Addiction (Biology)

Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-α signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined d...

Background and aimsGraph theoretic analysis of structural covariance networks (SCN) provides an assessment of brain organization that has not yet been applied to alcohol dependence (AD). We estimated whether SCN differences are present in adults with AD and heavy‐drinking adolescents at age 19 and age 14, prior to substantial exposure to alcohol.DesignCross‐sectional sample of adults and a cohort of adolescents. Correlation matrices for cortical thicknesses across 68 regions were summarized with graph theoretic metrics.Setting and participantsA total of 745 adults with AD and 979 non‐dependent controls from 24 sites curated by the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA)–Addiction consortium, and 297 hazardous drinking adolescents and 594 controls at ages 19 and 14 from the IMAGEN study, all from Europe.MeasurementsMetrics of network segregation (modularity, clustering coefficient and local efficiency) and integration (average shortest path length and global ef...

The study develops a novel method to measure System 1 (fast, cue-based, thought-light) smoking frequency as an outcome measure to overcome the limitations of existing measures. It also examines its relationship to System 2 (slow, deliberative) measures. 116 participants met in two sessions set at 48 hours apart. System 2 measure of smoking frequency was measured via self-reported 24-hour smoking frequency. System 1 smoking frequency was measured by observing the number of cigarettes participants carried and asking about the number of cigarette packs consumed between the two sessions. System 2 measure of smoking frequency underestimated System 1 smoking frequency by 47.4%. Results also revealed that System 1 smoking attitudes only predicted the newly developed System 1 smoking frequency significantly, while System 2 smoking attitudes predicted only System 2 smoking frequency significantly. Hence, interventions that modify explicit attitudes (System 2) might have a limited impact on observed (System 1) smoking behaviours.

The present study investigated changes in behaviour associated with oral monosodium glutamate (a flavouring agent), using the open field, elevated plus maze and conditioned place preference (CPP) paradigms, respectively. Mice were assigned to two groups for CPP [monosodium glutamate (MSG)-naïve (n = 40) and MSG-pretreated (n = 40)] and two groups for open field (OF) and elevated plus maze (EPM) tests [n = 40 each], respectively. Animals in respective groups were then divided into four subgroups (n = 10) (vehicle or MSG (80, 160 and 320 mg/kg)). MSG-naïve mice were observed in the CPP box in three phases (pre-conditioning, conditioning and post-conditioning). Mice were conditioned to MSG or an equivalent volume of saline. The MSG pretreatment group received vehicle or respective doses of MSG daily for 21 days, prior to conditioning. Mice in the OF or EPM groups received vehicle or doses of MSG (orally) for 21 days, at 10 ml/kg. Open field or EPM behaviours were assessed on days 1 and 21. At the end of the experiments, mice in the OF groups were sacrificed and brain homogenates used to assay glutamate and glutamine. Results showed that administration of MSG was associated with a decrease in rearing, dose-related mixed horizontal locomotor, grooming and anxiety-related response and an increase in brain glutamate/glutamine levels. Following exposure to the CPP paradigm, MSG-naïve and MSGpretreated mice both showed 'drug-paired' chamber preference. The study concluded that MSG (at the administered doses) was associated with changes in open field activities, anxiety-related behaviours and brain glutamate/glutamine levels; its ingestion also probably leads to a stimulation of the brain reward system.

This investigation was designed to determine the effect of melatonin supplementation on mental health parameters, metabolic and genetic profiles in patients under methadone maintenance treatment (MMT). This randomized, double-blind, placebo-controlled, clinical trial was conducted among 54 patients under MMT. Participants were randomly allocated to receive either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 26) or placebo (n = 28) once a day, 1 hour before bedtime for 12 weeks. Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -4.08; 95 percent CI, -5.51, -2.65; P < 0.001), Beck Depression Inventory index (β -5.46; 95% CI, -8.92, -2.00; P = 0.003) and Beck Anxiety Inventory index (β -3.87; 95% CI, -5.96, -1.77; P = 0.001) and significantly increased International Index of Erectile Functions (β 5.59; 95% CI, 1.76, 9.42; P = 0.005) compared with the placebo. Subjects who received melatonin supplements had significantly lower serum insulin...

