Addiction Biology

Cover image for Vol. 21 Issue 4

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Rainer Spanagel

Impact Factor: 4.547

ISI Journal Citation Reports © Ranking: 2015: 2/18 (Substance Abuse); 61/289 (Biochemistry & Molecular Biology)

Online ISSN: 1369-1600

Associated Title(s): Addiction


  1. 1 - 100
  2. 101 - 144
  1. Original Articles

    1. Prolonged withdrawal from cocaine self-administration affects prefrontal cortex- and basolateral amygdala–nucleus accumbens core circuits but not accumbens GABAergic local interneurons

      Anthony Purgianto, Michael E. Weinfeld and Marina E. Wolf

      Version of Record online: 25 JUL 2016 | DOI: 10.1111/adb.12430

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      We examined aspects of GABA transmission in nucleus accumbens (NAc) core after incubation of cocaine craving. Activity-dependent interneuron markers (e.g. parvalbumin) were unchanged, but local field potential recordings revealed differential adaptations in prefrontal cortex-NAc core and basolateral amygdala-NAc core circuits, some potentially involving GABA. Combined with other findings, our results suggest more pronounced changes in glutamate than GABA during incubation.

    2. You have full text access to this OnlineOpen article
      Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling

      Cristina Lao-Peregrín, Jesús Javier Ballesteros, Miriam Fernández, Alfonsa Zamora-Moratalla, Ana Saavedra, María Gómez Lázaro, Esther Pérez-Navarro, Deborah Burks and Eduardo D. Martín

      Version of Record online: 25 JUL 2016 | DOI: 10.1111/adb.12433

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      Caffeine, a stimulant that enhances cognitive function, is the most widely consumed behaviorally active substance in the world. Here, we show that caffeine, at moderate doses of human consumption, induces an NMDA receptor-independent form of long-term potentiation and increases calcium-dependent brain-derived neurotrophic factor secretion, which is necessary for long-term potentiation maintenance through a TrkB-mediated process and activation of IRS2/PI3K/Akt signaling.

    3. Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats

      Leigh C. Walker, Hanna E. Kastman, Jan A. Koeleman, Craig M. Smith, Christina J. Perry, Elena V. Krstew, Andrew L. Gundlach and Andrew J. Lawrence

      Version of Record online: 20 JUL 2016 | DOI: 10.1111/adb.12426

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      Bilateral injections into the rat nucleus incertus (NI) of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking, whereas astressin-2B (200 ng/0.25 µl) had no significant effect. CRF-receptor 1, but not CRF-receptor 2, mRNA was upregulated in the NI following chronic ethanol intake. Corticotrophin-releasing factor (CRF) mRNA is expressed within the rat NI; CRF-containing neurons were confirmed by immunohistochemistry. NI neurons apparently contribute to alcohol seeking, via CRF-receptor 1 signaling. Chronic ethanol intake causes neuroadaptive changes in NI CRF and relaxin-3 systems.

    4. Varenicline, the clinically effective smoking cessation agent, restores probabilistic response reversal performance during withdrawal from nicotine

      Anne Jackson, Sarah Silk, Yazead Buhidma and Mohammed Shoaib

      Version of Record online: 20 JUL 2016 | DOI: 10.1111/adb.12423

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      Research in smokers has suggested that good performance monitoring is associated with successful abstinence from smoking. In a rodent model, execution of a probabilistic response reversal task was disrupted by nicotine withdrawal. Performance was restored by varenicline, suggesting the model to be useful for investigating new treatments to aid smoking cessation.

    5. The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens

      Eun Young Jang, Chae Ha Yang, David M. Hedges, Soo Phil Kim, Jun Yeon Lee, Tyler G. Ekins, Brandon T. Garcia, Hee Young Kim, Ashley C. Nelson, Nam Jun Kim and Scott C. Steffensen

      Version of Record online: 14 JUL 2016 | DOI: 10.1111/adb.12419

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      In this study, we utilized physiological, neurochemical, molecular, immunohistochemical and behavioral methodologies to show that methamphetamine (METH) enhances the production of reactive oxygen species, which leads to enhanced dopamine release in the nucleus accumbens and METH self-administration behavior. Drugs that reduce reactive oxygen species effectively reduced METH enhancement of dopamine release and subsequent self-administration behavior.

    6. Effects of naltrexone on alcohol self-administration and craving: meta-analysis of human laboratory studies

      Christian S. Hendershot, Jeffrey D. Wardell, Andriy V. Samokhvalov and Jürgen Rehm

      Version of Record online: 14 JUL 2016 | DOI: 10.1111/adb.12425

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      This meta-analysis examined the aggregate effects of naltrexone versus placebo on alcohol self-administration and craving across human laboratory studies. Meta-analyses of self-administration (N = 490) and craving (N = 748) confirmed that naltrexone reduces laboratory consumption and acute craving relative to placebo. These results provide further evidence as to potential treatment mechanisms, also establishing effect sizes to inform future human laboratory trials.

    7. Neural correlates of impaired self-awareness of apathy, disinhibition and dysexecutive deficits in cocaine-dependent individuals

      Laura Moreno-López, Natalia Albein-Urios, José M. Martínez-González, Carles Soriano-Mas and Antonio Verdejo-García

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/adb.12422

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      In cocaine-dependent individuals, impaired self-awareness about apathy, disinhibition and dysexecutive symptoms is underpinned by structural brain phenotypes involving the dorsal striatum, the orbitofrontal cortex and the dorsolateral prefrontal cortex.

    8. Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2/D3 dopamine system

      Philippe Pfeifer, Oliver Tüscher, Hans Georg Buchholz, Gerhard Gründer, Ingo Vernaleken, Michael Paulzen, Ulrich S. Zimmermann, Stephan Maus, Klaus Lieb, Thomas Eggermann, Christoph Fehr and Mathias Schreckenberger

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/adb.12424

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      We applied PET imaging using the dopamine D2/D3 ligand [18F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol. In the alcohol condition, no response (reduction of BPND) was observed in striatal and extrastriatal regions. We found a positive correlation for “liking” alcohol in extrastriatal regions.

  2. Errata

    1. You have free access to this content
  3. Original Articles

    1. Harm reduction—a systematic review on effects of alcohol reduction on physical and mental symptoms

      Katrin Charlet and Andreas Heinz

      Version of Record online: 29 JUN 2016 | DOI: 10.1111/adb.12414

      This systematic review shows that a reduction of the individual alcohol consumption can contribute to a minimization of various physical and mental health risks in harmful, hazardous or alcohol-dependent drinkers (together with socioeconomic cost benefits) within a harm reduction approach. Here, individuals with heightened vulnerability further benefit significantly from alcohol reduction (e.g. individuals with hypertension, hepatitis C, psychiatric co-morbidities, pregnant or breastfeeding women, and also among adolescents and young adults).

  4. Special Issues

    1. How to study sex differences in addiction using animal models

      Marilyn E. Carroll and Wendy J. Lynch

      Version of Record online: 26 JUN 2016 | DOI: 10.1111/adb.12400

      The importance of studying sex as a biological variable in biomedical research is becoming increasingly apparent. This review focuses on methodology that has been developed in preclinical studies to examine sex differences in the behavioral aspects and neurobiological mechanisms related to addiction across the full range of the addiction process. This review also discusses strategic/technical issues that need to be considered when comparing females and males, including ovarian hormones and interactions of sex with other vulnerability factors in addiction.

  5. Original Articles

    1. Association between pubertal stage at first drink and neural reward processing in early adulthood

      Regina Boecker-Schlier, Nathalie E. Holz, Erika Hohm, Katrin Zohsel, Dorothea Blomeyer, Arlette F. Buchmann, Sarah Baumeister, Isabella Wolf, Günter Esser, Martin H. Schmidt, Andreas Meyer-Lindenberg, Tobias Banaschewski, Daniel Brandeis and Manfred Laucht

      Version of Record online: 26 JUN 2016 | DOI: 10.1111/adb.12413

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      We investigated the links between pubertal stage at first drink (PSFD), neural correlates of reward processing, and alcohol-related problems [Alcohol Use Disorder Identification Test (AUDIT)] during early adulthood. Both reward anticipation and delivery revealed altered neuronal activation (functional magnetic resonance and electroencephalogram) in pubertal versus postpubertal beginners. Moreover, an association between PSFD and AUDIT was mediated by fMRI activation of the right medial frontal gyrus during reward anticipation. These results implicate PSFD as a potential modulator of psychopathology, involving altered reward anticipation.

    2. Decreased subcortical volumes in alcohol dependent individuals: effect of polysubstance use disorder

      Erica N. Grodin and Reza Momenan

      Version of Record online: 23 JUN 2016 | DOI: 10.1111/adb.12421

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      This study investigated subcortical volumes in three groups: individuals with alcohol dependence only (ADO), individuals with polysubstance use disorder (PS), and healthy control participants. Compared with healthy control participants, ADO had decreased subcortical volume in the bilateral hippocampus, right nucleus accumbens, and right thalamus, while PS has decreased subcortical volume in the bilateral thalamus. PS had significantly larger right caudate volume compared with ADO. These findings indicate that the use of multiple substances may mask alcohol-induced damage or may function neuroprotectively.

