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.

Pilot study of assertive community treatment methods to engage alcohol-dependent individuals.

AIMS: Assertive approaches to treatment, which are becoming established for individuals with severe and enduring mental illness, may also be beneficial for engaging alcohol-dependent individuals without severe psychiatric co-morbidity, but so far there has been little research on this. This pilot study looked at the feasibility and potential benefits of introducing assertive community methods into the treatment of alcohol-dependent individuals with a history of poor engagement. METHODS: Non-randomized parallel cohort study comparing a Flexible Access Clinic employing assertive community treatment methods with the Usual Care Clinic. Participants were individuals re-referred to our service after they had previously disengaged from treatment. RESULTS: Patients receiving assertive treatment attended assessment a mean of 14 days earlier than those receiving treatment as usual. Treatment at the Flexible Access Clinic was associated with significantly higher rates of completing assisted alcohol withdrawal (35% versus 26%) and entering an aftercare placement (23% versus 14%). Aftercare was entered significantly earlier in the Flexible Access Clinic group (93 days versus 125 days). CONCLUSIONS: These promising results point to the feasibility and potential efficacy of assertive community treatment methods for alcohol dependence, and the need for a randomized controlled trial of effectiveness and cost effectiveness.

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

This corrects the article DOI: 10.1038/npp.2016.289.

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.

Discrimination in autism within different sensory modalities.

Recent studies have suggested that unusual visual processing in autism might stem from enhanced visual discrimination. Although there are also many anecdotal reports of auditory and tactile processing disturbances in autism these have received comparatively little attention. It is possible that the enhanced discrimination ability in vision in autism might extend to other modalities and further that they may underlie many reports of unusual touch and audition. The present study investigated the performance of children with and without autism on auditory and tactile discrimination tasks and revealed superior auditory but comparable tactile discrimination in autism relative to controls. These results extend previous findings of perceptual discrimination in autism and may be relevant for a neuro-developmental hypothesis of the disorder.

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.

Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task.

RATIONALE: Converging evidence suggests that dopaminergic and serotonergic mechanisms affect distinct aspects of cognitive performance. Experiments using the rodent five-choice reaction time task have established a critical role for dopaminergic mechanisms in the rat medial prefrontal cortex (mPFC), but have yielded only incomplete evidence regarding the specific functions of serotonin receptors. OBJECTIVES: To contrast the effects of systemic or intra-mPFC administration of dopamine or serotonin agents on performance of the five-choice reaction time task. METHODS: Two groups of rats trained on the five-choice reaction time task received systemic administration of either the dopamine D(1) receptor partial agonist SKF 38393 (0, 1, 3 or 10 mg/kg IP) or the serotonin 5-HT(2A/C) receptor antagonist ketanserin (0, 0.3, 0.6 or 1 mg/kg SC) prior to testing; a further group was implanted with chronic guide cannulae and received ketanserin (0, 0.025, 0.1 or 0.4 micro g/side) infused into the mPFC prior to testing. RESULTS: SKF 38393 affected aspects of accuracy and vigour of responding, while regardless of the route of administration ketanserin reduced premature responding without any effect on choice accuracy. CONCLUSIONS: Together with our previous findings of increased choice accuracy following intra-mPFC SKF 38393 (Granon et al. 2000), the present results support the notion that the functions of dopamine and serotonin receptors in the mPFC relate to two distinct domains of executive control. Dopamine D(1) receptors are critical to optimise response selection in skilled non-automatic tasks, while serotonin 5-HT(2A) receptors regulate the execution of primed responses.

Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions.

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia.

The Stigma Scale: development of a standardised measure of the stigma of mental illness.

BACKGROUND: There is concern about the stigma of mental illness, but it is difficult to measure stigma consistently. AIMS: To develop a standardised instrument to measure the stigma of mental illness. METHOD: We used qualitative data from interviews with mental health service users to develop a pilot scale with 42 items. We recruited 193 service users in order to standardise the scale. Of these, 93 were asked to complete the questionnaire twice, 2 weeks apart, of whom 60 (65%) did so. Items with a test-retest reliability kappa coefficient of 0.4 or greater were retained and subjected to common factor analysis. RESULTS: The final 28-item stigma scale has a three-factor structure: the first concerns discrimination, the second disclosure and the third potential positive aspects of mental illness. Stigma scale scores were negatively correlated with global self-esteem. CONCLUSIONS: This self-report questionnaire, which can be completed in 5-10 min, may help us understand more about the role of stigma of psychiatric illness in research and clinical settings.

The frontal cortex of the rat and visual attentional performance: dissociable functions of distinct medial prefrontal subregions.

A previous study using a rodent five-choice test of attention found poor choice accuracy and increased perseverative responding following medial prefrontal cortex (mPFC) lesions. As this rat cortical area includes at least two anatomically distinguishable subregions, the present study investigated their specific contributions to performance of this task. Rats were trained on the five-choice task prior to receiving excitotoxic lesions or sham surgery. In the first experiment, lesions of the dorsal mPFC (Zilles's Cg1) resulted in poor accuracy, but no changes in perseverative responding. Introducing variable delays for stimulus presentation abolished these accuracy deficits, suggesting that Cg1-lesioned rats were impaired at using temporal cues to guide performance. In the second experiment, lesions of the ventral mPFC increased perseverative responding, but had only short-lasting effects on accuracy. Rats with complete mPFC lesions had both choice accuracy impairments and increased perseverative responding. Additional evidence of the functional dissociation of dorsal and ventral mPFC came from the analysis of the spatial and temporal distribution of the correct and incorrect responses. Only rats with ventral mPFC lesions showed delay-dependent deficits and bias towards a location that had recently been associated with reward. Taken together, these results suggest dissociable 'executive' functions of mPFC subregions. Circuits centred on Cg1 are critical for the temporal organization of behaviour, while networks involving the ventral mPFC are important for maintaining behavioural flexibility.