Showing papers in "Addiction Biology in 2015"

The prefrontal dysfunction in individuals with Internet gaming disorder: a meta-analysis of functional magnetic resonance imaging studies.

Abstract: With the advancement in high-resolution magnetic resonance imaging (MRI) technology and automated analysis, studies on functional MRI (fMRI) made it possible to identify the functional activity of brain in vivo in individuals with Internet gaming disorder (IGD), and to explore the underpinning neuroscience basis of IGD. Yet, no available literature has systemically reviewed the fMRI studies of IGD using meta-analyses. This study reviewed 61 candidate articles and finally selected 10 qualified voxel-wise whole-brain analysis studies for performing a comprehensive series of meta-analyses employing effect size signed differential mapping approach. Compared with healthy controls, subjects with IGD showed a significant activation in the bilateral medial frontal gyrus (MFG) and the left cingulate gyrus, as well as the left medial temporal gyrus and fusiform gyrus. Furthermore, the on-line time of IGD subjects was positively correlated with activations in the left MFG and the right cingulated gyrus. These findings implicate the important role of dysfunctional prefrontal lobe in the neuropathological mechanism of IGD. Considering the overlapped role of prefrontal lobe in the reward and self-regulatory system, our results provided supportive evidence for the reclassification of IGD as a behavioural addiction.

Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.

Abstract: Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.

Incubation of alcohol craving during abstinence in patients with alcohol dependence.

Abstract: Time-dependent increases in cue-induced nicotine and methamphetamine craving during abstinence were recently reported in human drug-dependent individuals. In the present study, we sought to determine whether this 'incubation of craving' phenomenon also occurs in alcoholics. Four groups of 80 inpatient adult male alcoholics were assessed in a single session (between-group design) for cue-induced alcohol craving at 7, 14, 30 and 60 days of abstinence. Another group that included 19 patients was repeatedly tested for cue-induced alcohol craving at the same abstinence days as above. Other psychological and physiological measures were assessed at the four abstinence timepoints. Cue-induced alcohol craving measured with visual analogue scales was the highest at 60 days of abstinence both between and within groups. However, heart rate, blood pressure and skin conductance responses did not differ between abstinent groups. These results provide evidence of the incubation of alcohol craving in humans, extending previous reports with smokers and methamphetamine addicts.

[18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users

Abstract: Δ(9) -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [(18) F]MK-9470 to obtain in vivo measurements of cerebral CB1 receptor availability in 10 chronic cannabis users (age = 26.0 ± 4.1 years). Each patient underwent [(18) F]MK-9470 PET within the first week following the last cannabis consumption. A population of 10 age-matched healthy subjects (age = 23.0 ± 2.9 years) was used as control group. Parametric modified standardized uptake value images, reflecting CB1 receptor availability, were calculated. Statistical parametric mapping and volume-of-interest (VOI) analyses of CB1 receptor availability were performed. Compared with controls, cannabis users showed a global decrease in CB1 receptor availability (-11.7 percent). VOI-based analysis demonstrated that the CB1 receptor decrease was significant in the temporal lobe (-12.7 percent), anterior (-12.6 percent) and posterior cingulate cortex (-13.5 percent) and nucleus accumbens (-11.2 percent). Voxel-based analysis confirmed this decrease and regional pattern in CB1 receptor availability in cannabis users. These findings revealed that chronic cannabis use may alter specific regional CB1 receptor expression through neuroadaptive changes in CB1 receptor availability, opening the way for the examination of specific CB1 -cannabis addiction interactions which may predict future cannabis-related treatment outcome.

Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2

Abstract: The paraventricular nucleus of the thalamus (PVT) has been shown to participate in hedonic feeding and is thought to influence drug seeking This understudied nucleus contains anterior (aPVT) and posterior (pPVT) subregions, which receive dense projections from hypothalamic orexin/hypocretin (OX) but exhibit anatomical and functional differences This study sought to characterize in Long-Evans rats the involvement of these PVT subregions and their OX receptor activity in consumption of the drug, ethanol Compared with those maintained on water and chow only (water group), rats trained to drink pharmacologically relevant levels of ethanol (ethanol group) showed increased neuronal activation in the PVT, specifically the aPVT but not pPVT, as indicated by c-Fos immunoreactivity Similar results were obtained in rats administered ethanol via oral gavage, indicating that this site-specific effect was due to ethanol exposure In support of the involvement of OX, the ethanol group also showed increased mRNA levels of this neuropeptide in the hypothalamus and of OX 2 receptor (OX2R) but not OX 1 receptor (OX1R), again in the aPVT but not pPVT Similarly, ethanol gavage increased double labeling of c-Fos with OX2R but not OX1R, specifically in the aPVT Evidence directly supporting a role for aPVT OX2R in ethanol consumption was provided by results with local injections, showing ethanol intake to be enhanced by OX-A or OX-B in the aPVT but not pPVT and reduced by a local antagonist of OX2R but not OX1R These results focus attention on the aPVT and specifically its OX2R in mediating a positive feedback relationship with ethanol intake

Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence

Abstract: Neuroinflammatory signaling pathways in the central nervous system 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

Predicting subsequent relapse by drug-related cue-induced brain activation in heroin addiction: an event-related functional magnetic resonance imaging study

Abstract: Abnormal salience attribution is implicated in heroin addiction. Previously, combining functional magnetic resonance imaging (fMRI) and a drug cue-reactivity task, we demonstrated abnormal patterns of subjective response and brain reactivity in heroin-dependent individuals. However, whether the changes in cue-induced brain response were related to relapse was unknown. In a prospective study, we recruited 49 heroin-dependent patients under methadone maintenance treatment, a gold standard treatment (average daily dose 41.8 ± 16.0 mg), and 20 healthy subjects to perform the heroin cue-reactivity task during fMRI. The patients' subjective craving was evaluated. They participated in a follow-up assessment for 3 months, during which heroin use was assessed and relapse was confirmed by self-reported relapse or urine toxicology. Differences between relapsers and non-relapsers were analyzed with respect to the results from heroin-cue responses. Compared with healthy subjects, relapsers and non-relapsers commonly demonstrated significantly increased brain responses during the processing of heroin cues in the mesolimbic system, prefrontal regions and visuospatial-attention regions. However, compared with non-relapsers, relapsers demonstrated significantly greater cue-induced craving and the brain response mainly in the bilateral nucleus accumbens/subcallosal cortex and cerebellum. Although the cue-induced heroin craving was low in absolute measures, the change in craving positively correlated with the activation of the nucleus accumbens/subcallosal cortex among the patients. These findings suggest that in treatment-seeking heroin-dependent individuals, greater cue-induced craving and greater specific regional activations might be related to reward/craving and memory retrieval processes. These responses may predict relapse and represent important targets for the development of new treatment for heroin addiction.

Plasma profile of pro-inflammatory cytokines and chemokines in cocaine users under outpatient treatment: influence of cocaine symptom severity and psychiatric co-morbidity

Abstract: The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.

Common single nucleotide variants underlying drug addiction: more than a decade of research.

Abstract: Drug-related phenotypes are common complex and highly heritable traits. In the last few years, candidate gene (CGAS) and genome-wide association studies (GWAS) have identified a huge number of single nucleotide polymorphisms (SNPs) associated with drug use, abuse or dependence, mainly related to alcohol or nicotine. Nevertheless, few of these associations have been replicated in independent studies. The aim of this study was to provide a review of the SNPs that have been most significantly associated with alcohol-, nicotine-, cannabis- and cocaine-related phenotypes in humans between the years of 2000 and 2012. To this end, we selected CGAS, GWAS, family-based association and case-only studies published in peer-reviewed international scientific journals (using the PubMed/MEDLINE and Addiction GWAS Resource databases) in which a significant association was reported. A total of 371 studies fit the search criteria. We then filtered SNPs with at least one replication study and performed meta-analysis of the significance of the associations. SNPs in the alcohol metabolizing genes, in the cholinergic gene cluster CHRNA5-CHRNA3-CHRNB4, and in the DRD2 and ANNK1 genes, are, to date, the most replicated and significant gene variants associated with alcohol- and nicotine-related phenotypes. In the case of cannabis and cocaine, a far fewer number of studies and replications have been reported, indicating either a need for further investigation or that the genetics of cannabis/cocaine addiction are more elusive. This review brings a global state-of-the-art vision of the behavioral genetics of addiction and collaborates on formulation of new hypothesis to guide future work.