    3. Regional brain volume changes in alcohol-dependent individuals during early abstinence: associations with relapse following treatment

      Timothy C. Durazzo, Anderson Mon, Stefan Gazdzinski and Dieter J. Meyerhoff

      Version of Record online: 22 JUN 2016 | DOI: 10.1111/adb.12420

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      Regional grey matter (GM) and white matter volumes, at 1 and 4 weeks of abstinence, were compared among individuals who resumed drinking within 12 months of treatment (Relapsers) and those who were abstinent over 12 months following treatment (Abstainers). At 1 and 4 weeks of sobriety, Relapsers demonstrated smaller bilateral frontal GM volumes than Abstainers. The frontal GM volume deficits in Relapsers over 4 weeks of sobriety may represent an endophenotype that differentiates response to typical psychosocial/pharmacological interventions.

    4. Multi-modal MRI classifiers identify excessive alcohol consumption and treatment effects in the brain

      Alejandro Cosa, Andrea Moreno, Jesús Pacheco-Torres, Roberto Ciccocioppo, Petri Hyytiä, Wolfgang H. Sommer, David Moratal and Santiago Canals

      Version of Record online: 8 JUN 2016 | DOI: 10.1111/adb.12418

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      Neuroimaging biomarkers in alcohol addiction have been limited to late stages of the disease. In this study, we propose a data-driven multimodal MRI fingerprint decomposition as a tool to identify robust changes in brain parenchyma at early stages. Using a preclinical animal model we demonstrate that one month drinking is enough to imprint a highly specific signature of alcohol consumption.

    5. Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice

      Camilla Karlsson, Jesse R. Schank, Faazal Rehman, Andrea Stojakovic, Karl Björk, Estelle Barbier, Matthew Solomon, Jenica Tapocik, David Engblom, Annika Thorsell and Markus Heilig

      Version of Record online: 7 JUN 2016 | DOI: 10.1111/adb.12416

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      Proinflammatory signaling has been suggested to play a role in alcohol intake and stress-responses. Here, we show that mice with a genetic double deletion of interleukin 1 and TNF-1 receptors decrease voluntary alcohol consumption and stress-induced drinking following chronic social defeat stress. However, single deletion of either the interleukin 1 or TNF-1 receptor results in modest or no effect on alcohol intake, suggesting that both receptors together are involved in regulation of alcohol consumption and stress-induced drinking.

    6. Transcranial direct current stimulation produces long-lasting attenuation of cocaine-induced behavioral responses and gene regulation in corticostriatal circuits

      Solène Pedron, Joel Beverley, Emmanuel Haffen, Patrice Andrieu, Heinz Steiner and Vincent Van Waes

      Version of Record online: 6 JUN 2016 | DOI: 10.1111/adb.12415

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      Transcranial direct current stimulation (tDCS) is a promising tool to modulate cortical excitability and has opened up new perspectives in addiction treatment. Here, we demonstrate that repeated tDCS over the frontal cortex in mice attenuates the molecular (transcription factor Zif268) and behavioral responses to cocaine for several weeks. This finding provides pre-clinical evidence that tDCS may be useful to modify the psychostimulant addiction risk.

    7. Morphine-induced inhibition of Ca2+-dependent d-serine release from astrocytes suppresses excitability of GABAergic neurons in the nucleus accumbens

      Jian Wu, Rui Zhao, Lin Guo and Xuechu Zhen

      Version of Record online: 29 MAY 2016 | DOI: 10.1111/adb.12417

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      Morphine decreases d-serine release from astrocyte vesicles in the nucleus accumbens by inhibiting intracellular Ca2+ signals. Decrease in extracellular d-serine levels contributes to morphine-repressed N-methyl-d-aspartate glutamate receptor-mediated synaptic transmission and leads to suppression of postsynaptic excitability of GABAergic neurons in the nucleus accumbens. Administration of exogenous d-serine may prevent this suppression and may attenuate morphine-induced conditioned place preference and hyper-locomotion.

    8. Effects of binge drinking and hangover on response selection sub-processes—a study using EEG and drift diffusion modeling

      Ann-Kathrin Stock, Sven Hoffmann and Christian Beste

      Version of Record online: 29 MAY 2016 | DOI: 10.1111/adb.12412

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      We assessed differential effects of a high-dose (1.2‰) alcohol intoxication and subsequent hangover on cognitive control in healthy human male subjects. Combining drift diffusion modeling of behavioral data with neurophysiological (EEG) data, we found that intoxication decreases the drift rate (v) and non-decisional processes of information encoding (T), while hangover increases the drift rate. These effects were reflected in modulations of the N2, P1 and N1 event-related potentials as well as modulations of the anterior cingulate cortex and occipital networks

    9. Brain CYP2B induction can decrease nicotine levels in the brain

      Kristine L. P. Garcia, Anh Dzung Lê and Rachel F. Tyndale

      Version of Record online: 27 MAY 2016 | DOI: 10.1111/adb.12411

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      Brain CYP2B induction, through 7-day nicotine treatment, can increase brain nicotine levels. This treatment did not alter liver CYP2B and blood nicotine levels, suggesting the induction was brain-specific. Brain nicotine levels from a single nicotine challenge following a washout period without treatment were similar to a challenge at baseline, indicating that altering brain CYP2B levels can influence brain nicotine levels.

    10. Bi-directional cannabinoid signalling in the basolateral amygdala controls rewarding and aversive emotional processing via functional regulation of the nucleus accumbens

      Tasha Ahmad, Ninglei Sun, Danika Lyons and Steven R. Laviolette

      Version of Record online: 27 MAY 2016 | DOI: 10.1111/adb.12406

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      Drugs that modulate the brain's cannabinoid system such as marijuana can powerfully modulate both positive and negative affective states. In this study, we examine the role of cannabinoid CB1 receptor (CB1R) transmission in the basolateral amygdala>nucleus accumbens pathway in the control of opiate-related reward processing. Interestingly, we report that CB1R transmission in the basolateral amygdala can bi-directionally control whether opiate signaling produces rewarding or aversive affective states through functional control of neuronal populations in the nucleus accumbens.

    11. Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction

      Alicia Rivera, Belén Gago, Diana Suárez-Boomgaard, Takashi Yoshitake, Ruth Roales-Buján, Alejandra Valderrama-Carvajal, Ainhoa Bilbao, José Medina-Luque, Zaida Díaz-Cabiale, Kathleen Van Craenenbroeck, Dasiel O. Borroto-Escuela, Jan Kehr, Fernando Rodríguez de Fonseca, Luis Santín, Adelaida de la Calle and Kjell Fuxe

      Version of Record online: 22 MAY 2016 | DOI: 10.1111/adb.12407

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      The D4R agonist PD168,077 prevents morphine-induced activation of the nigrostriatal dopamine pathway leading to a restoration of dopamine tone in the dorsal striatum. In addition, D4R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. The present work provides a new insight into D4R function, which seems to act by buffering the dysregulation of nigral dopaminergic signaling induced by morphine through a D4R/MOR functional interaction.

    12. Plasma concentrations of oleoylethanolamide and other acylethanolamides are altered in alcohol-dependent patients: effect of length of abstinence

      Nuria Garcia-Marchena, Francisco J. Pavon, Antoni Pastor, Pedro Araos, Maria Pedraz, Pablo Romero-Sanchiz, Montserrat Calado, Juan Suarez, Estela Castilla-Ortega, Laura Orio, Anna Boronat, Marta Torrens, Gabriel Rubio, Rafael de la Torre, Fernando Rodriguez de Fonseca and Antonia Serrano

      Version of Record online: 22 MAY 2016 | DOI: 10.1111/adb.12408

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      Plasma concentration of oleoylethanolamide (OEA) and other acylethanolamides are increased in alcohol-dependent patients in abstinence.

      OEA, arachidonoylethanolamide (AEA) and docosatetraenoylethanolamide (DEA) are the best explanatory variables to distinguish alcohol-dependent patients in abstinence from controls.

      Plasma concentration of OEA, AEA and DEA are negatively correlated to the duration of the abstinence.

    13. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment

      Yue Pei, Aman Asif-Malik, Marius Hoener and Juan J. Canales

      Version of Record online: 19 MAY 2016 | DOI: 10.1111/adb.12410

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      The trace amine-associated receptor 1 (TAAR1) has been proposed as a candidate for the development of new medications for stimulant addiction. The present experiments showed that the partial TAAR1 agonist, RO5263397, did not sustain self-administration, decreased the motivation to self-administer methamphetamine, blocked methamphetamine-primed reinstatement of methamphetamine seeking and attenuated methamphetamine-induced elevations in dopamine transmission in the nucleus accumbens. Taking together, these findings warrant further investigation of TAAR1 as a target for novel pharmacotherapeutics in stimulant addiction.

    14. The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations

      Željko Čupić, Ana Stanojević, Vladimir M. Marković, Ljiljana Kolar-Anić, Lars Terenius and Vladana Vukojević

      Version of Record online: 18 MAY 2016 | DOI: 10.1111/adb.12409

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      A stoichiometric model is developed to succinctly describe ethanol effects on neurochemical transformations underlying the hypothalamic-pituitary-adrenal (HPA) axis. This enables the investigation of ethanol effects on HPA axis activity with high temporal resolution, where experimental data are scarce. Mathematical modelling shows that ethanol effects on HPA axis activity are complex and dependent on ethanol dose, timing and administration strategy; it enables us to shed light on so far inconclusive experimental results and may help to design further experiments.

