Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Interoception and alcohol: Mechanisms, networks, and implications.

Interoception refers to the perception of the internal state of the body and is increasingly being recognized as an important factor in mental health disorders. Drugs of abuse produce powerful interoceptive states that are upstream of behaviors that drive and influence drug intake, and addiction pathology is impacted by interoceptive processes. The goal of the present review is to discuss interoceptive processes related to alcohol. We will cover physiological responses to alcohol, how interoceptive states can impact drinking, and the recruitment of brain networks as informed by clinical research. We also review the molecular and brain circuitry mechanisms of alcohol interoceptive effects as informed by preclinical studies. Finally, we will discuss emerging treatments with consideration of interoception processes. As our understanding of the role of interoception in drug and alcohol use grows, we suggest that the convergence of information provided by clinical and preclinical studies will be increasingly important. Given the complexity of interoceptive processing and the multitude of brain regions involved, an overarching network-based framework can provide context for how focused manipulations modulate interoceptive processing as a whole. In turn, preclinical studies can systematically determine the roles of individual nodes and their molecular underpinnings in a given network, potentially suggesting new therapeutic targets and directions. As interoceptive processing drives and influences motivation, emotion, and subsequent behavior, consideration of interoception is important for our understanding of processes that drive ongoing drinking and relapse.

Effects of acetate on cerebral blood flow, systemic inflammation, and behavior in alcohol use disorder.

BACKGROUND: Alcohol use disorders (AUDs) are associated with altered regulation of physiological processes in the brain. Acetate, a metabolite of ethanol, has been implicated in several processes that are disrupted in AUDs including transcriptional regulation, metabolism, inflammation, and neurotransmission. To further understand the effects of acetate on brain function in AUDs, we investigated the effects of acetate on cerebral blood flow (CBF), systemic inflammatory cytokines, and behavior in AUD. METHODS: Sixteen participants with AUD were recruited from a nonmedical, clinically managed detoxification center. Each participant received acetate and placebo in a randomly assigned order of infusion and underwent 3T MR scanning using quantitative pseudo-continuous arterial spin labeling. Participants and the study team were blinded to the infusion. CBF values (ml/100 g/min) extracted from thalamus were compared between placebo and acetate using a mixed effect linear regression model accounting for infusion order. Voxel-wise CBF comparisons were set at threshold of p < 0.05 cluster-corrected for multiple comparisons, voxel-level p < 0.0001. Plasma cytokine levels and behavior were also assessed between infusions. RESULTS: Fifteen men and 1 woman were enrolled with Alcohol Use Disorders Identification Test (AUDIT) scores between 13 and 38 with a mean of 28.3 ± 9.1. Compared to placebo, acetate administration increased CBF in the thalamus bilaterally (Left: 51.2 vs. 68.8, p < 0.001; Right: 53.7 vs. 69.6, p = 0.001), as well as the cerebellum, brainstem, and cortex. Older age and higher AUDIT scores were associated with increases in acetate-induced thalamic blood flow. Cytokine levels and behavioral measures did not differ between placebo and acetate infusions. CONCLUSIONS: This pilot study in AUD suggests that during the first week of abstinence from alcohol, the brain's response to acetate differs by brain region and this response may be associated with the severity of alcohol dependence.

Use of Topiramate in the Spectrum of Addictive and Eating Disorders: A Systematic Review Comparing Treatment Schemes, Efficacy, and Safety Features.