Background:Level of response (LR) to alcohol has been shown to be associated with the risk of developing alcohol dependence and can be measured using the self‐rating of the effects of alcohol (SRE) questionnaire. This study examined the heritability of the SRE‐measured LR and the relationship between LR and recent alcohol drinking history (RDH) in a predominantly African American nonalcohol‐dependent population.Methods:This was a sibling study of 101 social drinkers aged 21 to 35 years recruited from the Washington, DC metropolitan area. Participants were administered the SRE to assess LR and the timeline followback (TLFB) to assess RDH. The indices of SRE used were total SRE score (SRTT), early drinking SRE score (SRED), regular drinking SRE score (SRRD), and heavy drinking SRE score (SRHD). Pearson's product‐moment correlation and linear regression were used to analyze SRE indices and RDH variables (quantity and drinks per drinking occasion). Heritability analysis was conducte...

Cross-sectional structural magnetic resonance (MR) imaging studies of individuals with an alcohol use disorder (AUD) report that those who relapse after treatment, relative to individuals who maintain a period of extended abstinence, show greater morphological abnormalities in multiple brain regions near the inception of treatment, particularly in the frontal lobe. However, given the cross-sectional design of previous studies, it is unclear if the baseline morphological differences between future abstainers and relapsers were maintained over the course of early recovery. The primary goal of this study was to determine if frontal lobe tissue volume recovery during early abstinence is associated with long-term abstinence from alcohol. We compared frontal, parietal, temporal and occipital grey matter (GM) and white matter (WM) volumes, at 1 and 4 weeks of abstinence, among individuals who resumed alcohol consumption within 12 months of treatment (Relapsers) and those who showed sustained abstinence over 12 months following treatment (Abstainers). At 1 and 4 weeks of sobriety, both Abstainers and Relapsers demonstrated significantly smaller GM volumes than Controls in the majority of ROIs, but Relapsers exhibited significantly smaller bilateral frontal GM volumes than Abstainers. No significant group differences were observed for any WM region of interest. The persistent bilateral frontal GM volume deficits in Relapsers over 4 weeks from last alcohol use may represent an endophenotype that differentiates those who respond more favorably to the typical psychosocial and pharmacological interventions provided for AUD.

The drive to eat is regulated by two compensatory brain pathways termed as homeostatic and hedonic. Hypothalamic orexinergic (ORX) neurons regulate metabolism, feeding and reward, thus controlling physiological and hedonic appetite. Circadian regulation of feeding, metabolism and rhythmic activity of ORX cells are driven by the brain suprachiasmatic clock. How the circadian clock impacts on ORX signalling and feeding-reward rhythms is, however, unknown. Here we used mice lacking the nuclear receptor REV-ERBα, a transcription repressor and a key component of the molecular clockwork, to study food-reward behaviour. Rev-Erbα mutant mice showed highly motivated behaviours to obtain palatable food, an increase in the intake and preference for tasty diets, and in the expression of the ORX protein in the hypothalamus. Palatable food intake was inhibited in animals treated with the ORX1R antagonist. Analyzing the Orx promoter, we found Retinoic acid-related Orphan receptor Response Element binding sites for Rev-Erbα. Furthermore, Rev-Erbα dampened the activation of Orx in vitro and in vivo. Our data provide evidence for a possible repressive role of Rev-Erbα in the regulation of ORX signalling, highlighting an implication of the circadian clockwork in modulating food-reward behaviours with an important impact for the central regulation of overeating.

Rationale-Combined medication approaches, by targeting multiple neurotransmitter systems involved in alcohol use disorders (AUDs), may be more efficacious than single-medication approaches. Objectives-We examined, in animals models of consumption and reinforcement, the combined effects of naltrexone (an opioid antagonist) and topiramate (a GABA/glutamate modulator), two medications that have shown promise for treating AUDs, hypothesizing that their combination would be more efficacious than either alone. Methods-The effects of naltrexone and topiramate on ethanol consumption were examined in alcohol preferring (P) rats (N=10) and in rats from their background strain (Wistar, N=9) using conditions that induce high levels of consumption (24-hr, 3-bottle, free-choice procedure). Low doses of each medication (1 mg/kg, naltrexone; 10 mg/kg, topiramate) were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. Their effects on ethanol reinforcement were assessed under a progressive-ratio schedule in additional groups of (N=22) P rats. A moderate dose of topiramate (20 mg/kg) was also included to verify topiramate's efficacy on its own. Results-In P rats, but not Wistar rats, the combination effectively and persistently reduced consumption; whereas, neither dose alone was effective. The combination and naltrexone alone were equally effective at reducing ethanol reinforcement; however, with the combination, but not naltrexone alone, this effect was selective for ethanol. All treatments produced a similar decrease in home-cage food consumption. The 20 mg/kg dose of topiramate also effectively reduced ethanol consumption and reinforcement. Conclusions-With greater efficacy and fewer side-effects, the combination shows promise as a treatment for AUDs.