    15. Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood

      Evan J. Kyzar, Huaibo Zhang, Amul J. Sakharkar and Subhash C. Pandey

      Version of Record online: 15 MAY 2016 | DOI: 10.1111/adb.12404

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      Adolescent intermittent ethanol exposure causes a lasting increase in global and gene-specific histone H3 lysine 9 dimethylation possibly because of decreased LSD1 and Lsd1+8a expression in the amygdala leading to anxiety-like behaviors in adulthood.

    16. An association study revealed substantial effects of dominance, epistasis and substance dependence co-morbidity on alcohol dependence symptom count

      Gang Chen, Futao Zhang, Wenda Xue, Ruyan Wu, Haiming Xu, Kesheng Wang and Jun Zhu

      Version of Record online: 5 MAY 2016 | DOI: 10.1111/adb.12402

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      We conducted a genome-wide association studies of alcohol dependence symptom count with a full genetic model considering additive, dominance, epistasis and their interactions with ethnicity, as well as conditions of co-morbid substance dependence. Twenty quantitative trait SNPs (QTSs) were identified, including four previously reported genes such as ADH1C, four novel genes, two non-coding RNAs and two epistasis loci. The detected QTSs contributed to about 20 percent of total heritability, in which dominance and epistasis effects accounted for over 50 percent.

    17. Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

      Jérôme A.J. Becker, Brigitte L. Kieffer and Julie Le Merrer

      Version of Record online: 28 APR 2016 | DOI: 10.1111/adb.12405

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      In this study, we investigated whether protracted abstinence to morphine, nicotine, △9-tetrahydrocannabinol and alcohol, which produce a common transcriptional signature in the extended amygdala, would also share common behavioral features and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and exacerbated anxiety in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct pattern of adaptations at behavioral, neuronal activation and transcriptional levels.

    18. Prefrontal gray matter volume recovery in treatment-seeking cocaine-addicted individuals: a longitudinal study

      Muhammad A. Parvaz, Scott J. Moeller, Federico d'Oleire Uquillas, Amanda Pflumm, Tom Maloney, Nelly Alia-Klein and Rita Z. Goldstein

      Version of Record online: 28 APR 2016 | DOI: 10.1111/adb.12403

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      This study reports the longitudinal recovery in prefrontal cortical gray matter volume, particularly in regions that are adversely affected by chronic drug use, after 6months abstinence or reduction in cocaine use in treatment seeking individuals with chronic cocaine use. The study also reports longitudinal improvements in decision making and cognitive flexibility, with the latter correlated significantly with longitudinal increase in prefrontal gray matter volume. Results reflect a quantifiable positive impact of significantly reduced drug use on cortical structural integrity.

    19. Role of DOR in neuronal plasticity changes promoted by food-seeking behaviour

      Samantha Mancino, Sueli Mendonça-Netto, Elena Martín-García and Rafael Maldonado

      Version of Record online: 21 APR 2016 | DOI: 10.1111/adb.12401

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      Our results revealed a critical role of delta opioid receptor (DOR) in mediating the reinforcing aspects of food-seeking behaviour, the motivation and the impulsive-like behaviour induced by operant training maintained by chocolate flavoured-pellets. Interestingly, a neurobiological correlate was reported and prolonged operant training to obtain palatable food differentially modified structural plasticity in the prefrontal cortex, hippocampus, and nucleus accumbens shell of DOR constitutive knockout mice and their wild-type littermates suggesting a specific involvement of DOR in the structural plasticity changes, responsible of these behavioural responses.

    20. A prospective study of genetic factors, human laboratory phenotypes, and heavy drinking in late adolescence

      Christian S. Hendershot, Jeffrey D. Wardell, Matthew D. McPhee and Vijay A. Ramchandani

      Version of Record online: 5 APR 2016 | DOI: 10.1111/adb.12397

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      This study examined prospective associations among subjective responses to intravenous alcohol, intravenous alcohol self-administration, and future heavy drinking in late adolescence. Family history of alcohol dependence and OPRM1 genotype were also examined. Subjective responses during alcohol challenge predicted subsequent self-administration, which in turn predicted future self-reported heavy drinking. Results also showed significant indirect associations of genetic factors (OPRM1, family history) with future drinking via laboratory outcomes. These results support the utility of human laboratory phenotypes in prospective studies of alcohol dependence risk.

    21. Escalation of intravenous self-administration of methylone and mephedrone under extended access conditions

      Jacques D. Nguyen, Yanabel Grant, Kevin M. Creehan, Sophia A. Vandewater and Michael A. Taffe

      Version of Record online: 5 APR 2016 | DOI: 10.1111/adb.12398

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      Recreational use of substituted cathinones continues to grow worldwide, yet few laboratory studies are available to distinguish the abuse liability of the various drugs. Extended daily access (6 h) to intravenous self-administration of cocaine or methamphetamine results in escalated drug intake relative to short access (2 h) representing a better model of drug addiction. Mephedrone and methylone self-administration escalate under 6 h access conditions similar to traditional stimulants; however, mephedrone represents the greater risk for dysregulated drug consumption.

    22. Distress tolerance among substance users is associated with functional connectivity between prefrontal regions during a distress tolerance task

      Stacey B. Daughters, Thomas J. Ross, Ryan P. Bell, Jennifer Y. Yi, Jonathan Ryan and Elliot A. Stein

      Version of Record online: 2 APR 2016 | DOI: 10.1111/adb.12396

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      A computerized distress tolerance (DT) task was modified for use in functional magnetic resonance imaging (fMRI). Greater activation in the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG), and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not healthy controls. Greater task-specific functional connectivity during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not healthy controls.

  6. Special Issue

    1. Why we should consider sex (and study sex differences) in addiction research

      Carla Sanchis-Segura and Jill Becker

      Version of Record online: 31 MAR 2016 | DOI: 10.1111/adb.12382

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      Sex is a multilayered source of biological bias that promotes multiple physiological divergences and convergences in females and males' development and activities, including their social and environmental interactions (gender). Current evidence suggests that sex and gender modulate drug consumption and the transition towards drug dependence and addiction as well as the engagement and outcomes of their therapeutic treatment. We provide a framework with which to classify and guide investigation into sex differences and sex sameness in addiction and in other domains of bio-behavioral research.

  7. Original Articles

    1. You have full text access to this OnlineOpen article
      Smoking and caffeine consumption: a genetic analysis of their association

      Jorien L. Treur, Amy E. Taylor, Jennifer J. Ware, Michel G. Nivard, Michael C. Neale, George McMahon, Jouke-Jan Hottenga, Bart M. L. Baselmans, Dorret I. Boomsma, Marcus R. Munafò and Jacqueline M. Vink

      Version of Record online: 30 MAR 2016 | DOI: 10.1111/adb.12391

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      Mechanisms behind the strong observational correlation between smoking and caffeine consumption were investigated with bivariate twin modelling, LD-score regression and Mendelian randomization analysis. Sizeable genetic correlations were found between smoking behaviour and caffeine consumption (r0.3–r0.5), while environmental correlations were considerably lower (r0.0–r0.3). Our findings suggests that the association between smoking behaviour and caffeine consumption is mostly explained by genetic factors.

    2. Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells

      Nancy Stanslowsky, Kirsten Jahn, Anna Venneri, Maximilian Naujock, Alexandra Haase, Ulrich Martin, Helge Frieling and Florian Wegner

      Version of Record online: 30 MAR 2016 | DOI: 10.1111/adb.12394

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      High dosages of the endocannabinoid anandamide (AEA) or Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, significantly reduced synaptic activity of neurons differentiated from human induced pluripotent stem cells. Lower concentrations of THC had no marked effect, while low AEA doses even enhanced the frequency of synaptic currents. Changes in endocannabinoid signalling might therefore lead to neurobiological changes influencing brain development, function and behaviour.

    3. Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence

      L. Lalanne, G. Ayranci, D. Filliol, C. Gavériaux-Ruff, K. Befort, B. L. Kieffer and P-E Lutz

      Version of Record online: 22 MAR 2016 | DOI: 10.1111/adb.12392

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      In the clinic, reversing or preventing social dysfunction frequently observed in opiate addicts has the potential to limit the risk of relapse. Here, we show in a mouse model that prolonged abstinence from heroin is characterized by the development of social withdrawal. Two systemic injections with the kappa opioid receptor antagonist norbinaltorphimine were sufficient to prevent, and to reverse, heroin-induced social withdrawal. Therefore, the kappa opioid receptor represents a promising target in the management of opiate addiction.

    4. Risk-preferring rats make worse decisions and show increased incubation of craving after cocaine self-administration

      Jacqueline-Marie N. Ferland and Catharine A. Winstanley

      Version of Record online: 22 MAR 2016 | DOI: 10.1111/adb.12388

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      Several clinical studies using the Iowa Gambling Task implicate poor decision-making as a hallmark trait seen in substance use disorder. However, it is not clear whether this cognitive deficit is a cause or consequence of drug use. The current study used a rat gambling task to determine whether baseline disadvantageous decision-making contributed to the expression of the addictive phenotype as modeled by cocaine self-administration and incubation of craving. Results show that risk-preferring animals were uniquely and adversely affected by drug-seeking.