BACKGROUND AND OBJECTIVE: Topiramate has been approved by the US Food and Drug Administration for the treatment of epilepsy since the 1990s, and it has also been used off-label in the treatment of many types of addictive disorders. To date, no systematic review has embraced the entire field of addiction, both substance use and behavioral addictions, including eating disorders, to compare topiramate-based protocols and the related level of evidence in each addictive disorder. Our objective is to fill this gap. METHODS: A systematic search was conducted using the MEDLINE, PsycINFO, and Cochrane databases without a date or language limit. All trials and meta-analyses assessing the efficacy of topiramate in alcohol use disorder; cocaine use disorder; methamphetamine, nicotine, cannabis, opiate, and benzodiazepine use disorders; binge eating disorder; bulimia; and pathological gambling were analyzed. The quality of the studies was rated using the Cochrane Risk-of-Bias tool for randomized trials (ROB-2), the Risk of Bias In Nonrandomized Studies (ROBINS-I), or the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, depending on the study design. Safety features were assessed based on a wider non-systematic review. RESULTS: Sixty-two articles were reviewed. Treatment protocols were relatively homogenous across addictive disorders, with slow dose titration schemes and a maximum dose range of 200-400 mg per day. The most supportive evidence for topiramate efficacy was found in alcohol use disorder for drinking reduction parameters only. To a lesser extent, topiramate could be a promising therapeutic option for binge eating disorder and cocaine use disorder. Evidence was weak for other addictive disorders. No major tolerability issues were found, provided that basic safety rules were followed. Adverse drug reactions could lead to early treatment discontinuation. DISCUSSION: Though off-label, addiction specialists should consider topiramate as a second-line option for drinking reduction in alcohol use disorder, as well as for binge eating disorder or cocaine use disorder.

The Neural Processes Interlinking Social Isolation, Social Support, and Problem Alcohol Use.

BACKGROUND: Subjective feeling of social isolation, as can be measured by perceived burdensomeness (PB), is a major risk factor for alcohol misuse. Heightened PB is associated with elevated stress response and diminished cognitive control, both of which contribute to problem drinking. Here, we sought to identify the neural substrates underlying the relationship between PB and alcohol misuse. METHODS: We employed resting-state functional magnetic resonance imaging data collected from 61 problem drinkers to characterize the functional connectivity of the hypothalamus and ventral striatum (VS) in relation to PB. We specifically examined whether the connectivities of the hypothalamus and VS were differentially influenced by PB to produce contrasting effects on alcohol use. Finally, we evaluated how individual differences in social support modulate the inter-relationships of social isolation, neural connectivity, and the severity of problem drinking. RESULTS: Whole-brain multiple regressions show a positive relationship between PB and hypothalamic connectivity with the hippocampus and an inverse pattern for VS connectivity with the middle frontal gyrus. Difference in strength between the 2 connectivities predicted the severity of problem drinking, suggesting an imbalance involving elevated hypothalamic and diminished prefrontal cortical modulation in socially isolated problem drinkers. A path analysis further revealed that the lack of social support was associated with a bias toward low prefrontal connectivity, which in turn increased PB and facilitated problem drinking. CONCLUSIONS: Altered hypothalamus and VS connectivity may underlie problem drinking induced by social isolation. The current findings also highlight the important role of social support as a potential protective factor against alcohol misuse.

Putative role of vitamin D in the mechanism of alcoholism and other addictions - a hypothesis.

OBJECTIVE: Vitamin D deficiency may be a clinical problem in patients with addictions. The authors systematically searched for studies addressing vitamin D and addiction and develop a hypothesis which can direct future research of the possible mechanistic role of vitamin D in the process of addiction. METHODS: Systematic review of the literature found in PubMed and EMBASE followed by narrative review combined with clinical experiences leading to hypotheses for future research. RESULTS: Only five articles were identified about a role of vitamin D in the pathophysiology of addiction. Their results are in line with a possible influence of vitamin D in dopaminergic transmission. The cerebral vitamin D status depends on the functionality of genetic variants of vitamin D receptor and other involved genes. Routine serum calcidiol levels may not adequately reflect cerebral vitamin D status. Uncertainty exists regarding appropriate calcidiol blood levels and proper dosages for affecting the central nervous system (CNS). CONCLUSIONS: The putative pathophysiological role of vitamin D in substance abuse has been insufficiently studied which calls to more studies how to measure cerebral vitamin D status in clinical practice. Research is indicated whether vitamin D supplementation should use higher dosages and aim to reach higher calcidiol serum levels. Measuring dopaminergic functioning within the prefrontal cortex as reflected by neuropsychological tests selected as suitable could be a appropriate proxy for the cerebral vitamin D status when studying the pharmacogenomics of this functionality in patients.

Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder.

BACKGROUND: Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. METHODS: Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. RESULTS: Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not. CONCLUSIONS: Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.

Alcohol use disorders and the brain.