Oral submucous fibrosis (OSF) is a high risk precancerous condition characterized by changes in the connective tissue fibers of the lamina propria and deeper parts leading to stiffness of the mucosa and restricted mouth opening. Patients with severe cases have distinct difficulties in chewing, swallowing and speaking. It predominantly occurs in Indians and other population of the Indian subcontinent with certain oral habits. In patients with submucous fibrosis, the oral epithelium becomes atrophic and thereby becomes more vulnerable to carcinogens. It is now accepted that chewing areca is the most important aetiological factor for developing OSF. The atrophic epithelium shows first an intercellular edema and later epithelial atypia associated with moderate epithelial hyperplasia. From then on, carcinoma may develop any time. It is suggested that submucous fibrosis should be regarded as a condition that causes predisposition to the development of oral cancer. Here we are presenting two cases of oral submucous fibrosis showing malignant potential and development of oral squamous cell carcinoma.

Nicotine use remains highly prevalent with tobacco and e‐cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self‐administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine‐sired mice, as assessed in a self‐administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocamp...

Background: Somatoform disorders are associated with deficits in emotion processing. The neurophysiological correlates of this relationship are not well known. Pupillary responses provide information about arousal to affective information. Hence, we investigated the relationship between individual's tendency for somatization and affective processing through pupillary responses to affective images, emotion recognition, and alexithymia. Methods: Forty college students filled surveys for modelling of somatization, current symptoms of depression, anxiety, dissociation and alexithymia, in addition to various measures of stress and resilience. Pupillary responses to affective images (neutral, fear, sadness, happiness, and disgust) were measured. Participants also completed the Emotion Recognition-40 task (ER40). Results: Higher scores in alexithymia, dissociative experiences scale, and anxiety correlated with fewer correct responses to fear recognition (p<.001). In addition, alexithymia scores correlated with amplification of somatic symptoms (p<.001), attribution to physical disease (p<.01) and larger mean pupil diameter differences in early and late post image onset (MPDDinELPIO) of sadness (p<.01), whereas somatic dissociation questionnaire (SDQ) scores correlated with larger MPDDinELPIO of disgust (p<.01). Independent of stress, depression, anxiety, somatic attribution, emotion recognition, age, and gender, MPDDinELPIO of disgust was predicted by SDQ (p<.01); and MPDDinELPIO of sadness was predicted by both SDQ (p<.01) and alexithymia (p<0.001). Conclusions: Our findings suggest that alexithymia and somatic dissociation are associated with increased somatic complaints and differentiated pupillary responses to some negative emotional stimuli. Assessment of pupillary responses to negative valence stimuli could be used to understand the neurophysiological correlates of somatization.

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2 -/-) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine-and amphetamine-induced behavioral sensitization is deficient in D2 -/-mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve-and in cocaine-or amphetamine-treated D2 -/-mice. Moreover, c-Fos expression observed in D2 -/-mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.

Ethanol (EtOH) induces cognitive impairment through modulation of synaptic plasticity notably in the hippocampus. The cellular mechanism(s) of these EtOH effects may range from synaptic signaling modulation to alterations of the epigenome. Previously, we reported that two binge‐like exposures to EtOH (3 g/kg, ip, 9 h apart) in adolescent rats abolished long‐term synaptic depression (LTD) in hippocampus slices, induced learning deficits, and increased N‐methyl‐d‐aspartate (NMDA) receptor signaling through its GluN2B subunit after 48 hours. Here, we tested the hypothesis of EtOH‐induced epigenetic alterations leading to modulation of GluN2B and GluN2A NMDA receptor subunits. Forty‐two days old rats were treated with EtOH or the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB, 600 mg/kg, ip) injected alone or 30 minutes before EtOH. After 48 hours, learning was tested with novel object recognition while synaptic plasticity and the role of GluN2A and GluN2B subunits in NMDA‐f...

Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc− system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self‐administration in both rats and humans. The objective of this study was to determine whether a treatment with N‐acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self‐administration, ethanol‐seeking behavior and reacquisition of ethanol self‐administration. Male Long Evans rats were trained to self‐administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluat...

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norephinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10-20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were selfadministered by rats at 0.03 mg/kg/injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Dose-effect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.