  8. Special Issue

    1. Sex differences in substance use disorders: focus on side effects

      Roberta Agabio, Ilaria Campesi, Claudia Pisanu, Gian Luigi Gessa and Flavia Franconi

      Version of Record online: 22 MAR 2016 | DOI: 10.1111/adb.12395

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      This article summarizes human sex differences observed in side effects induced by alcohol, nicotine, heroin, marijuana, and cocaine, and medications approved for substance use disorders (SUDs). Women are at higher risk than men of developing side effects induced by alcohol, tobacco, heroin, marijuana, cocaine, and medications used to treat SUDs. Women should be advised of their high vulnerability of developing side effects after consumption of substances of abuse and receive doses of medications adjusted according to body weight.

  9. Original Articles

    1. A high-fat diet combined with food deprivation increases food seeking and the expression of candidate biomarkers of addiction

      José Manuel Pérez-Ortiz, Adrian Galiana-Simal, Elisabet Salas, Carmen González-Martín, Marcial García-Rojo and Luis F. Alguacil

      Version of Record online: 21 MAR 2016 | DOI: 10.1111/adb.12389

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      A diet that combined high fat with food deprivation periods delayed the acute extinction of preference for places associated to palatable food in C57BL/6J male mice. This persistence in food seeking, as quantified by the time spent in food areas at longer intervals, correlated with the expression of three putative biomarkers of addiction in the nucleus accumbens: fumarate hydratase, ATP synthase subunit alpha and transketolase.

    2. Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice

      Nurul Iman W. Ismail, Nanthini Jayabalan, Sharif Mahsufi Mansor, Christian P. Müller and Mustapha Muzaimi

      Version of Record online: 17 MAR 2016 | DOI: 10.1111/adb.12385

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      This study investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour, and cognition in mice using an IntelliCage® system, and compared with morphine and ▵-9-tetrahydorcannabinol(THC). A chronic mitragynine significantly potentiated spontaneous locomotor activity, enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences, and impaired place learning and its reversal. These effects closely resembled that of morphine- and THC- sensitisation.

    3. Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors

      Esa R. Korpi, Anni-Maija Linden, Heidi R. Hytönen, Nelli Paasikoski, Elena Vashchinkina, Mateusz Dudek, Deron R. Herr and Petri Hyytiä

      Version of Record online: 15 MAR 2016 | DOI: 10.1111/adb.12393

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      Opioid receptor antagonists naltrexone and nalmefene reduced alcohol drinking of alcohol-preferring AA rats without tolerance when given as daily injections but not when the same doses were given as continuous delivery via osmotic minipumps. After 1 week of treatment, μ-opioid (and to lesser extent also κ-opioid) receptor supersensitivity was seen in many brain regions after continuous delivery, but not after injections. The results support as-needed dosing of the opioid antagonists in the treatment of alcoholism.

    4. Granger causality reveals a dominant role of memory circuit in chronic opioid dependence

      Yi Zhang, Qiang Li, Xiaotong Wen, Weiwei Cai, Guanya Li, Jie Tian, Yi Edi Zhang, Jixin Liu, Kai Yuan, Jizheng Zhao, Wei Wang, Zhenyu Zhou, Mingzhou Ding, Mark S. Gold, Yijun Liu and Gene-Jack Wang

      Version of Record online: 14 MAR 2016 | DOI: 10.1111/adb.12390

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      The results revealed stronger effective connectivity between the hippocampus and amygdala implicated in mediating learning-memory, and anterior cingulate cortex involved in mediating inhibitory control while putamen mediated the learned habit, suggesting that the hippocampus and anterior cingulate cortex may propel the memory circuit to override the control circuit and drive the learned habit in heroin-dependent individuals during methadone treatment. The results implicate that the learning-memory and inhibitory control may contribute jointly and form a basis for relapse risk.

    5. Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine

      Sweta Adhikary, Daniele Caprioli, Marco Venniro, Paige Kallenberger, Yavin Shaham and Jennifer M. Bossert

      Version of Record online: 14 MAR 2016 | DOI: 10.1111/adb.12386

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      1. Incubation of craving is primarily mediated by time-dependent increases in non-reinforced operant responding
      2. Discrete– but not context– or priming-induced reinstatement incubates after withdrawal
      3. Incubation of craving is context-independent.
    6. Aberrant interhemispheric functional and structural connectivity in heroin-dependent individuals

      Ying-wei Qiu, Gui-hua Jiang, Xiao-fen Ma, Huan-Huan Su, Xiao-fei Lv and Fu-zhen Zhuo

      Version of Record online: 9 MAR 2016 | DOI: 10.1111/adb.12387

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      Heroin dependent-individual (HDI) presented with CC1, CC5 subregion abnormalities and attenuated inter-hemispheric homotopic functional connectivity. Abnormalities of the inter-hemispheric brain measures correlated with impulsivity behavior in HDI. Abnormalities of the inter-hemispheric brain measures correlated with duration of heroin consumption in HDI. More importantly, impairment of inter-hemispheric homotopic functional connectivity partially mediated the association between CC abnormalities and higher impulsivity behavior in HDI.

    7. Behavioral flexibility predicts increased ability to resist excessive methamphetamine self-administration

      Marine Istin, Nathalie Thiriet and Marcello Solinas

      Version of Record online: 9 MAR 2016 | DOI: 10.1111/adb.12384

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      Deficits in executive functions appear to play an important role in addiction, but whether they are the cause or the consequence of excessive drug taking is not known. Here, we show that performance in a behavioral flexibility procedure predicts the ability of rats to limit their methamphetamine intake and escalation. Thus, pre-existent inflexibility traits appear to be key factors in determining the vulnerability to transition from control to uncontrolled methamphetamine use.

    8. Disruption of blood–brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model

      Ana Rubio-Araiz, Francesca Porcu, Mercedes Pérez-Hernández, Mª Salud García-Gutiérrez, María Auxiliadora Aracil-Fernández, María Dolores Gutierrez-López, Consuelo Guerri, Jorge Manzanares, Esther O'Shea and María Isabel Colado

      Version of Record online: 7 MAR 2016 | DOI: 10.1111/adb.12376

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      Chronic ethanol consumption increases degradation of tight junctions and extracellular matrix in postmortem human brain, and these effects are associated with increased matrix metalloproteinase (MMP)-9 activity, activation of ERK1/2 and p-38 and a marked neuroinflammatory response that might be promoting leukocyte infiltration. The ethanol-induced impairment of blood-brain barrier is not evident in TLR4-KO mice exposed to a binge-like ethanol protocol, indicating a role for TLR4 signaling in the underlying mechanism leading to blood-brain barrier disruption.

    9. Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential

      Brandon S. Bentzley and Gary Aston-Jones

      Version of Record online: 3 MAR 2016 | DOI: 10.1111/adb.12380

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      Economic demand for drugs of abuse is associated with addiction severity in patients and numerous addiction-like behaviors in rats. Here, we show that bilateral inactivation of the rat subthalamic nucleus reduces economic demand for cocaine as well as several measures of cocaine seeking and relapse. These results indicate substantial potential for the therapeutic utility of subthalamic nucleus-targeting therapies for treatment of substance use disorders.

  10. Special Issues

    1. Sex differences in impulsive and compulsive behaviors: a focus on drug addiction

      Liana Fattore and Miriam Melis

      Version of Record online: 3 MAR 2016 | DOI: 10.1111/adb.12381

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      Men and women differ in their ability to inhibit a behavior and control impulses. The differences in behavior between men and women often reflect the simultaneous influence of gender (that may influence the expression of biological traits) and sex (biological features that may amplify gender differences). Understanding sex/gender differences in impulsivity is paramount for developing effective and biologically based intervention and prevention strategies for treating neuropsychiatric disorders, such as attention deficit-hyperactivity disorder, pathological gambling and drug addiction.

  11. Original Articles

    1. Attenuated frontal and sensory inputs to the basal ganglia in cannabis users

      Laura Blanco-Hinojo, Jesus Pujol, Ben J Harrison, Dídac Macià, Albert Batalla, Santiago Nogué, Marta Torrens, Magí Farré, Joan Deus and Rocío Martín-Santos

      Version of Record online: 3 MAR 2016 | DOI: 10.1111/adb.12370

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      The basal ganglia are central in the motivation system. Using resting-state fMRI, we examined basal ganglia functional connectivity in 28 chronic cannabis users without comorbid psychiatric disorders and 29 controls. Compared with controls, cannabis users showed abnormal (attenuated) functional coupling of the striatum with converging frontal and sensory cortical areas. Connectivity alterations were associated with lower arousal in response to affective pictures. Our findings suggest that functional changes associated with active cannabis use have a tendency to recover with abstinence.

  12. Special Issues

    1. Sociocultural context for sex differences in addiction

      Jill B. Becker, Michelle McClellan and Beth Glover Reed

      Version of Record online: 3 MAR 2016 | DOI: 10.1111/adb.12383

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      Addiction is both a cultural and biological phenomenon and interactions between biology and the environment are continuously played out throughout development. Lessons from the historical record illustrate how context and attitudes affect the way that substance abuse and treatment can differentially affect men and women. Animal models and clinical research need to consider how contextual and social factors may influence the biological processes of addiction and relapse differentially in males and females.