A diagnosis of alcohol use disorder is associated with a higher risk of dementia, but a dose-response relationship between alcohol intake consumption and cognitive impairment remains unclear. Alcohol is associated with a range of effects on the central nervous system at different doses and acts on a number of receptors. Acute disorders include Wernicke's encephalopathy (WE), traumatic brain injury, blackouts, seizures, stroke and hepatic encephalopathy. The most common manifestations of chronic alcohol consumption are Korsakoff's syndrome (KS) and alcohol-related dementia (ARD). There is limited evidence for benefit from memantine in the treatment of ARD, but stronger evidence for the use of high-dose parenteral thiamine in the progression of neuropsychiatric symptoms for WE. Accumulating evidence exists for pharmacological treatment in the prevention of hepatic encephalopathy. Rehabilitation of people with ARD may take several years, and requires an approach that addresses physical and psychosocial factors.

Neural Substrates Underlying Eyeblink Classical Conditioning in Adults With Alcohol Use Disorders.

BACKGROUND: Excessive alcohol consumption produces changes in the brain that often lead to cognitive impairments. One fundamental form of learning, eyeblink classical conditioning (EBC), has been widely used to study the neurobiology of learning and memory. Participants with alcohol use disorders (AUD) have consistently shown a behavioral deficit in EBC. The present functional magnetic resonance imaging (fMRI) study is the first to examine brain function during conditioning in abstinent AUD participants and healthy participants. METHODS: AUD participants met DSM-IV criteria for alcohol dependence, had at least a 10-year history of heavy drinking, and were abstinent from alcohol for at least 30 days. During fMRI, participants received auditory tones that predicted the occurrence of corneal airpuffs. Anticipatory eyeblink responses to these tones were monitored during the experiment to assess learning-related changes. RESULTS: Behavioral results indicate that AUD participants showed significant conditioning deficits and that their history of lifetime drinks corresponded to these deficits. Despite this learning impairment, AUD participants showed hyperactivation in several key cerebellar structures (including lobule VI) during conditioning. For all participants, history of lifetime drinks corresponded with their lobule VI activity. CONCLUSIONS: These findings suggest that excessive alcohol consumption is associated with abnormal cerebellar hyperactivation and conditioning impairments.

Evoked K-complexes and altered interaction between the central and autonomic nervous systems during sleep in alcohol use disorder.

There is evidence for impairment in both central nervous system (CNS) and autonomic nervous system (ANS) function with prolonged alcohol use. While these impairments persist into abstinence, partial recovery of function has been demonstrated in both systems during sleep. To investigate potential ANS dysfunction associated with cortical CNS responses (impairment in CNS-ANS coupling), we assessed phasic heart rate (HR) fluctuation associated with tones that did and those that did not elicit a K-complex (KC) during stable N2 non-rapid eye movement (NREM) sleep in a group of 16 recently abstinent alcohol use disorder (AUD) patients (41.6 ± 8.5 years) and a group of 13 sex- and age-matched control participants (46.6 ± 9.3 years). Electroencephalogram (EEG) and electrocardiogram (ECG) data were recorded throughout the night. Alcohol consumption questionnaires were also administered to the AUD patients. AUD patients had elevated HR compared to controls at baseline prior to tone presentation. The HR fluctuation associated with KCs elicited by tone presentation was significantly smaller in amplitude, and tended to be delayed in time, in the AUD group compared with the control group, and the subsequent deceleration was also smaller in AUD patients. In both groups, the increase in HR was larger and occurred earlier when KCs were produced than when they were not, and there was no difference in the magnitude of the KC effect between groups. Phasic HR changes associated with KCs elicited by tones are impaired in AUD participants, reflecting ANS dysfunction possibly caused by an alteration of cardiac vagal trafficking. However, only the timing of the HR response was found to relate to estimated lifetime alcohol consumption in AUD. The clinical meaning and implications of these novel findings need to be determined.

In vivo two-photon imaging of neuronal and brain vascular responses in mice chronically exposed to ethanol.