3,4-Methylenedioxypyrovalerone (MDPV) is a commonly abused synthetic cathinone in the United States and is associated with dangerous side effects. MDPV is a dopamine transporter blocker that is 10-fold more potent than cocaine as a locomotor stimulant in rats. Previous in vitro and in vivo metabolism studies identified 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) as the two primary MDPV metabolites. This study examined MDPV pharmacokinetics and metabolism, along with associated pharmacodynamic effects in rats receiving 0.5, 1.0 and 2.0 mg/kg subcutaneous (s.c.) MDPV. Blood was collected by an indwelling jugular catheter before dosing and at 10, 20, 30, 60, 120, 240 and 480 minutes thereafter. Plasma specimens were analyzed by liquid chromatography coupled to high-resolution tandem mass spectrometry. Maximum concentrations (C max ) and areaunder-the-curve (AUC) for MDPV and two metabolites increased proportionally with administered dose, showing linear pharmacokinetics. MDPV exhibited the highest C max at all doses (74.2-271.3 μg/l) and 4-OH-3-MeOH-PV the highest AUC (11 366-47 724 minutes per μg/l), being the predominant metabolite. MDPV time to C max (T max ) was 12.9-18.6 minutes, while 3,4-catechol-PV and 4-OH-3-MeO-PV peaked later with T max 188.6-240 minutes after s.c.

Prior research utilizing whole-brain neuroimaging techniques has identified structural differences in gray matter in opioid-dependent individuals. However, the results have been inconsistent. The current study meta-analytically examines the neuroimaging findings of studies published before 2016 comparing opioid-dependent individuals to drug-naïve controls. Exhaustive search of five databases yielded 12 studies that met inclusion criteria. Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) was used to analyze the data extracted by three independent researchers. Voxel-based AES-SDM distinguishes increases and decreases in brain matter significant at the whole-brain level. AES-SDM identified the fronto-temporal region, bilaterally, as being the primary site of gray matter deficits associated with opioid use. Moderator analysis revealed that length of opioid use was negatively associated with gray matter in the left cerebellar vermis and the right Rolandic operculum, including the i...

Inhalants containing the volatile solvent toluene are misused to induce euphoria or intoxication. Inhalant abuse is most common during adolescence and can result in cognitive impairments during an important maturational period. Despite evidence suggesting that epigenetic modifications may underpin the cognitive effects of inhalants, no studies to date have thoroughly investigated toluene‐induced regulation of the transcriptome or discrete epigenetic modifications within the brain. To address this, we investigated effects of adolescent chronic intermittent toluene (CIT) inhalation on gene expression and DNA methylation profiles within the rat medial prefrontal cortex (mPFC), which undergoes maturation throughout adolescence and has been implicated in toluene‐induced cognitive deficits. Employing both RNA‐seq and genome‐wide Methyl CpG Binding Domain (MBD) Ultra‐seq analysis, we demonstrate that adolescent CIT inhalation (10 000 ppm for 1 h/day, 3 days/week for 4 weeks) induces both t...

The regulation of cue‐induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self‐efficacy, faith in one&#39;s own ability, in smokers. However, no study has examined the neural basis of self‐efficacy during the control of craving. We examined whether self‐efficacy can affect the neural response to smoking cues in smokers and ex‐smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking‐related images passively, (2) to view the smoking‐related images with a strategy focused on self‐efficacy to control cue‐induced craving or (3) to view neutral images. In smokers, the self‐efficacy strategy significantly reduced self‐reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex‐smokers. Furthermore, smokers showed increased effective conn...

Specific binding of [ 3 H]MK801 to N-methyl-D-aspartate (NMDA) receptors in the frontal cortex and hippocampus (CA1 and gyrus dentatus) was measured by receptor autoradiography in 16 Caucasian chronic alcohol consumers free of clinical manifestations of alcoholism, and compared to 16 Caucasian control subjects. Binding densities were not significantly different between heavy and moderate drinkers, neither between alcohol consumers that were abstinent or non-abstinent before death, nor between ethanol drinkers and controls. Continued alcohol consumption, in the absence of hepatic, neurologic or psychiatric disorders related to alcoholism, does not alter the binding properties of NMDA receptors in the brain areas studied.

Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey-matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed-based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the

ABSTRACTThere are well‐established links between impulsivity and alcohol use in humans and other model organisms; however, the etiological nature of these associations remains unclear. This is likely due, in part, to the heterogeneous nature of the construct of impulsivity. Many different measures of impulsivity have been employed in human studies, using both questionnaire and laboratory‐based tasks. Animal studies also use multiple tasks to assess the construct of impulsivity. In both human and animal studies, different measures of impulsivity often show little correlation and are differentially related to outcome, suggesting that the impulsivity construct may actually consist of a number of more homogeneous (and potentially more meaningful) subfacets. Here, we provide an overview of the different measures of impulsivity used across human and animal studies, evidence that the construct of impulsivity may be better studied in the context of more meaningful subfacets, and recommendat...

the encouraging and supporting by providing necessary materials. I would like to thank Dr. Tsegaye Deyu, head of the department of chemistry for his fast and appreciable response in my research work. Generally, I would like to express my gratitude to all who take part in sharing ideas and encouraging me for the betterment of my work and achievement of my goal.

Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a 'Diagnostic and Statistical Manual of Mental Disorders IV/V-like' diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review.

The demand for fresh strategies to analyze intricate multidimensional data in neuroscience is increasingly evident. One of the most complex events during our neurodevelopment is adolescence, where our nervous system suffers constant changes, not only in neuroanatomical traits but also in neurophysiological components. One of the most impactful factors we deal with during this time is our environment, especially when encountering external factors such as social behaviors or substance consumption. Binge drinking (BD) has emerged as an extended pattern of alcohol consumption in teenagers, not only affecting their future lifestyle but also changing their neurodevelopment. Recent studies have changed their scope into finding predisposition factors that may lead adolescents into this kind of patterns of consumption. Methods: In this article, using unsupervised machine learning (UML) algorithms, we analyze the relationship between electrophysiological activity of healthy teenagers and the levels of consumption they had 2 years later. We used hierarchical agglomerative UML techniques based on Ward's minimum variance criterion to clusterize relations between power spectrum and functional connectivity and alcohol consumption, based on similarity in their correlations, in frequency bands from theta to gamma. We found that all frequency bands studied had a pattern of clusterization based on anatomical regions of interest related to neurodevelopment and cognitive and behavioral aspects of addiction, highlighting the dorsolateral and medial prefrontal, the sensorimotor, the medial posterior, and the occipital cortices. All these patterns, of great cohesion and coherence, showed an abnormal electrophysiological activity, representing a dysregulation in the development of core resting-state networks. The clusters found maintained not only plausibility in nature but also robustness, making this a great example of the usage of UML in the analysis of electrophysiological activity-a new perspective into analysis that, while contributing to classical statistics, can clarify new characteristics of the variables of interest. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Chronic alcohol consumption is associated with neurocognitive and memory deficits, dramatically affecting plasticity and connectivity, with maximal expression as dementia. Neurotrophic factors may contribute to alcohol-related cognitive decline. For further investigation, a cross-sectional study was performed to evaluate the association of cognitive impairment, by using frontal assessment battery, and memory loss, using memory failures everyday, with the circulating levels of the neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in abstinent subjects with alcohol use disorders (AUDs, N = 58, average of 17.9 years of problematic use and 4.3 months of abstinence) compared with healthy control subjects (N = 22). This association was also explored in a pre-clinical model of adolescent rats chronically exposed to alcohol up to adulthood (~77 days old) in a three-bottle free-choice (5-10-20 percent), repeated abstinence and relapse paradigm. AUD subjects had ...

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

Our previous studies consistently showed that MDMA‐induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation.We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2‐deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6‐hydrodoxyopamine, 6‐OHDA) lesion of the VS could affect locomotor r...

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 (CB1) agonist oral Δ 9 tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal, but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers, and compare these with dronabinol's effects. Participants (4F; 10M) smoking marijuana 6.6 (SD = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over 7 sessions, the time-dependent subjective, cognitive, and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect, and/or `high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements, and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol and effects were more dose-related, suggesting improved bioavailability. Nabilone was well-tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence.

White matter impairment is associated with opioid dependence. However, the specific neuropathology related to opioid dependence is still not fully understood. The main aims of this study were to: (1) assess the association between white matter impairment and duration of dependence; (2) examine whether this impairment correlates with treatment outcome measures in opioid‐dependent patients post‐detoxification. Fifty‐eight opioid‐dependent patients participated, 20 females and 38 males, across three groups: less than 10 years use (n = 18), 10–15 years use (n = 26) and 16–25+ years use (n = 14). Diffusion tensor imaging was used to assess white matter impairment; whole brain voxel‐wise analysis of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed by Tract‐Based‐Spatial‐Statistics to pinpoint abnormalities in white matter. The longer the subjects were dependent on opioids, the more widespread and severely the white‐matter inte...

Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n=96) and a comparison group (n=41) were examined on tests assessing 6 cognitive and motor domains. Signs of historically-determined subclinical Wernicke's encephalopathy were detected using the Caine et al. criteria, which were based on postmortem examination and chart review of antemortem data of alcoholic cases with postmortem evidence for Wernicke's encephalopathy. Herein, four Caine criteria provided quantification of dietary deficiency, cerebellar dysfunction, low general cognitive functioning, and oculomotor abnormalities in 86 of the 96 ALC participants. Subgrouping by number of Caine criteria met yielded a graded effect, where those meeting more criteria exhibited greater impairment than those meeting no to fewer criteria. These results could not be accounted for by history of drug dependence. Multiple regression indicated that compromised performance on an ataxia battery, indicative of cerebellar dysfunction, predicted nonmnemonic and upper motor deficits, whereas low whole blood thiamine level, consistent with limbic circuit dysfunction, predicted mnemonic deficits. This double dissociation indicates biological markers that contribute to heterogeneity in expression of functional impairment in ALC. That nonmnemonic and mnemonic deficits are subserved by the dissociable neural systems of frontocerebellar and limbic circuitry, both commonly disrupted in ALC, suggests neural mechanisms that can differentially affect selective functions, thereby contributing to heterogeneity in pattern and extent of dysfunction in ALC.

Social stress in adulthood enhances cocaine self-administration, and this effect has been related with an increase in ERK and p38α MAPK phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference (CPP), and quantitative analysis of claudin-5, laminin, collage-IV and IgG immunoreactivity were performed three weeks after RSD. Mice socially defeated during adolescence developed CPP and exhibited reinstated preference with a non-effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine selfadministration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin-5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen-IV expression) in the nucleus accumbens (NAc) and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen-IV expression in the hippocampus was more pronounced in RSD mice. In summary, these findings suggest that stress and cocaine can synergize to produce long-term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB.

Topiramate reduces drinking, but little is known about the mechanisms that precipitate this effect. This double‐blind randomized placebo‐controlled study assessed the putative mechanisms by which topiramate reduces alcohol use among 96 adult non‐treatment‐seeking heavy drinkers in a laboratory‐based alcohol cue reactivity assessment and in the natural environment using ecological momentary assessment methods. Topiramate reduced the quantity of alcohol heavy drinkers consumed on drinking days and reduced craving while participants were drinking but did not affect craving outside of drinking episodes in either the laboratory or in the natural environment. Topiramate did not alter the stimulant or sedative effects of alcohol ingestion during the ascending limb of the blood alcohol curve. A direct test of putative mechanisms of action using multilevel structural equation mediation models showed that topiramate reduced drinking indirectly by blunting alcohol‐induced craving. These findin...

Adolescent alcohol use is associated with myriad adverse consequences and contributes to the leading causes of mortality among youth. Despite the magnitude of this public health problem, evidenced‐based treatment initiatives for alcohol use disorders in youth remain inadequate. Identifying promising pharmacological approaches may improve treatment options. Naltrexone is an opiate receptor antagonist that is efficacious for reducing drinking in adults by attenuating craving and the rewarding effects of alcohol. Implications of these findings for adolescents are unclear; however, given that randomized trials of naltrexone with youth are non‐existent. We conducted a randomized, double‐blinded, placebo‐controlled cross‐over study, comparing naltrexone (50 mg/daily) and placebo in 22 adolescent problem drinkers aged 15–19 years (M = 18.36, standard deviation = 0.95; 12 women). The primary outcome measures were alcohol use, subjective responses to alcohol consumption, and alcohol–cue‐elic...

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood–brain barrier (BBB) transport of mitragynine and 7‐hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7‐hydroxymitragynine transport across the BBB, with an investigation of their post‐BBB intra‐brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P‐glycoprotein (P‐gp). Mitragynine showed higher apical‐to‐basolateral (A‐B, i.e. blood‐to‐brain side) permeability than 7‐hydroxymitragynine. 7‐Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B‐A/A‐B) of 1.39. Both were found to inhibit the P‐gp and are also subject to efflux by the P‐gp. Assessment of the extent of BBB transport in vivo in rats from u...