  13. Invited Reviews

    1. Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder

      Mira Fauth-Bühler, Karl Mann and Marc N. Potenza

      Version of Record online: 3 MAR 2016 | DOI: 10.1111/adb.12378

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      This review examines important findings in relation to ‘Pathological Gambling’, with the aim of enabling a well-informed decision to be made regarding its classification in the upcoming eleventh edition of the International Classification of Diseases. The strongest arguments for subsuming ‘Pathological Gambling’ under a larger ‘Substance-related and Addictive Disorders’ category are the existence of similar diagnostic characteristics, the high co-morbidity rates between the disorders, their common core features including reward-related aspects and the findings that the same brain structures are involved.

  14. Original Articles

    1. Wnt/β-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations

      Santiago Cuesta, Maria J. Severin, Jorgelina Batuecas, Silvana B. Rosso and Alejandra M. Pacchioni

      Version of Record online: 22 FEB 2016 | DOI: 10.1111/adb.12377

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      Our main goal was to evaluate the role Wnt/β-catenin pathway in cocaine-induced neuroadaptations. We found that the activity of the pathway is reduced in the prefrontal cortex (PFC) of sensitized animals. Moreover, the systemic activation of this pathway blocks cocaine-induced sensitization, while the inhibition exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role of the Wnt/β-catenin pathway in the cocaine-induced neuroadaptations that underlie behavioral sensitization.

    2. You have full text access to this OnlineOpen article
      Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature

      Luisa Lo Iacono, Alessandro Valzania, Federica Visco-Comandini, Eleonora Aricò, Maria Teresa Viscomi, Luciano Castiello, Diego Oddi, Francesca R. D'Amato, Elisa Bisicchia, Olga Ermakova, Stefano Puglisi-Allegra and Valeria Carola

      Version of Record online: 12 FEB 2016 | DOI: 10.1111/adb.12373

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      This study provides novel insights into the mechanism by which childhood maltreatment heightens risk for relapse in cocaine-dependent individuals. We modeled childhood maltreatment by exposing juvenile mice to a threatening social experience. This influenced the propensity to reinstate cocaine seeking after periods of withdrawal in adulthood. We found that this phenotype was associated with greater blood coagulation and impairments in brain microvasculature. Notably, treatment with an anticoagulant agent during withdrawal abolished the susceptibility to reinstate cocaine seeking in these mice.

    3. Perseveration of craving: effects of stimuli conditioned to drugs of abuse versus conventional reinforcers differing in demand

      Rémi Martin-Fardon and Friedbert Weiss

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/adb.12374

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      Here we showed that behavior guided by associations between environmental stimuli and drugs of abuse are characterized by perseverating, apparently highly extinction-resistant reward seeking, whereas behavior controlled by stimuli associated with conventional reward extinguishes rapidly in the absence of primary reinforcement. Reward seeking elicited by stimuli associated with natural reward can, however, become perseverative during physiological deprivation states. Possibly, perseverating drug seeking engages mechanisms overlapping with those that have evolved to promote alleviation of physiological deprivation to secure survival.

    4. White matter alterations in cocaine users are negatively related to the number of additionally (ab)used substances

      Anne Marije Kaag, Guido A. van Wingen, Matthan W. A. Caan, Judith R. Homberg, Wim van den Brink and Liesbeth Reneman

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/adb.12375

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      Polysubstance use is a widespread phenomenon among cocaine users. In the current diffusion tensor imaging study, we demonstrated that the degree of white matter alterations is related to the number of different types of substances used (cocaine, alcohol and marijuana). These alterations are suggested to explain why treatment outcome is poorer among polysubstance users compared with single-substance users.

    5. Cannabis use and symptoms of anxiety in adolescence and the moderating effect of the serotonin transporter gene

      Roy Otten, Anja C. Huizink, Karin Monshouwer, Hanneke E. Creemers and Simone Onrust

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/adb.12372

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      This study examined the relationship between cannabis use and symptoms of anxiety by taking a developmental molecular-genetic perspective with a focus on a polymorphism involved in the regulation of serotonin. Results showed that cannabis use is associated with an increase in symptoms of anxiety, but only in carriers of the short allele of the 5-HTTLPR genotype, thereby suggesting that the link between cannabis use and anxiety is conditional on an individuals' genetic makeup.

    6. Alcohol withdrawal induces long-lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex

      Gaelle Dominguez, Catherine Belzung, Christophe Pierard, Vincent David, Nadia Henkous, Laurence Decorte, Nicole Mons and Daniel Beracochea

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/adb.12371

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      We showed here (1) that long-lasting glucocorticoids dysregulation in the prefrontal cortex (PFC) is responsible for the maintenance of working memory (WM) deficits and phosphorylated CREB alterations in alcohol-withdrawn (1 and 6 weeks) mice previously submitted to a 6-months alcohol consumption (12% v/v); (2) that a systemic injection of metyrapone (which inhibits corticosterone synthesis) before testing restored both WM and PFC-phosphorylated CREB activity in withdrawn mice; and (3) that the intra-PFC blockade of mineralocorticoid receptors by spironolactone reverses the withdrawal-associated WM deficits.

    7. Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration

      María Antón, Francisco Alén, Raquel Gómez de Heras, Antonia Serrano, Francisco Javier Pavón, Juan Carlos Leza, Borja García-Bueno, Fernando Rodríguez de Fonseca and Laura Orio

      Version of Record online: 9 FEB 2016 | DOI: 10.1111/adb.12365

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      In this study, we reported a beneficial role for the lipid oleoylethanolamide (OEA) to treat alcohol binge drinking because of its antiinflammatory, antioxidant, neuroprotective and antidepressant-like effects. Pre#x2010;treatment with OEA during binging episodes blocked the expression of HMGB1/TLR4 cell danger signaling and inhibited the nuclear factor-kappa B-related cascade of proinflammatory mediators, affording protection against ethanol-induced lipid peroxidation and apoptosis in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone induced by alcohol binge and had antidepressant-like actions during early withdrawal.

    8. Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats

      Cristiane Ribeiro de Carvalho and Reinaldo Naoto Takahashi

      Version of Record online: 1 FEB 2016 | DOI: 10.1111/adb.12366

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      This study examines the effects of an acute injection of cannabidiol (CBD) post-reactivation on reconsolidation of drug associated memories in rats. CBD persistently disrupts the reconsolidation of morphine-CPP and suppresses subsequent morphine-CPA to the same context (see figure). Our findings suggest CBD may be a potentially pharmacologic adjunct to cue exposure cognitive behavior therapy used for developing novel treatments for weakening memories induced by drugs of abuse and subsequently reducing the risk of withdrawal and relapse.

    9. Medications development for the treatment of alcohol use disorder: insights into the predictive value of animal and human laboratory models

      Megan M. Yardley and Lara A. Ray

      Version of Record online: 1 FEB 2016 | DOI: 10.1111/adb.12349

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      The primary goal of this paper was to provide a perspective on medications development for alcohol use disorder along with an illustrative review of the literature encompassing preclinical, human laboratory, and clinical trials. This review highlights the marked need for standardization of testing procedures at each level of medications development, including standard protocols for experimental paradigms, population characteristics (in both animal and human studies), and analyses of predefined primary and secondary outcomes. Such standardization would allow us to more effectively integrate results from various studies using both critical reviews of the literature as well as quantitative studies and advance treatment development in this area.

    10. You have full text access to this OnlineOpen article
      Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment

      Ryan P. Vetreno, Richard Yaxley, Beatriz Paniagua, G. Allan Johnson and Fulton T. Crews

      Version of Record online: 1 FEB 2016 | DOI: 10.1111/adb.12364

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      Magnetic resonance imaging and histology was used to determine the effect of ageing and adolescent binge ethanol exposure on cortical thickness in adult rats. We discovered that the cerebral cortex continues to undergo age-associated cortical thinning and expansion into adulthood, which was altered by prior adolescent binge ethanol exposure. These data reveal that the cerebral cortex continues to undergo refinement into adulthood and that adolescent binge ethanol treatment alters adult cortical thickness that might contribute to behavioural dysfunction.

    11. Characterization of white matter integrity deficits in cocaine-dependent individuals with substance-induced psychosis compared with non-psychotic cocaine users

      Taylor S. Willi, Alasdair M. Barr, Kristina Gicas, Donna J. Lang, Fidel Vila-Rodriguez, Wayne Su, Allen E. Thornton, Olga Leonova, Chantelle J. Giesbrecht, Ric M. Procyshyn, Alexander Rauscher, William G. MacEwan, William G. Honer and William J. Panenka

      Version of Record online: 1 FEB 2016 | DOI: 10.1111/adb.12363

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      Similarity in psychotic presentation between substance-induced psychosis and schizophrenia spectrum disorders suggests that similar neural deficits contribute to the expression of psychosis across these disorders. Diffusion tensor imaging was employed to investigate white matter abnormalities in a cocaine-associated psychosis group (n = 24) compared with a cocaine-dependent non-psychotic group (n = 43). Voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways had significantly lower fractional anisotropy values in the psychosis group, similar to pathways altered in schizophrenia spectrum disorders.

