mick I, et al., 2015, An fMRI study of nalmefene on alcohol effects in reward anticipation in alcohol dependence, 28th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S602-S603, ISSN: 0924-977X
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