Effects of cognitive bias modification training on neural signatures of alcohol approach tendencies in male alcohol-dependent patients.

Abstract: Alcohol-dependent patients have been shown to faster approach than avoid alcohol stimuli on the Approach Avoidance Task (AAT). This so-called alcohol approach bias has been associated with increased brain activation in the medial prefrontal cortex and nucleus accumbens. Cognitive bias modification (CBM) has been used to retrain the approach bias with the clinically relevant effect of decreasing relapse rates one year later. The effects of CBM on neural signatures of approach/avoidance tendencies remain hitherto unknown. In a double-blind placebo-controlled design, 26 alcohol-dependent in-patients were assigned to a CBM or a placebo training group. Both groups performed the AAT for three weeks: in CBM training, patients pushed away 90 percent of alcohol cues; this rate was 50 percent in placebo training. Before and after training, patients performed the AAT offline, and in a 3 T magnetic resonance imaging scanner. The relevant neuroimaging contrast for the alcohol approach bias was the difference between approaching versus avoiding alcohol cues relative to soft drink cues: [(alcohol pull > alcohol push) > (soft drink pull > soft drink push)]. Before training, both groups showed significant alcohol approach bias-related activation in the medial prefrontal cortex. After training, patients in the CBM group showed stronger reductions in medial prefrontal cortex activation compared with the placebo group. Moreover, these reductions correlated with reductions in approach bias scores in the CBM group only. This suggests that CBM affects neural mechanisms involved in the automatic alcohol approach bias, which may be important for the clinical effectiveness of CBM.

Pathological gambling and alcohol dependence: neural disturbances in reward and loss avoidance processing.

Abstract: Pathological gambling (PG) shares clinical characteristics such as craving and loss of control with substance use disorders and is thus considered a behavioral addiction. While functional alterations in the mesolimbic reward system have been correlated with craving and relapse in substance use disorders, only a few studies have examined this brain circuit in PG, and no direct comparison has been conducted so far. Thus, we investigated the neuronal correlates of reward processing in PG in contrast to alcohol-dependent (AD) patients and healthy subjects. Eighteen PG patients, 15 AD patients and 17 controls were investigated with a monetary incentive delay task, in which visual cues predict the consequence (monetary gain, avoidance of loss, none) of a fast response to a subsequent target stimulus. Functional magnetic resonance imaging data were analyzed to account for possible confounding factors such as local gray matter volume. Activity in the right ventral striatum during loss anticipation was increased in PG patients compared with controls and AD patients. Moreover, PG patients showed decreased activation in the right ventral striatum and right medial prefrontal cortex during successful loss avoidance compared with controls, which was inversely associated with severity of gambling behavior. Thus, despite neurobiological similarities to substance use disorders in reward processing, as reported by previous studies, we found relevant differences with respect to the anticipation of loss as well as its avoidance (negative reinforcement), which further contributes to the understanding of PG.

Drug versus sweet reward: greater attraction to and preference for sweet versus drug cues.

Abstract: Despite the unique ability of addictive drugs to directly activate brain reward circuits, recent evidence suggests that drugs induce reinforcing and incentive effects that are comparable to, or even lower than some nondrug rewards. In particular, when rats have a choice between pressing a lever associated with intravenous cocaine or heroin delivery and another lever associated with sweet water delivery, most respond on the latter. This outcome suggests that sweet water is more reinforcing and attractive than either drug. However, this outcome may also be due to the differential ability of sweet versus drug levers to elicit Pavlovian feeding-like conditioned responses that can cause involuntary lever pressing, such as pawing and biting the lever. To test this hypothesis, rats first underwent Pavlovian conditioning to associate one lever with sweet water (0.2% saccharin) and a different lever with intravenous cocaine (0.25 mg) or heroin (0.01 mg). Choice between these two levers was then assessed under two operant choice procedures: one that permitted the expression of Pavlovian-conditioned lever press responses during choice, the other not. During conditioning, Pavlovian-conditioned lever press responses were considerably higher on the sweet lever than on either drug lever, and slightly greater on the heroin lever than on the cocaine lever. Importantly, though these differences in Pavlovian-conditioned behavior predicted subsequent preference for sweet water during choice, they were not required for its expression. Overall, this study confirms that rats prefer the sweet lever because sweet water is more reinforcing and attractive than cocaine or heroin.