    12. Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats

      Hai-Ying Zhang, Ming Gao, Hui Shen, Guo-Hua Bi, Hong-Ju Yang, Qing-Rong Liu, Jie Wu, Eliot L. Gardner, Antonello Bonci and Zheng-Xiong Xi

      Version of Record online: 1 FEB 2016 | DOI: 10.1111/adb.12367

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      The presence of neuronal CB2 receptor in the brain has been controversial. The present study provides convincing evidence demonstrating that CB2 gene (mRNA) and receptors are not only expressed in midbrain dopamine neurons, but also functionally modulate dopamine neuronal excitability, striatal dopamine release and intravenous cocaine self-administration. In addition, cocaine self-administration up-regulates CB2 gene expression in dopamine neurons, suggesting that brain CB2 receptor may constitute a new target in medication development for treatment of addiction or other dopamine-related central nervous system disorders.

    13. Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens

      Sebastian T. Peters, Michael T. Bowen, Kathrin Bohrer, Iain S. McGregor and Inga D. Neumann

      Version of Record online: 25 JAN 2016 | DOI: 10.1111/adb.12362

      Here, we describe the possible mechanisms underlying the inhibitory effect of oxytocin on voluntary ethanol self-administration. Central infusion of oxytocin prevented the ethanol-induced activation of the mesolimbic dopamine system, specifically the rise in dopamine release within the nucleus accumbens both after acute and chronic ethanol administration in rats. Although these, together with our recent findings, suggest that OXT may interfere with ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens via interaction with δ subunit-containing GABAA receptors, further molecular mechanisms of the action of oxytocin need to be revealed before an oxytocin-related treatment option for alcoholism can be considered.

    14. Intra-cerebral and intra-nasal melanocortin-4 receptor antagonist blocks withdrawal hyperalgesia in alcohol-dependent rats

      Emily A. Roltsch Hellard, Renata A. Impastato and Nicholas W. Gilpin

      Version of Record online: 24 JAN 2016 | DOI: 10.1111/adb.12360

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      Alcohol-dependent rats exhibit thermal hyperalgesia, which is abolished by alcohol drinking, bolus alcohol, and intra-ventricular and intra-nasal melanocortin 4 receptor (MC4R) antagonists. These manipulations did not affect thermal nociception in non-dependent drinkers and alcohol-naïve controls, suggesting that alcohol dependence produces neuroadaptations in brain MC4R systems. These results suggest that brain MC4R systems may be an effective therapeutic target for reducing nociception in alcohol-dependent organism.

    15. Loss of δ-GABAA receptor-mediated tonic currents in the adult prelimbic cortex following adolescent alcohol exposure

      Samuel W. Centanni, Elizabeth J. Burnett, Heather Trantham-Davidson and L. Judson Chandler

      Version of Record online: 24 JAN 2016 | DOI: 10.1111/adb.12353

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      The adolescent prefrontal cortex (PFC) is particularly vulnerable to developmental insults from alcohol abuse. Using a rat model of adolescent alcohol exposure, the present study examined the effect of adolescent alcohol exposure on GABAergic neurotransmission in the adult PFC. We show that adult rats exposed to alcohol during adolescence exhibit prolonged deficits in tonic GABAergic currents. These observations may contribute to deficits in decision-making and behavioral control in adulthood.

    16. Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala

      Florence P. Varodayan, Michal Bajo, Neeraj Soni, George Luu, Samuel G. Madamba, Paul Schweitzer and Marisa Roberto

      Version of Record online: 20 JAN 2016 | DOI: 10.1111/adb.12369

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      Endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) signaling modulates basolateral nucleus of the amygdala (BLA) GABA release, a mechanism critical for anxiety-driven alcohol drinking and relapse. Our electrophysiological results show that BLA GABA release was increased by CB1 activation and decreased by CB1 blockade; chronic ethanol exposure blunted these effects, suggesting a functional impairment of eCB/CB1 signaling. Also, CB1 blockade and acute ethanol increased GABA release in an additive manner, suggesting that they have different presynaptic sites of action.

    17. Cocaine addiction is associated with abnormal prefrontal function, increased striatal connectivity and sensitivity to monetary incentives, and decreased connectivity outside the human reward circuit

      Lucía Vaquero, Estela Cámara, Frederic Sampedro, José Pérez de los Cobos, Francesca Batlle, Josep Maria Fabregas, Joan Artur Sales, Mercè Cervantes, Xavier Ferrer, Gerardo Lazcano, Antoni Rodríguez-Fornells and Jordi Riba

      Version of Record online: 19 JAN 2016 | DOI: 10.1111/adb.12356

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      Using a lottery task and magnetic resonance imaging, we demonstrate that cocaine-dependent patients show functional and structural brain abnormalities. While patients show hypersensitivity to incentives in subcortical regions, they fail to engage the prefrontal cortex following adverse behavioral outcomes. Structurally, they show increased gray and white matter in reward-processing areas but decreased white matter integrity in antero-posterior association bundles. These findings suggest that abnormal fronto-subcortical function, hypertrophy and hyper-connectivity within the reward circuit, and decreased connectivity outside this network, characterize cocaine addiction.

    18. Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder

      Evangelos Zois, Falk Kiefer, Tagrid Lemenager, Sabine Vollstädt-Klein, Karl Mann and Mira Fauth-Bühler

      Version of Record online: 15 JAN 2016 | DOI: 10.1111/adb.12368

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      The first morphometric investigation to examine gray matter volume alterations in pathological gamblers controlling for the impact of substance use disorder by comparing non-comorbid gamblers and two comorbid groups – alcohol and polysubstance. One hundred and seven patients were included in the analysis and 98 healthy controls. We demonstrated specific frontal-cortex gray-matter deficits in gamblers with and without substance use disorder comorbidity. Those frontal alterations are associated with addicted gambling behavior independent of toxic substance effects.

    19. Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication

      Elizabeth B. de Sousa Fernandes Perna, Eef L. Theunissen, Kim P. C. Kuypers, Elisabeth A. Evers, Peter Stiers, Stefan W. Toennes, Jurriaan Witteman, Wim van Dalen and Johannes G. Ramaekers

      Version of Record online: 14 JAN 2016 | DOI: 10.1111/adb.12351

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      We examined brain reactivity to alcohol and cannabis marketing during sobriety as well as intoxication and compared brain network activation and implicit cognition during both states. Our findings suggest that alcohol and drug marketing can trigger similar brain responses to those that occur during drug use and drug craving, but the reinforcing strength of drug marketing cues appear to be reduced following alcohol and cannabis intoxication.

    20. Cocaine craving during protracted withdrawal requires PKCε priming within vmPFC

      Bailey W. Miller, Melissa G. Wroten, Arianne D. Sacramento, Hannah E. Silva, Christina B. Shin, Philip A. Vieira, Osnat Ben-Shahar, Tod E. Kippin and Karen K. Szumlinski

      Version of Record online: 14 JAN 2016 | DOI: 10.1111/adb.12354

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      Incubated cocaine-craving during protracted withdrawal in rats was associated with time-dependent changes in protein kinase C (PKC) epsilon priming within the ventromedial aspect of the prefrontal cortex (vmPFC). The local infusion of an inhibitor of PKC epsilon translocation blocked cue-elicited drug-seeking during later, but not earlier, withdrawal. These data argue an important role for PKC epsilon-dependent signaling within vmPFC for heightened craving during protracted cocaine withdrawal.

    21. You have full text access to this OnlineOpen article
      Central administration of the anorexigenic peptide neuromedin U decreases alcohol intake and attenuates alcohol-induced reward in rodents

      Daniel Vallöf, Lisa Ulenius, Emil Egecioglu, Jörgen A. Engel and Elisabet Jerlhag

      Version of Record online: 14 JAN 2016 | DOI: 10.1111/adb.12355

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      In contrast to the common view of the function of gut–brain peptides, such as neuromedin U (NMU), to regulate food intake, a novel role in reinforcement mediation has been implied. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference as well as decreased alcohol intake in rodents. Our data suggest that NMU analogues deserve to be evaluated as novel treatment of alcohol use disorder, a major health-care challenge, in humans.

    22. Frontostriatal circuits, resting state functional connectivity and cognitive control in internet gaming disorder

      Kai Yuan, Dahua Yu, Chenxi Cai, Dan Feng, Yangding Li, Yanzhi Bi, Jixin Liu, Yi Zhang, Chenwang Jin, Linling Li, Wei Qin and Jie Tian

      Version of Record online: 14 JAN 2016 | DOI: 10.1111/adb.12348

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      Reduced resting-state functional connectivity between the right caudate and the right dorsolateral prefrontal cortex was negatively correlated with more errors during incongruent condition in Stroop task in IGD subjects.

    23. Posterior hippocampal regional cerebral blood flow predicts abstinence: a replication study

      Bryon Adinoff, Thomas S. Harris, Hong Gu and Elliot A. Stein

      Version of Record online: 11 JAN 2016 | DOI: 10.1111/adb.12361

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      The posterior hippocampus (pHp) is linked to striatal-limbic circuits involved with craving. We recently reported increased pHp ASL-assessed basal regional cerebral blood flow (rCBF) predicted days to cocaine relapse following residential treatment. In this secondary analysis, increased pHp rCBF (by single photon emission computerized tomography) successfully predicted 30-day point prevalence substance use 60 days following residential treatment in an independent group of cocaine-dependent participants. This replicative finding that suggests heightened pHp activation predicts future substance use, possibly reflecting a neural susceptibility to drug cues.