The administration of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') to the rat results in mitochondrial oxidative damage in the central nervous system, namely lipid and protein oxidation and mitochondrial DNA deletions with subsequent impairment of the correspondent protein expression. Although these toxic effects were shown to be prevented by monoamine oxidase B inhibition, the role of monoamine oxidase A (MAO-A) in MDMA-mediated mitochondrial damage remains to be evaluated. Thus, the aim of the present study was to clarify the potential interference of a specific inhibition of MAO-A by clorgyline, on the deleterious effects produced by a binge administration of a neurotoxic dose of MDMA (10 mg MDMA/kg of body weight, intraperitoneally, every 2 hours in a total of four administrations) to an adolescent rat model. The parameters evaluated were mitochondrial lipid peroxidation, protein carbonylation and expression of the respiratory chain protein subunits II of reduced nicotinamide adenine dinucleotide dehydrogenase (NDII) and I of cytochrome oxidase (COXI). Considering that hyperthermia has been shown to contribute to the neurotoxic effects of MDMA, another objective of the present study was to evaluate the body temperature changes mediated by MDMA with a MAO-A selective inhibition by clorgyline. The obtained results demonstrated that the administration of a neurotoxic binge dose of MDMA to an adolescent rat model previously treated with the specific MAO-A inhibitor, clorgyline, resulted in synergistic effects on serotonin-(5-HT) mediated behaviour and body temperature, provoking high mortality. Inhibition of MAO-A by clorgyline administration had no protective effect on MDMA-induced alterations on brain mitochondria (increased lipid peroxidation, protein carbonylation and decrease in the expression of the respiratory chain subunits NDII and COXI), although it aggravated MDMA-induced decrease in the expression of COXI. These results reinforce the notion that the concomitant use of MAO-A inhibitors and MDMA is counter indicated because of the resulting severe synergic toxicity.

This study aimed to compare various components of sleep quality between cigarette smokers of various intensities and non-smokers in young Saudi males. In total, 73 healthy male participants (31 smokers and 42 non-smokers) aged 17–33 years were recruited over three months (August 2018 to October 2018). All participants completed the Pittsburgh Sleep Quality Index (PSQI) questionnaire. The smokers were then divided into three groups, according to their Smoking Index* (SI) (Cigarettes Per Day (CPD) X Years of Tobacco Use), into mild, moderate, and heavy smokers. The PSQI was significantly higher in heavy smokers than in mild smokers (P=0.022) or non-smokers (p=0.013). A significant positive correlation was observed between the PSQI and the smoking index (p=0.005). Sleep duration was significantly longer in heavy smokers compared to mild (p=0.032) and nonsmokers (p=0.047). Sleep disturbance was significantly higher in moderate than nonsmokers (p=0.035) and moderate than mild smokers (p=...

Khat (Catha edulis) chewing is a highly prevalent habit in the Arabian Peninsula and East Africa, and has recently spread to Western countries. The association between khat chewing and oral mucosal lesions is well documented in the literature. However, there is no concrete evidence on the association between khat chewing and periodontal disease. The purpose of this systematic review was to analyze the influence of khat chewing on periodontal health. A literature search of PubMed, Scopus and Web of Sciences databases was carried out to identify relevant articles published from 1990 to May 2017. The inclusion criteria were all clinical studies that assessed the relationship between khat chewing and periodontal disease. The search yielded 122 articles, of which 10 were included in this systematic review. Most of the studies exhibited a positive correlation between khat chewing and periodontal disease. Altogether, the analysis of the current evidence reveals that khat chewing is destruc...

Previous studies have shown that brief access to cocaine yields an increase in D2 receptor binding in the medial prefrontal cortex (mPFC), but that extended access to cocaine results in normalized binding of D2 receptors (i.e. the D2 binding returned to control levels). Extended access conditions have also been shown to produce increased expression of the NR2 subunit of the NMDA receptor in the mPFC. These results implicate disrupted glutamate and dopamine function within this area. Therefore, in the present study, we monitored glutamate and dopamine content within the mPFC during, or 24 hrs after, cocaine self-administration, in animals that experienced various amounts of exposure to the drug. Naïve subjects showed decreased glutamate, and increased dopamine, levels within the mPFC during cocaine self-administration. Exposure to 7 lhr daily cocaine self-administration sessions did not alter the response to self-administered cocaine, but resulted in decreased basal dopamine levels. While exposure to 17 lhr sessions also resulted in reduced basal dopamine levels, these animals showed increased dopaminergic, but completely diminished glutamatergic, response to self-administered cocaine. Finally, exposure to 17 cocaine self-administration sessions, the last ten of which being 6h sessions, resulted in diminished glutamatergic response to self-administered cocaine and reduced basal glutamate levels within the mPFC, while normalizing (i.e. causing a return to control levels) both the dopaminergic response to self-administered cocaine as well as basal dopamine levels within this area. These data demonstrate directly that the transition to escalated cocaine use involves progressive changes in dopamine and glutamate function within the mPFC.