Postdependent state in rats as a model for medication development in alcoholism

Abstract: 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.

Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol

Abstract: This study examines the role of the cannabinoid CB2 receptor (CB2r) on the vulnerability to ethanol consumption. The time-related and dose-response effects of ethanol on rectal temperature, handling-induced convulsions (HIC) and blood ethanol concentrations were evaluated in CB2KO and wild-type (WT) mice. The reinforcing properties of ethanol were evaluated in conditioned place preference (CPP), preference and voluntary ethanol consumption and oral ethanol self-administration. Water-maintained behavior schedule was performed to evaluate the degree of motivation induced by a natural stimulus. Preference for non-alcohol tastants assay was performed to evaluate the differences in taste sensitivity. Tyrosine hydroxylase (TH) and μ-opioid receptor gene expressions were also measured in the ventral tegmental area and nucleus accumbens (NAcc), respectively. CB2KO mice presented increased HIC score, ethanol-CPP, voluntary ethanol consumption and preference, acquisition of ethanol self-administration, and increased motivation to drink ethanol compared with WT mice. No differences were found between genotypes in the water-maintained behavior schedule or preference for non-alcohol tastants. Naive CB2KO mice presented increased μ-opioid receptor gene expression in NAcc. Acute ethanol administration (1–2 g/kg) increased TH and μ-opioid receptor gene expressions in CB2KO mice, whereas the lower dose of ethanol decreased TH gene expression in WT mice. These results suggest that deletion of the CB2r gene increased preference for and vulnerability to ethanol consumption, at least in part, by increased ethanol-induced sensitivity of the TH and μ-opioid receptor gene expressions in mesolimbic neurons. Future studies will determine the role of CB2r as a target for the treatment of problems related with alcohol consumption.

Recent updates on incubation of drug craving: a mini-review

Abstract: Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving. Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. Here, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving.

The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals.

Abstract: Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

Persistent palatable food preference in rats with a history of limited and extended access to methamphetamine self-administration.

Abstract: Recent studies have shown that when given a mutually exclusive choice between cocaine and palatable foods, most rats prefer the non-drug rewards over cocaine. Here, we used a discrete choice procedure to assess whether palatable food preference generalizes to rats with a history of limited (3 hours/day) or extended (6 or 9 hours/day) access to methamphetamine self-administration. On different daily sessions, we trained rats to lever-press for either methamphetamine (0.1-0.2 mg/kg/infusion) or palatable food (five pellets per reward delivery) for several weeks; regular food was freely available. We then assessed food-methamphetamine preference either during training, after priming methamphetamine injections (0.5-1.0 mg/kg), following a satiety manipulation (palatable food exposure in the home cage) or after 21 days of withdrawal from methamphetamine. We also assessed progressive ratio responding for palatable food and methamphetamine. We found that independent of the daily drug access conditions and the withdrawal period, the rats strongly preferred the palatable food over methamphetamine, even when they were given free access to the palatable food in the home cage. Intake of methamphetamine and progressive ratio responding for the drug, both of which increased or escalated over time, did not predict preference in the discrete choice test. Results demonstrate that most rats strongly prefer palatable food pellets over intravenous methamphetamine, confirming previous studies using discrete choice procedures with intravenous cocaine. Results also demonstrate that escalation of drug self-administration, a popular model of compulsive drug use, is not associated with a cardinal feature of human addiction of reduced behavioral responding for non-drug rewards.

Right anterior insula connectivity is important for cue-induced craving in nicotine-dependent smokers.