    24. Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area

      John W. Dutton III, Hu Chen, Chang You, Mark S. Brodie and Amy W. Lasek

      Version of Record online: 11 JAN 2016 | DOI: 10.1111/adb.12358

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      We tested anaplastic lymphoma kinase (ALK) inhibitors in a mouse model of binge drinking and found that ALK inhibition reduced binge-like alcohol consumption. ALK appears to act in the ventral tegmental area to regulate binge-like drinking and may affect ethanol consumption through modulation of dopamine D2 receptor activity. Our results indicate that treatment with small molecule inhibitors of ALK might be a viable therapeutic strategy to reduce binge drinking in individuals with alcohol use disorders.

    25. Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence

      Alena Becker, Martina Kirsch, Martin Fungisai Gerchen, Falk Kiefer and Peter Kirsch

      Version of Record online: 11 JAN 2016 | DOI: 10.1111/adb.12352

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      Neurobiological theories of addiction highlight the role of the prefrontal cortex not only through its engagement in executive functions but also through monitoring the mesolimbic reward system. We investigated the neural activation and connectivity underlying non-drug reward anticipation in alcohol dependence. Alcohol-dependent patients showed increased activation of the ventral striatum, along with decreased frontostriatal connectivity, during the anticipation of monetary reward. This diminished frontostriatal connectivity was associated with increased craving, as measured by the Obsessive Compulsive Drinking Scale.

    26. The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice

      Omkar L. Patkar, Arnauld Belmer, Joan Y. Holgate, Josephine R. Tarren, Masroor R. Shariff, Michael Morgan, Matthew J. Fogarty, Mark C. Bellingham, Selena E. Bartlett and Paul M. Klenowski

      Version of Record online: 11 JAN 2016 | DOI: 10.1111/adb.12359

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      In this study, we show that the antihypertensive drug pindolol reduces ethanol consumption in mice following long-term binge-like intake. Pindolol did not have non-specific effects on locomotor activity, ethanol sensitivity or consumption of the natural reward sucrose. We also show that pindolol reduces excitatory post-synaptic current frequency in naïve mice but increases excitatory post-synaptic current frequency in long-term ethanol consuming mice. Combined, these results demonstrate that pindolol represents a novel treatment option of the management of alcohol use disorders. Figure 1 highlights the key finding of the study.

    27. Topiramate and motivational enhancement therapy for cannabis use among youth: a randomized placebo-controlled pilot study

      Robert Miranda Jr., Hayley Treloar, Alexander Blanchard, Alicia Justus, Peter M. Monti, Thomas Chun, Robert Swift, Jennifer W. Tidey and Chad J. Gwaltney

      Version of Record online: 11 JAN 2016 | DOI: 10.1111/adb.12350

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      Results of this double-blind, placebo-controlled pilot study showed that topiramate, combined with motivational enhancement therapy, reduced how much cannabis adolescents smoked when they used but it did not affect abstinence rates. Significant increases in abstinence rates were observed in both medication conditions. Topiramate was poorly tolerated by many youths, however, and the magnitude of its effect on cannabis use was modest, which calls to question the clinical importance of these findings.

    28. Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner

      Reginald Cannady, Kristen R. Fisher, Caitlin Graham, Jesse Crayle, Joyce Besheer and Clyde W. Hodge

      Version of Record online: 6 JAN 2016 | DOI: 10.1111/adb.12357

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      Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Here, we show that low-dose alcohol self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 in rat central amygdala and that CaMKII-dependent activation of AMPA receptors in the amygdala increases the positive reinforcing effects of alcohol. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction.

    29. Striatal dopaminergic reward response relates to age of first drunkenness and feedback response in at-risk youth

      Barbara J. Weiland, Robert A. Zucker, Jon-Kar Zubieta and Mary M. Heitzeg

      Version of Record online: 5 JAN 2016 | DOI: 10.1111/adb.12341

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      The mesolimbic dopamine system is hypothesized to play a role in vulnerability to substance use disorders. Using multi-modal methods (functional magnetic resonance imaging and positron emission tomography), we tested whether young adult male subjects at high risk for substance use disorders based on family history and early drunkenness had differences in response to monetary rewards compared with controls. We found heightened striatal dopamine response in high-risk male subjects during positron emission tomography. This was further associated with age of first drunkenness, suggesting it may represent a neurobiological risk phenotype.

    30. You have full text access to this OnlineOpen article
      Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid ‘Spice’ compounds: comparison with Δ9-tetrahydrocannabinol

      Alexander F. Hoffman, Matthew D. Lycas, Jakub R. Kaczmarzyk, Charles E. Spivak, Michael H. Baumann and Carl R. Lupica

      Version of Record online: 5 JAN 2016 | DOI: 10.1111/adb.12334

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      Three synthetic cannabinoids commonly found in illicit ‘Spice’ compounds were evaluated for their acute effects on hippocampal synaptic transmission and compared with THC. Although the compounds varied in their potency, both THC and the synthetic cannabinoids strongly suppressed glutamate release and disrupted hippocampal long-term potentiation. These actions will likely contribute to adverse consequences of synthetic cannabinoids on cognitive and behavioral function and highlight the need to further understand the neurobiological effects of these rapidly emerging new psychoactive substances.

    31. Activation of the ventral and dorsal striatum during cue reactivity in Internet gaming disorder

      Lu Liu, Sarah W. Yip, Jin-Tao Zhang, Ling-Jiao Wang, Zi-Jiao Shen, Ben Liu, Shan-Shan Ma, Yuan-Wei Yao and Xiao-Yi Fang

      Version of Record online: 5 JAN 2016 | DOI: 10.1111/adb.12338

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      For the individuals with Internet gaming disorder (IGD), cue-induced activity within the left ventral striatum was correlated negatively with cue-induced craving, whereas positive associations were found between activations within the dorsal striatum (right putamen, pallidum, and left caudate) and duration of IGD.

    32. Cocaine self-administration induces changes in synaptic transmission and plasticity in ventral hippocampus

      Madhusudhanan M. Keralapurath, Sherri B. Briggs and John J. Wagner

      Version of Record online: 22 DEC 2015 | DOI: 10.1111/adb.12345

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      Changes in synaptic transmission and long-term potentiation (LTP) occur in the CA1 region of the ventral hippocampus following extended access to cocaine self-administration in rats. Increased AMPA/NMDA ratio, increased basal-evoked excitatory transmission, and a decreased capacity to express LTP were observed following 3–5 weeks of withdrawal following a cocaine short access/long access experience. These results indicate that withdrawal following extended access to cocaine self-administration can result in a chronically potentiated state in the CA1 region of the ventral hippocampus.

    33. Loss of brain graph network efficiency in alcohol dependence

      Zsuzsika Sjoerds, Steven M. Stufflebeam, Dick J. Veltman, Wim Van den Brink, Brenda W. J. H. Penninx and Linda Douw

      Version of Record online: 22 DEC 2015 | DOI: 10.1111/adb.12346

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      In this study, we applied graph theory on resting state functional magnetic resonance imaging to investigate the complex brain network in alcohol dependent patients. Patients with alcohol dependence showed lower global brain network efficiency and strength with longer alcohol dependence duration, and with more severe alcohol use. Alcohol use severity was not associated with brain network efficiency in healthy controls. Longer alcohol-dependence duration was additionally associated with reduced clustering coefficient and weighted degree in ventromedial and anterior striatum.

    34. Re-exposure to morphine-associated context facilitated long-term potentiation in the vSUB-NAc glutamatergic pathway via GluN2B-containing receptor activation

      Yi-Jing Li, Xing-Jie Ping, Chong Qi, Fang Shen, Lin-Lin Sun, Xiao-Wei Sun, Fei-Fei Ge, Guo-Gang Xing and Cai-Lian Cui

      Version of Record online: 22 DEC 2015 | DOI: 10.1111/adb.12343

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      Re-exposure to the morphine-associated context facilitated the long-term potentiation induction in the vSUB-nucleus accumbens (NAc) pathway. Intra-NAc shell injection of GluN2B–N-methyl-d-aspartate receptor antagonist RO25-6981 prevented the long-term potentiation facilitation. The inhibition of the GluN2B–N-methyl-d-aspartate receptors in the vSUB-NAc pathway prevented morphine conditioned place preference expression.

    35. You have free access to this content
      Brain connectivity and psychiatric comorbidity in adolescents with Internet gaming disorder

      Doug Hyun Han, Sun Mi Kim, Sujin Bae, Perry F. Renshaw and Jeffrey S. Anderson

      Version of Record online: 22 DEC 2015 | DOI: 10.1111/adb.12347

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      This study measured brain functional connectivity in 151 adolescents with and without compulsive video game playing. Subjects with Internet gaming disorder showed higher connectivity between sensory cortex, salience network, and dorsal attention network, possibly adaptive training effects of gaming, but also increased connectivity between default mode and executive networks, which may relate to psychiatric comorbidity. The findings were not explained by depression or ADHD in the study population.

