Louise M. Paterson

Measuring endogenous 5-HT release by emission tomography: promises and pitfalls.

Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system. The principles behind visualising fluctuations in neurotransmitters are introduced, with reference to the dopaminergic system. Studies that aim to image acute, endogenous 5-HT release or depletion at 5-HT receptor targets are summarised, with particular attention to studies in humans. Radiotracers targeting the 5-HT1A, 5-HT2A, and 5-HT4 receptors and the serotonin reuptake transporter have been explored for their sensitivity to 5-HT fluctuations, but with mixed outcomes; tracers for these targets cannot reliably image endogenous 5-HT in humans. Shortcomings in our basic knowledge of the mechanisms underlying changes in binding potential are addressed, and suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve our chances of successfully imaging endogenous neurotransmitters in the future.

5‐HT radioligands for human brain imaging with PET and SPECT

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5‐HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5‐HT) receptors, the 5‐HT transporter (SERT), and 5‐HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5‐HT system in humans include antagonists for the 5‐HT1A, 5‐HT1B, 5‐HT2A, and 5‐HT4 receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

Sleep and its disorders in translational medicine

The study of sleep is a useful approach to studying the brain in psychiatric disorders and in investigating the effects of psychotropic drugs. Sleep physiology lends itself well to pharmacological and physiological manipulation, as it has the advantage of a functional output, the electroencephalograph, which is common to all mammals, and can be measured in freely moving (or naturally sleeping) animals under controlled laboratory conditions or in a naturalistic home environment. The complexity of sleep architecture varies between species but all share features which are comparable. In addition, sleep architecture is sensitive to changes in brain neurotransmitters such as serotonin, so cross-species sleep measurement can be combined with pharmacological manipulation to investigate the receptor mechanisms controlling sleep–wake regulation and sleep architecture in response to known and novel agents. Translational approaches such as these have improved our understanding of sleep circuitry and facilitated the development of new treatments for sleep disorders, particularly insomnia. This review provides examples of how research findings within the sleep field have been translated between animal models, healthy volunteers and patient populations with particular focus on the serotonergic system.

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. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.

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

RationaleDependence 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.ObjectivesWe 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.MethodsData were collected from the ICCAM study: 57 control and 86 AbDs, comprising a group with a history of dependence on alcohol only (n = 27) and a group with history of dependence on multiple substances (“polydrug”, n = 59). All participants completed self-report measures of impulsivity: Barratt Impulsiveness Scale, UPPS Impulsive Behaviour Scale, Behaviour Inhibition/Activation System and Obsessive-Compulsive Inventory. They also performed three behavioural tasks: Stop Signal, Intra-Extra Dimensional Set-Shift and Kirby Delay Discounting; and completed a Go/NoGo task during fMRI.ResultsAbDs scored significantly higher than controls on self-report measures, but alcohol and polydrug dependent groups did not differ significantly from each other. Polydrug participants had significantly higher discounting scores than both controls and alcohol participants. There were no group differences on the other behavioural measures or on the fMRI measure.ConclusionsThe results suggest that the current set of self-report measures of impulsivity is more sensitive in abstinent individuals than the behavioural or fMRI measures of neuronal activity. This highlights the importance of developing behavioural measures to assess different, more relevant, aspects of impulsivity alongside corresponding cognitive challenges for fMRI.

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.

Acute naltrexone does not remediate fronto‐striatal disturbances in alcoholic and alcoholic polysubstance‐dependent populations during a monetary incentive delay task

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 brains 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.

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. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol‐dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly‐substance‐dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

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. 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.

Preclinical Aspects of Nicotinic Acetylcholine Receptor Imaging

Recent developments in radiochemistry have opened new vistas for investigations of nicotinergic acetylcholine receptors (nAChRs) in living brain by positron emission tomography (PET) and by single photon emission computed tomography (SPECT). In parallel, dedicated instrumentation for molecular imaging in small animals has facilitated preclinical investigations in a number of models in which perturbations in nAChR signalling are implicated, notably Alzheimer’s disease and other neurodegenerative conditions, schizophrenia and other neuropsychiatric disorders, substance abuse and traumatic brain injury. The nAChRs are members of a family of ligand-gated ion channels composed of five subunits, most commonly occurring in the central nervous system as heteropentamers designated α4β2, with lesser amounts of the α7 homopentamer. We present a systematic review of preclinical findings with the diverse nAChR ligands which have been investigated to date. Molecular imaging of the α4β2 nAChR subtype by PET has been successfully achieved by 2-[18F]fluoro-A-85380. Newer agents such as (−)-[18F]flubatine permit quantitation of α4β2 receptors with PET recordings not exceeding 90 min, without the toxicity characteristic of earlier epibatidine derivatives. Imaging studies of α7 nAChRs have been hampered by inadequate pharmacological specificity of available ligands and by the low natural abundance of this receptor subtype in the brain. However, a continued search for optimal ligands is justified by the particular association of α7 nAChRs with aspects of cognitive function. We note that no molecular imaging ligands have been developed for α6-containing nAChRs, despite their importance for the psychopharmacology of nicotine actions in the basal ganglia. Finally, we review the competitive binding model, in which the availability of α4β2 binding sites is altered by competition from endogenous acetylcholine, noting that this approach has yet to be applied for monitoring acetylcholine release in disease models.