Abstract: The insula has been implicated in cue-induced craving and relapse in nicotine-dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue-induced craving in healthy (free of Axis I psychiatric disorders) nicotine-dependent tobacco cigarette smokers. Functional magnetic resonance imaging (fMRI) data were collected from 63 healthy nicotine-dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction (PPI) approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z>2.3, p=0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue-induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self-awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r2=0.15; p<0.01). These data suggest that among smokers, cue-induced craving may be a function of connectivity between two regions involved in interoception and self-awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue-induced craving and relapse in nicotine-dependent smokers.

Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety‐like behavior and hyperalgesia in rats

Abstract: Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self-administration. Here, we tested the hypothesis that the activation of corticotropin-releasing factor-1 (CRF1) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self-administration. ShA and LgA rats were tested for anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5α)pyrimidin-7-amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence-induced increases in anxiety-like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra-CeA MPZP infusion prevented abstinence-induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self-administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended-intermittent access to nicotine self-administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence-induced anxiety-like behavior, hyperalgesia and excessive nicotine intake.

Involvement of reactive oxygen species in cocaine-taking behaviors in rats.

Abstract: Reactive oxygen species (ROS) have been implicated in the development of behavioral sensitization following repeated cocaine exposure. We hypothesized that increased ROS following cocaine exposure would act as signaling molecules in the mesolimbic dopamine (DA) system, which might play an important role in mediating the reinforcing effects of cocaine. The aim of this study was to evaluate cocaine enhancement of brain metabolic activity and the effects of ROS scavengers on cocaine self-administration behavior, cocaine-induced ROS production in the nucleus accumbens (NAc) and cocaine enhancement of DA release in the NAc. Metabolic neural activity monitored by temperature and oxidative stress were increased in NAc following cocaine exposure. Systemic administration of the ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), either pre- or post-treatment, significantly decreased cocaine self-administration without affecting food intake. Infusion of TEMPOL into the NAc inhibited cocaine self-administration. Increased oxidative stress was found mainly on neurons, but not astrocytes, microglia or oligodendrocytes, in NAc of rats self-administering cocaine. TEMPOL significantly attenuated cocaine-induced enhancement of DA release in the NAc, compared to saline controls. TEMPOL had no effect on the enhancement of DA release produced by the DA transporter inhibitor GBR12909. Taken together, these findings suggest that enhancement of ROS production in NAc neurons contributes to the reinforcing effect of cocaine.

Brains online: structural and functional correlates of habitual Internet use.

Abstract: In the past decades, the Internet has become one of the most important tools to gather information and communicate with other people. Excessive use is a growing concern of health practitioners. Based on the assumption that excessive Internet use bears resemblance with addictive behaviour, we hypothesized alterations of the fronto-striatal network in frequent users. On magnetic resonance imaging scans of 62 healthy male adults, we computed voxel-based morphometry to identify grey matter (GM) correlates of excessive Internet use, assessed by means of the Internet Addiction Test (IAT) and functional connectivity analysis and amplitude of low-frequency fluctuation (ALFF) measures on resting state data to explore the functional networks associated with structural alterations. We found a significant negative association between the IAT score and right frontal pole GM volume (P < 0.001, family wise error corrected). Functional connectivity of right frontal pole to left ventral striatum was positively associated with higher IAT scores. Furthermore, the IAT score was positively correlated to ALFF in bilateral ventral striatum. The alterations in the fronto-striatal circuitry associated with growing IAT scores could reflect a reduction of top-down modulation of prefrontal areas, in particular, the ability to maintain long-term goals in face of distraction. The higher activation of ventral striatum at rest may indicate a constant activation in the context of a diminished prefrontal control. The results demonstrate that excessive Internet use may be driven by neuronal circuits relevant for addictive behaviour.

Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history

Abstract: Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys, and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here we addressed two fundamental questions regarding yohimbine’s effect on reinstatement of reward seeking: (1) whether the drug’s effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine’s effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever-pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine’s effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine.