    36. Genetic and pharmacological manipulation of glyoxalase 1 regulates voluntary ethanol consumption in mice

      Katherine M. J. McMurray, Preetpal S. Sidhu, James M. Cook, Leggy A. Arnold and Abraham A. Palmer

      Version of Record online: 22 DEC 2015 | DOI: 10.1111/adb.12333

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      We have discovered that gene glyoxalase 1 (Glo1) is a novel regulator of ethanol consumption. Mice overexpressing Glo1 voluntarily consumed more ethanol. Furthermore, Glo1 knockdown mice and mice treated with a pharmacological inhibitor of GLO1 consumed less ethanol. None of our manipulations of GLO1 altered water, sucrose or saccharin consumption nor did they alter the duration of loss of righting reflex or footslips on a balance beam. Therefore, pharmacological inhibition of GLO1 may constitute a novel target for treatment of alcohol use disorders.

    37. Chronic EtOH effects on putative measures of compulsive behavior in mice

      Anna K. Radke, Nicholas J. Jury, Adrina Kocharian, Catherine A. Marcinkiewcz, Emily G. Lowery-Gionta, Kristen E. Pleil, Zoe A. McElligott, Jessica M. McKlveen, Thomas L. Kash and Andrew Holmes

      Version of Record online: 21 DEC 2015 | DOI: 10.1111/adb.12342

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      Footshock punishment suppressed operant responding for ethanol (EtOH). Punished-suppression was absent in mice with a history of chronic exposure to EtOH vapors. Loss of sensitivity to punishment following chronic EtOH exposure was associated with increased NMDA receptor (GluN1, GluN2A subunits) expression and NMDA receptor synaptic currents in the medial orbitofrontal cortex. These findings demonstrate a link between cortical glutamate signaling and increased compulsive-like EtOH-seeking.

    38. Prefrontal functional connectivity measured with near-infrared spectroscopy during smoking cue exposure

      Agnes M. Kroczek, Florian B. Haeussinger, Andreas J. Fallgatter, Anil Batra and Ann-Christine Ehlis

      Version of Record online: 21 DEC 2015 | DOI: 10.1111/adb.12344

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      We investigated cue reactivity in smokers during smoking cue exposure by means of changes in the prefrontal cortex (assessed by functional near-infrared spectroscopy) and subjective craving ratings. During the time course of the cue exposure, smokers showed increased craving ratings. Changes in craving (range) correlated with hemodynamics in the orbitofrontal cortex (OFC), while the reported minimum craving for each subject correlated with hemodynamics in the dorsolateral prefrontal cortex (dlPFC). Connectivity between OFC and dlPFC was increased in smokers compared with controls.

  15. Invited Reviews

    1. Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking

      Rose Chesworth and Laura H. Corbit

      Version of Record online: 21 DEC 2015 | DOI: 10.1111/adb.12337

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      This review summarizes and evaluates recent developments in the behavioural and pharmacological facilitation of extinction of drug seeking, in both preclinical models and clinical trials. We highlight areas where promising preclinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. The clinical translation of preclinical behavioural and pharmacological findings has had limited success, and suggestions for methodological improvements are made based on a theoretical understanding of extinction learning.

  16. Original Articles

    1. Altered white matter integrity in whole brain and segments of corpus callosum, in young social drinkers with binge drinking pattern

      Kathleen W. Smith, Fabien Gierski, Judith Andre, Nicholas G. Dowell, Mara Cercignani, Mickaël Naassila and Theodora Duka

      Version of Record online: 21 DEC 2015 | DOI: 10.1111/adb.12332

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      Mean fractional anisotropy (FA), measured at two time points 8–12 months apart, shows reduced efficiency of white matter connectivity in the body of corpus callosum, in male, but not female, binge drinkers compared with non-binge drinkers. Lower FA in the prefrontal segment of corpus callosum was associated with higher binge score in men and worse spatial working memory both in men and in women.

    2. Excessive alcohol consumption increases mortality in later life: a genetic analysis of the health in men cohort study

      Osvaldo P. Almeida, Kieran McCaul, Graeme J. Hankey, Bu B. Yeap, Jonathan Golledge and Leon Flicker

      Version of Record online: 8 DEC 2015 | DOI: 10.1111/adb.12340

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      We found a triangular association between ADH1B rs1229984 G>A polymorphism, regular alcohol intake and mortality. The findings indicate that excessive alcohol use is a direct cause of death in later life and that there is no obvious survival advantage associated with mild to moderate drinking. Health messages regarding the safe use of alcohol may benefit from taking notice of these results.

    3. Rev-erbα modulates the hypothalamic orexinergic system to influence pleasurable feeding behaviour in mice

      Céline A. Feillet, Claire Bainier, Maria Mateo, Aurea Blancas-Velázquez, Nora L. Salaberry, Jürgen A. Ripperger, Urs Albrecht and Jorge Mendoza

      Version of Record online: 2 DEC 2015 | DOI: 10.1111/adb.12339

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      •Orexin (ORX) neurons regulate metabolic and hedonic feeding

      •The clock gene Rev-Erb-alpha has an important role in the regulation of ORX signalling

      •Rev-Erb-alpha mutations lead to an increase in hypothalamic ORXergic activity and in food-reward behaviour in mice

    4. Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the amygdala of the cynomolgus monkey

      Matthew C. Beattie, Antoniette M. Maldonado-Devincci, Patrizia Porcu, Todd K. O'Buckley, James B. Daunais, Kathleen A. Grant and A. Leslie Morrow

      Version of Record online: 2 DEC 2015 | DOI: 10.1111/adb.12326

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      Neuroactive steroids such as [3α, 5α]3-hydroxy-pregnan-20-one (3α,5α-THP) enhance the GABAergic effects of ethanol, and chronic ethanol consumption reduces plasma and brain 3α,5α-THP levels. We explored the relationship between 3α,5α-THP levels in amygdala sub-regions and voluntary ethanol consumption in the cynomolgus monkey following 12 months of daily self-administration. Prolonged ethanol consumption reduced cellular 3α,5α-THP immunoreactivity in the lateral amygdala and the basolateral amygdala that was inversely correlated with average daily ethanol intake. Amygdala 3α,5α-THP appears to regulate ethanol consumption in nonhuman primates.

    5. Extended nicotine self-administration increases sensitivity to nicotine, motivation to seek nicotine and the reinforcing properties of nicotine-paired cues.

      Kelly J. Clemens, Belinda P. P. Lay and Nathan M. Holmes

      Version of Record online: 2 DEC 2015 | DOI: 10.1111/adb.12336

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      An array of pharmacological and environmental factors influences the development and maintenance of tobacco addiction. The present study demonstrated that with extended training, rats become more sensitive to changing doses of nicotine, more motivated to work for nicotine and increasingly controlled by nicotine-associated cues and that the partial nicotine receptor agonist varenicline has dissociable effects on responding for nicotine versus a nicotine-paired cue. Together, these results show that nicotine seeking is controlled by multiple sources and, therefore, highly resistant to change.

    6. Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress

      Maria Vrettou, Linnea Granholm, Aniruddha Todkar, Kent W. Nilsson, Åsa Wallén-Mackenzie, Ingrid Nylander and Erika Comasco

      Version of Record online: 27 NOV 2015 | DOI: 10.1111/adb.12331

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      Using a rodent maternal separation (MS) model, the study assessed the effect of early life stress (ELS) and adult voluntary ethanol drinking on expression of Vesicular Glutamate Transporter (Vglut) and DNA methylation-related genes in the mesocorticolimbic circuit and dorsal striatum. The results indicated interaction effects between ELS and ethanol consumption in a gene-dependent and region-dependent manner, mirrored by changes in the epigenetic machinery.

    7. Reduced activity in functional networks during reward processing is modulated by abstinence in cocaine addicts

      Víctor Costumero, Juan Carlos Bustamante, Patricia Rosell-Negre, Paola Fuentes, Juan José Llopis, César Ávila and Alfonso Barrós-Loscertales

      Version of Record online: 27 NOV 2015 | DOI: 10.1111/adb.12329

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      Independent component analysis was performed in functional magnetic resonance imaging data to investigate differences between cocaine addicts and healthy controls in the response to erotic images.

      Cocaine addicts displayed diminished modulation of the left frontoparietal network in response to erotic pictures. The modulation of the left frontoparietal network by unpredicted erotic images in cocaine addicts correlated with length of abstinence.

      These results suggest that cocaine addiction contributes to reduce sensitivity to rewarding stimuli and that abstinence may mitigate this effect.

    8. Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil

      Kirsten A. Porter-Stransky, Brandon S. Bentzley and Gary Aston-Jones

      Version of Record online: 24 NOV 2015 | DOI: 10.1111/adb.12323

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      Using a within-session behavioral economic procedure, we observed in rats robust individual differences in motivation for the short-acting opioid remifentanil. High takers exhibited greater drug consumption at low cost, continued to work for drug despite increases in price (low demand elasticity), and withstood greater electrical shock to continue self-administering remifentanil. Antagonism of orexin 1 receptors reduced free consumption, demand elasticity, and cue-induced reinstatement of drug seeking in low takers but not in high takers, which exhibit an addition-like phenotype.


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