Postural stability is a multi‐factorial skill maintained implicitly. Components of quiet standing can decline with Alcohol Use Disorder (AUD), cause instability, and disrupt activities of daily living (ADL). To examine how stability factors contribute to ADL and balance, 638 force platform testing sessions measured sway paths acquired during quiet standing in 151 AUD and 96 control men and women, age 25–75. Structural equation (seq) path analysis estimated contributions from age, diagnosis, and sensory perception to sway and measures of ADL and roadside ataxia testing. Whether eyes were open or closed, older AUD and control participants had longer sway paths than younger ones; older men had longer sway paths than older women. Although each sensory ability tested declined with aging, different factor constellations influenced ADL, ataxia scores, or sway path. Seq‐path analysis indicated that ADL was strongly dependent on sensory (but not cognitive) systems with sway‐path length accou...

Background-Tobacco use is prevalent among persons with alcohol abuse and dependence. Varenicline has been shown to be the most effective pharmacotherapy for smoking cessation and may decrease alcohol consumption. The purpose of this study was to evaluate the efficacy of 12 weeks of varenicline for increasing smoking abstinence rates in smokers with alcohol abuse or dependence. Methods-Participants were eligible for enrollment if they were 18 years or older, smoked 10 or more cigarettes per day for at least 6 months, had current alcohol abuse or dependence, and were interested in quitting smoking. Participants were randomly assigned to receive 12 weeks of varenicline 1 mg twice daily or matching placebo. The primary end point was 7-day point prevalence smoking abstinence at week 12. Results-The 7-day point prevalence smoking abstinence rate at 12 weeks was significantly higher with varenicline (n=16) than placebo (n=17) (43.8% vs 5.9%; P=.01). At 24 weeks, the 7day point prevalence smoking abstinence rate was still significantly higher with varenicline than placebo (31.3% vs 0%; P=.02). At 12 weeks, mean (SD) drinks per drinking day was significantly lower with varenicline than placebo (5.7 [3.9] vs 9.0 [5.3] drinks; treatment effect estimate, -2.8 [90% CI, -6.6--1.0]). Adverse events were minor and comparable to varenicline clinical trials.

ABSTRACTMore than 76 million people world‐wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism&#39;s (NIAAA&#39;s) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, t...

Alcohol dependence (AD) is characterized by corticostriatal impairments in individual brain areas such as the striatum. As yet however, complex brain network topology in AD and its association with disease progression are unknown. We applied graph theory to resting-state functional magnetic resonance imaging (RS-fMRI) to examine weighted global efficiency and local (clustering coefficient, degree and eigenvector centrality) network topology and the functional role of the striatum in 24 AD patients compared with 20 matched healthy controls (HCs), and their association with dependence characteristics. Graph analyses were performed based on Pearson&#39;s correlations between RS-fMRI time series, while correcting for age, gender and head motion. We found no significant group differences between AD patients and HCs in network topology. Notably, within the patient group, but not in HCs, the whole-brain network showed reduced average cluster coefficient with more severe alcohol use, wherea...

Sport coaches are a population with its specific characteristics and because of their association with the athletes, especially the young, their lifestyle habits deserve attention. The aim of this study was to determine the habits related to alcohol consumption and smoking in the Croatian sport coaches. The study was conducted on 56 women and 147 men, coaches of various sport disciplines in 2012. AUDIT questionnaire, related to alcohol consumption, and FTND questionnaire to determine nicotine addiction were used. Most of the sports coaches of both genders have no problems with alcohol and their nicotine addiction is on average weak, although there are some very serious nicotine addicts.Sportski treneri su populacija sa svojim specifičnostima, a zbog njihove povezanosti s igračima, osobito mladima, njihov način života i navike zaslužuju pažnju. Cilj ovog istraživanja bio je utvrđivanje navika vezanih uz konzumaciju alkohola te pušenje cigareta hrvatskih sportskih trenera. Istraživanj...

Neuroinflammatory signaling pathways in the CNS are of current interest as potential pharmacotherapy targets for alcohol dependence. In this study, we examined the ability of ibudilast, a non-selective phosphodiesterase inhibitor, to reduce alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol dependent mice at doses which had no effect in non-dependent mice. These findings support the viability of ibudilast as a possible treatment for alcohol dependence.