Strain dependence of adolescent Cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats

Abstract: Adolescent Cannabis exposure has been hypothesized to act as a gateway to opiate abuse. In order to investigate the role of genetic background in cannabinoid-opiate interactions, we studied the effect of Δ(9) -tetrahydrocannabinol (THC) exposure of adolescent Lewis and Fischer 344 rats on the responsiveness of accumbens shell and core dopamine (DA), as monitored by microdialysis, to THC and heroin at adulthood. Heroin reward and reinstatement by heroin priming were studied by conditioned place preference (CPP) and cognitive and emotional functions by object recognition, Y maze and elevated plus maze paradigms. THC stimulated shell DA in Lewis but not in Fischer 344 rats. Adolescent THC exposure potentiated DA stimulant effects of heroin in the shell and core of Lewis and only in the core of Fischer 344 rats. Control Lewis rats developed stronger CPP to heroin and resistance to extinction compared with Fischer 344 strain. In Lewis rats, THC exposure did not affect heroin CPP but potentiated the effect of heroin priming. In Fischer 344 rats, THC exposure increased heroin CPP and made it resistant to extinction. Lewis rats showed seeking reactions during extinction and hedonic reactions in response to heroin priming. Moreover, adolescent THC exposure affected emotional function only in Lewis rats. These observations suggest that long-term effects of Cannabis exposure on heroin addictive liability and emotionality are dependent on individual genetic background.

Altered brain functional networks in heavy smokers.

Abstract: Recent neuroimaging studies have demonstrated that cigarette smoking is associated with changed brain structure and function. However, little is known about alterations of the topological organization of brain functional networks in heavy smokers. Thirty-one heavy smokers and 33 non-smokers underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding the correlation matrices of 90 brain regions and their topological properties were analyzed using graph network analysis. Non-parametric permutation tests were performed to investigate group differences in network topological measures and multiple regression analysis was conducted to determine the relationships between the network metrics and smoking-related variables. Both heavy smokers and non-smokers exhibited small-world architecture in their brain functional networks. Compared with non-smokers, however, heavy smokers showed altered topological measurements characterized by lower global efficiency, higher local efficiency and clustering coefficients and greater path length. Furthermore, heavy smokers demonstrated decreased nodal global efficiency mainly in brain regions within the default mode network, whereas increased nodal local efficiency predominated in the visual-related regions. In addition, heavy smokers exhibited an association between the altered network metrics and the duration of cigarette use or the severity of nicotine dependence. Our results suggest that heavy smokers may have less efficient network architecture in the brain, and chronic cigarette smoking is associated with disruptions in the topological organization of brain networks. Our findings may further the understanding of the effects of chronic cigarette smoking on the brain and the pathophysiological mechanisms underlying nicotine dependence.

Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia.

Abstract: Opioids represent effective drugs for the relief of pain, yet chronic opioid use often leads to a state of increased sensitivity to pain that is exacerbated during withdrawal. A sensitization of pain-related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro-adaptive changes occur as a consequence of excessive opioid exposure, including a recruitment of corticotropin-releasing factor (CRF) and norepinephrine (NE) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on hyperalgesia-like behavior during heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self-administered heroin produced a significant mechanical hypersensitivity. During acute opioid dependence, systemic administration of the CRF1 receptor antagonist MPZP (20 mg/kg) alleviated withdrawal-induced mechanical hypersensitivity. In contrast, several functional adrenergic system antagonists (clonidine, prazosin, propranolol) failed to alter mechanical hypersensitivity in this state. We then determined the effects of chronic MPZP or clonidine treatment on extended access heroin self-administration and found that MPZP, but not clonidine, attenuated escalation of heroin intake, whereas both drugs alleviated chronic dependence-associated hyperalgesia. These findings suggest that an early potentiation of CRF signaling occurs following opioid exposure that begins to drive both opioid-induced hyperalgesia and eventually intake escalation.

Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies

Abstract: Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction.

Increased impulsivity in rats as a result of repeated cycles of alcohol intoxication and abstinence.

Abstract: Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition.

Serial longitudinal magnetic resonance imaging data indicate non-linear regional gray matter volume recovery in abstinent alcohol-dependent individuals.