The effects of ethanol on brain function have been extensively studied using a variety of in vitro and in vivo techniques. For example, electrophysiological studies using brain slices from rodents and non-human primates have demonstrated that acute and chronic exposure to ethanol alters the intrinsic excitability and synaptic signaling of neurons within cortical and sub-cortical areas of the brain. In humans, neuroimaging studies reveal alterations in measures of brain activation and connectivity in subjects with alcohol use disorder. While complementary, these methods are inherently limited due to issues related to either disruption of normal sensory input (in vitro slice studies) or resolution (whole brain imaging). In the present study, we used 2-photon laser scanning microscopy in intact animals to assess the impact of chronic ethanol exposure on sensory-evoked neuronal and vascular responses. Adult male C57BL/6J mice were exposed to four weekly cycles of chronic intermittent ethanol (CIE) exposure, while control mice were exposed to air. After withdrawal (≥72 h), a cranial window was placed over the primary visual cortex (V1), and sensory-evoked responses were monitored using the calcium indicator OGB-1. CIE exposure produced small but significant changes in response amplitude (decrease) and orientation selectivity of V1 neurons (increase). While arteriole diameter did not differ between control and CIE mice under baseline conditions, sensory-evoked dilation was enhanced in vessels from CIE-exposed mice as compared to controls. This was accompanied by a reduced latency in response to stimulation. In separate experiments, pial arteriole diameter was measured in the barrel cortex of control and CIE-exposed mice. Baseline diameter of barrel cortex arterioles was similar between control and CIE-exposed mice, but unlike vessels in V1, sensory-evoked dilation of barrel cortex arterioles was similar between the two groups. Together, the results of these studies suggest that chronic exposure to alcohol induces changes in neurovascular coupling that are region-dependent.

Decreases in the Late Positive Potential to Alcohol Images Among Alcohol Treatment Seekers Following Mindfulness-Based Relapse Prevention.

AIM: Heightened craving among individuals with alcohol use disorder (AUD) has been attributed to a hypersensitivity to alcohol cues in attentional brain networks. Active mindfulness training has been shown to help improve attentional control. Here, we examined alcohol cue-related hypersensitivity among individuals with AUD who received rolling group mindfulness-based relapse prevention (MBRP) in combination with transcranial direct current stimulation (tDCS), over right inferior frontal gyrus. METHODS: Participants (n = 68) viewed a series of emotionally negative, emotionally neutral and alcohol-related images. Following image presentation, participants were asked to rate their level of craving for the alcohol cues, and their level of negative affect evoked by neutral and negative cues. During the task, electroencephalogram (EEG) was recorded to capture an event-related component shown to relate to emotionally salient stimuli: the late positive potential (LPP). Participants who completed a follow-up EEG (n = 37) performed the task a second time after up to eight sessions of MBRP coupled with active or sham tDCS. RESULTS: We found that both craving ratings and the LPP significantly decreased in response to alcohol cues from pre- to post-treatment, but not for other image cues. The magnitude of alcohol image craving reductions was associated with the number of MBRP group sessions attended. Active tDCS was not associated with craving ratings, but it was associated with greater LPP amplitudes across image types. CONCLUSIONS: Taken together, these results suggest that disruption of alcohol-cue hypersensitivity in people with AUD may be a target mechanism of MBRP.

Alcohol or Gut Microbiota: Who Is the Guilty?

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.

Decreased drinking in adults with co-occurring cannabis and alcohol use disorders in a treatment trial for marijuana dependence: Evidence of a secondary benefit?

The purpose of the present study was to investigate whether cannabis dependent users who met criteria for a secondary diagnosis of alcohol use disorder (AUD) would increase their use of alcohol in response to decreasing their use of marijuana in a behavioral treatment trial for cannabis use disorder (CUD). This phenomenon is commonly known as "substance substitution." Participants were randomly assigned to one of four 9-session treatment conditions with cannabis and alcohol use measured at baseline, posttreatment, and at 4 follow-ups through 14 months. Of those enrolled (n = 198), 27 (13.6%) also met criteria for AUD. Linear mixed models were used to analyze alcohol use over time with cannabis use and time as predictors. Findings demonstrated that there were no associations between declines in cannabis use and changes in alcohol consumption in the full sample. However, among those with CUD who also had AUD, declines in cannabis use significantly predicted concurrent declines in alcohol use (p < .05). This study did not find evidence of substance substitution among individuals receiving treatment for CUD. Contrary to expectations, the results indicated that individuals with AUD were more likely to decrease, rather than increase, their alcohol use when they reduced their marijuana use. Treatment for CUD in this study appeared to result in improvements in substance use generally, at least for those with comorbid AUD.