Abstract: The trajectory of regional volume changes during the first year of sustained abstinence in those recovering from an alcohol use disorder is unclear because previous research typically employed only two assessment points. To better understand the trajectory of regional brain volume recovery in treatment-seeking alcohol-dependent individuals (ALC), regional brain volumes were measured after 1 week, 1 month and 7.5 months of sustained abstinence via magnetic resonance imaging at 1.5 T. ALC showed significant volume increases in frontal, parietal and occipital gray matter (GM) and white matter (WM), total cortical GM and total lobar WM, thalamus and cerebellum, and decreased ventricular volume over 7.5 months of abstinence. Volume increases in regional GM were significantly greater over 1 week to 1 month than from 1 month to 7.5 months of abstinence, indicating a non-linear rate of change in regional GM over 7.5 months. Overall, regional lobar WM showed linear volume increases over 7.5 months. With increasing age, smoking ALC showed lower frontal and total cortical GM volume recovery than non-smoking ALC. Despite significant volume increases, ALC showed smaller GM volumes in all regions, except the frontal cortex, than controls after 7.5 months of abstinence. ALC and controls showed no regional WM volume differences at any assessment point. In non-smoking ALC only, increasing regional GM and WM volumes were related to improving processing speed. Findings may indicate a differential rate of recovery of cell types/cellular components contributing to GM and WM volume during early abstinence, and that GM volume deficits persist after 7.5 months of sustained sobriety in this ALC cohort.

MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats

Abstract: Dysregulation of the nociceptin (N/OFQ) system has been implicated in alcohol abuse and alcoholism and growing evidence suggests that targeting this system may be beneficial for treating alcoholism. To further explore the treatment target potential of the N/OFQ system, the novel non-peptide, small-molecule N/OFQ (NOP) agonist MT-7716, (R)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-N-methylacetamide hydrochloride hydrate, was examined for its effects on ethanol self-administration and stress induced reinstatement of alcohol seeking in non-dependent and post-dependent rats. Male Wistar rats were trained to self-administer ethanol and then made ethanol dependent via repeated intragastric ethanol intubation. The effects of MT-7716 (0.3 and 1 mg/kg; PO) on alcohol self-administration were determined two weeks following dependence induction, when baseline self-administration was restored. Effects of MT-7716 on stress-induced reinstatement were tested in separate cohorts of rats, one and three weeks post-withdrawal. MT-7716 reduced alcohol self-administration and stress-induced reinstatement of alcohol seeking in post-dependent rats, but was ineffective in non-dependent animals. Moreover, the prevention of stress-induced reinstatement by MT-7716 was more pronounced at 3 weeks post-dependence. The results further confirm treatment target potential for the NOP receptor and identify non-peptide NOP agonists as promising potential treatment drugs for alcohol abuse and relapse prevention. The findings also support dysregulation of the N/OFQ system as a factor in alcohol seeking and reinforcement.

Sleep changes in smokers before, during and 3 months after nicotine withdrawal.

Abstract: Nicotine may affect sleep by influencing sleep-regulating neurotransmitters. Sleep disorders can increase the risk for depression and substance dependency. To detect the influence of sleep disturbances on the effect of smoking cessation, we investigated polysomnographically (PSG) the sleep of smoking subjects during a period of smoking, during withdrawal and after a period of abstinence from nicotine. Thirty-three smokers (23 male, 10 female, median age 29 years, Fagerstrom Test for Nicotine Dependence score 6.3) were examined during smoking, 24-36 hours after smoking and 3 months after cessation. All subjects had an adaptation night followed by the PSG night. Compared with the smoking state, we found increased arousal index and wake time during nicotine withdrawal. Smokers who later relapsed (11) presented a higher degree of nicotine dependence and more withdrawal symptoms than those who abstained (22) and were characterized by less rapid eye movement (REM) sleep, a longer REM latency as well as by more intense sleep impairments in the subjective sleep rating during the withdrawal. Impairments of sleep during the withdrawal phase may reflect more severe nicotine dependence and may contribute to earlier relapse into smoking behaviours.