Endocannabinoid Signaling in the Central Amygdala and Bed Nucleus of the Stria Terminalis: Implications for the Pathophysiology and Treatment of Alcohol Use Disorder.

High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence. In the first part of this 2-part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry. In Part 2, we focus on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system. The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics. This review details the recent advances in our understanding of eCB signaling in 2 key regions of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect. Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB-based therapies to treat AUD-associated negative affect. In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD. Lastly, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.

The P300 in alcohol use disorder: A meta-analysis and meta-regression.

OBJECTIVE: The P300 ERP component is a marker of reduced capacity in alcohol use disorder (AUD) to engage attentional mechanisms and update memory representations. No meta-analysis to date has been completed comparing effect size estimates of auditory vs. visual stimuli in AUD. In addition, there is a lack of consensus on whether the P3b in women is reduced, or whether the P3a - an earlier, more frontally distributed component - is reduced in AUD. METHODS: Strict inclusion criteria and data-analysis plans were implemented. Eligible studies needed to diagnose AUD using DSM or ICD-10 and exclude patients with any psychiatric co-morbidities. Data analysis was completed using a refined variance estimator of the random effects model. RESULTS: Effect size estimates were large for both auditory (Hedges' g = 1.01, p = .056) and visual (Hedges' g = 0.77, p = .040) P300 amplitudes, but only marginally significant for the auditory modality. Auditory P300 latency was significantly increased in AUD patients (Hedges' g = 0.73, p = .027). The moderator analysis did not show significant sex differences for either auditory (p = .97) or visual (p = .45) P3b. Finally, the P3a was not reduced in patients with AUD (Hedges' g = 1.01; p = .59). CONCLUSION: This meta-analysis clarifies important questions related to P300 in AUD. By resolving inconsistencies, it is hoped that this information will facilitate the design of futurestudies.

Associations between dispositional mindfulness, craving, and drinking in alcohol-dependent patients: An ecological momentary assessment study.

Hazardous alcohol use remains a significant global public health problem. A better understanding of relapse may assist the development of new interventions. Low levels of dispositional mindfulness may be a risk factor for craving and alcohol use, but few studies have examined these associations prospectively in an alcohol-dependent sample. In an ecological momentary assessment (EMA) study, Dutch alcohol dependent patients (N = 43) carried around a personal digital assistant for 4 weeks while trying to maintain abstinence. Participants completed assessments at random times 3 times per day, and when they felt a strong urge to drink or came to the brink of drinking without doing so. At each assessment, stress, negative affect, craving, recent drinking, and attentional or approach bias were assessed. Dispositional mindfulness was assessed at baseline with the Mindful Attention Awareness Scale (MAAS). More mindful individuals (higher MAAS scores) reported lower craving than less mindful individuals. There was no evidence that stress, negative affect, attentional bias, or approach bias mediated the association between MAAS and craving. However, there was evidence for an indirect path from MAAS to drinking such that higher mindfulness was associated with lower craving ratings that in turn were associated with less drinking. There was no evidence that MAAS significantly moderated associations between stress/negative affect/cognitive biases and craving, or between craving and drinking. In sum, more mindful recovering alcohol dependent patients reported lower craving ratings than less mindful patients, and this association appeared to be independent of stress/negative affect and cognitive biases. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effect of pesticide exposure on the cholinesterase activity of the occupationally exposed tea garden workers of northern part of West Bengal, India.

Context: Pesticide poisoning and related deaths are a global concern, but there is little information about its effect on the occupationally exposed tea garden workers of North Bengal. Objective: This study investigates the level of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the blood of the tea garden workers at risk of exposure to a mixture of pesticides. Materials and methods: The study sample consisted of pesticide exposed workers, non-exposed (control), smokers and alcoholics. AChE and BuChE activity was measured and tested for significance. Results: Results showed that AChE activity was half in the pesticide exposed individuals than controls (p≤ 0.001). BuChE activity was also significantly decreased in the pesticide exposed individuals than controls (p≤ 0.001), while AChE and BuChE activity in smokers and alcoholics were not different from that of controls. However, significantly decreased AChE and BuChE activities were recorded in pesticide exposed workers compared to smokers and alcoholics. Conclusions: The results indicated that the decrease in enzyme activities in tea garden workers was due to mixed pesticides (containing organophosphates) exposure. Age was not found to influence the enzyme activities. However, the gender had little effect on the enzyme activities but the effect was not so prominent.

The effects of an acute bout of exercise on neural activity in alcohol and cocaine craving: study protocol for a randomised controlled trial.

BACKGROUND: Numerous studies suggest that exercise may be an effective adjunct treatment for substance use disorders. It has been suggested that exercise-induced improvements in inhibitory control may reduce craving for the substance of abuse. However, this potential mechanism has seldom been researched. OBJECTIVES: The aim of the ExAlCo Study is to examine how acute bouts of exercise, at varying intensities, impact on craving for cocaine or alcohol. Cerebral haemodynamic responses during cognitive tests of inhibitory control, and exposure to substance-related cue imagery, will also be assessed using functional near-infrared spectroscopy. DESIGN: The study is a crossover randomised controlled trial. Participants will be recruited from inpatient and outpatient psychiatric treatment centres, on the approval of their treating physician. A healthy control group will be recruited using online advertising. All participants will undergo each of three conditions in randomised order: 20 min of cycle ergometry at 50-60% of maximum heart rate; 20 min of exercise at 70-80% of maximum heart rate; and 20 min of quiet reading. Immediately before and after each condition, participants will be asked to complete a computerised Stroop test, watch a film containing substance-related images and self-report craving levels. During the Stroop test and film viewing, participants' neural activity will be measured via functional near-infrared spectroscopy. OUTCOMES: The primary outcome measures are self-reported craving, inhibitory control and cerebral haemodynamic response to the Stroop test and a substance-related film. It is hoped that the findings from this study will shed more light on the role of exercise in the treatment of substance use disorders, particularly its scope in preventing relapse through reduced craving severity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03502486 . Registered retrospectively on 5 April 2018.

Dietary Omega-3 Fatty Acids Differentially Impact Acute Ethanol-Responsive Behaviors and Ethanol Consumption in DBA/2J Versus C57BL/6J Mice.

BACKGROUND: Complex interactions between environmental and genetic factors influence the risk of developing alcohol use disorder (AUD) in humans. To date, studies of the impact of environment on AUD risk have primarily focused on psychological characteristics or on the effects of developmental exposure to ethanol (EtOH). We recently observed that modifying levels of the long-chain ω-3 (LC ω-3) fatty acid, eicosapentaenoic acid (EPA), alters acute physiological responses to EtOH in Caenorhabditis elegans. Because mammals derive ω-3 fatty acids from their diet, here we asked if manipulating dietary levels of LC ω-3 fatty acids can affect EtOH-responsive behaviors in mice. METHODS: We used 2 well-characterized inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), which differ in their responses to EtOH. Age-matched young adult male mice were maintained on isocaloric diets that differed only by being enriched or depleted in LC ω-3 fatty acids. Animals were subsequently tested for acute EtOH sensitivity (locomotor activation and sedation), voluntary consumption, and metabolism. Fat deposition was also determined. RESULTS: We found that dietary levels of LC ω-3s altered EtOH sensitivity and consumption in a genotype-specific manner. Both B6 and D2 animals fed high LC ω-3 diets demonstrated lower EtOH-induced locomotor stimulation than those fed low LC ω-3 diets. EtOH sedation and EtOH metabolism were greater in D2, but not B6 mice on the high LC ω-3 diet. Conversely, LC ω-3 dietary manipulation altered EtOH consumption in B6, but not in D2 mice. B6 mice on a high LC ω-3 diet consumed more EtOH in a 2-bottle choice intermittent access model than B6 mice on a low LC ω-3 diet. CONCLUSIONS: Because EtOH sensitivity is predictive of risk of developing AUD in humans, our data indicate that dietary LC ω-3 levels should be evaluated for their impact on AUD risk in humans. Further, these studies indicate that genetic background can interact with fatty acids in the diet to significantly alter EtOH-responsive behaviors.