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1.  Aberrant Learning and Memory in Addiction 
Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict's behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the preclinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory.
PMCID: PMC3138832  PMID: 21376820
addiction; extinction; reconsolidation; cue; reinstatement; memory; neuroadaptation
2.  Cocaine-induced Metaplasticity in the Nucleus Accumbens: Silent Synapse and Beyond 
Neuropharmacology  2011;61(7):1060-1069.
The neuroadaptation theory of addiction suggests that, similar to the development of most memories, exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain which likely mediate addiction-related memories or the addictive state. Compared to other types of memories, addiction-related memories develop fast and last extremely long, suggesting that the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. We recently demonstrated that repeated exposure to cocaine generated a large portion of “silent” glutamatergic synapses within the nucleus accumbens (NAc). Silent glutamatergic synapses are synaptic connections in which only N-methyl-D-aspartic acid receptor (NMDAR)-mediated responses are readily detected whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are absent or highly labile. Extensive experimental evidence suggests that silent synapses are conspicuously efficient plasticity sites at which long-lasting plastic changes can be more easily induced and maintained. Thus, generation of silent synapses can be regarded as a process of metaplasticity, which primes the NAc for subsequent durable and robust plasticity for addiction-related memories. Focusing on silent synapse-based metaplasticity, this review discusses how key brain regions, such as the NAc, utilize the metaplasticity mechanism to optimize the plasticity machineries to achieve fast and durable plastic changes following exposure to cocaine. A summary of recent related results suggests that upon cocaine exposure, newly generated silent synapses may prime excitatory synapses within the NAc for long-term potentiation (LTP), thus setting the direction of future plasticity. Furthermore, because cocaine-generated silent synapses are enriched in NMDARs containing the NR2B subunit, the enhanced NR2B-signaling may set up a selective recruitment of certain types of AMPARs. Thus, silent synapse-based metaplasticity may lead to not only quantitative but also qualitative alterations in excitatory synapses within the NAc. This review is one of the first systematic analyses regarding the hypothesis that drugs of abuse induce metaplasticity, which regulates the susceptibility, the direction, and the molecular details of subsequent plastic changes. Taken together, metaplasticity ultimately serves as a key step in mediating cascades of addiction-related plastic alterations.
PMCID: PMC3090702  PMID: 21232547
metaplasticity; silent synapses; cocaine; NMDA; AMPA; membrane excitability
3.  Kick back and destroy the ride: Alcohol-related violence and associations with drinking patterns and delinquency in adolescence 
To assess how drinking patterns and delinquency are associated with self-reported experiences of alcohol-related violence in an adolescent population.
Population and research design
Cross-sectional data were acquired from the Scania drug use survey 2005, consisting of 3847 students in 9th grade. Abstainers were omitted and 1873 responses analyzed, with binary and multi-variable logistic regression modeling.
All drinking pattern indicators were statistically significantly associated with alcohol-related violence, high usual volume of distilled spirits consumed (OR 2.2, CI 95 % 1.7–2.9) being the strongest. Delinquency had, when included in the analysis, a significant effect (OR 2.5, CI 95 % 1.8–3.6); however, the drinking pattern indicators also remained statistically significant. An analysis of the effect moderation between usual volume of distilled spirits consumed and delinquency showed that there was a synergetic effect between them (SI 1.6, CI 95 % 1.1–2.4). A separate analysis for non-delinquent students, those with little experience of delinquency, and those who engaged regularly in delinquent activities, showed that the effects of different drinking patterns, especially use of distilled spirits, were significant in both groups, however, differently distributed.
The results show that alcohol consumption pattern, with usual volume of distilled spirits being the most prominent one, had an effect on alcohol-related violence, and that this effect was amplified by delinquent behavior. The analyses also showed that there are similarities, regarding risk factors for alcohol-related violence, between delinquent and non-delinquent youth. This, indicating that consumption pattern cannot be discarded as a key factor in alcohol-related violence in adolescence.
Policy implications
The study shows that alcohol-related violence in adolescence is related to both alcohol consumption patterns, e.g. usual volume of distilled spirits consumed, and delinquency. In order to prevent the harm outcome, both phenomenons have to be targeted, either by alcohol or broader social policy initiatives.
PMCID: PMC1936421  PMID: 17605765
4.  Extant health behaviors and uptake of standardized vs tailored health messages among cancer survivors enrolled in the FRESH START trial: a comparison of fighting-spirits vs fatalists 
Psycho-Oncology  2010;21(1):108-113.
Cancer coping styles have been associated with several cancer-related outcomes. We examined whether baseline lifestyle behaviors differed between cancer survivors with fatalistic vs fighting-spirit coping styles, and whether there was differential response to two diet-exercise mailed-print interventions, one standardized and another individually tailored.
Baseline differences by coping style are presented for 628 breast and prostate cancer survivors who participated in the FRESH START trial, along with multivariable analyses on rates of uptake by coping style and arm assignment for those completing the 2-year trial.
At baseline, several differences were observed between fighting-spirits and fatalists, with the former significantly more likely to be white, younger, leaner, more-educated and at risk for depression, and less likely to consume 5+ fruits and vegetables (F&V)/day (p-values<0.05). Improvements in physical activity were observed, with fighting-spirits exhibiting the greatest gains from baseline to Year-1, regardless of intervention type; but by Year-2, these differences diminished as fatalists gained ground. Moreover, fatalists who received standardized intervention material also charted steady improvements in F&V intake over the study period; by Year-2, 58.1% of fatalists achieved the 5-a-day goal vs 44.6% of fighting-spirits (p-value<0.05).
Lifestyle behaviors and health message uptake differs by cancer coping style. Although tailored interventions appear most effective and minimize differential uptake, standardized interventions also can improve behaviors, though fighting-spirits may require additional boosters to maintain change.
PMCID: PMC3248978  PMID: 21061408
coping; personality traits; diet; exercise; interventions; cancer survivors
5.  Unravelling the spirits’ message: a study of help-seeking steps and explanatory models among patients suffering from spirit possession in Uganda 
As in many cultures, also in Uganda spirit possession is a common idiom of distress associated with traumatic experiences. In the DSM-IV and -5, possession trance disorders can be classified as dissociative disorders. Dissociation in Western countries is associated with complicated, time-consuming and costly therapies. Patients with spirit possession in SW Uganda, however, often report partial or full recovery after treatment by traditional healers.
The aim of this study is to explore how the development of symptoms concomitant help-seeking steps, and explanatory models (EM) eventually contributed to healing of patients with spirit possession in SW Uganda. Illness narratives of 119 patients with spirit possession referred by traditional healers were analysed using a mixed-method approach.
Treatments of two-thirds of the patients were unsuccessful when first seeking help in the medical sector. Their initially physical symptoms subsequently developed into dissociative possession symptoms. After an average of two help-seeking steps, patients reached a healing place where 99% of them found satisfactory EM and effective healing. During healing sessions, possessing agents were summoned to identify themselves and underlying problems were addressed. Often-mentioned explanations were the following: neglect of rituals and of responsibilities towards relatives and inheritance, the call to become a healer, witchcraft, grief, and land conflicts.
The results demonstrate that traditional healing processes of spirit possession can play a role in restoring connections with the supra-, inter-, intra-, and extra-human worlds. It does not always seem necessary to address individual traumatic experiences per se, which is in line with other research in this field. The study leads to additional perspectives on treatment of trauma-related dissociation in Western countries and on developing effective mental health services in low -and middle-income countries.
PMCID: PMC4060147  PMID: 24940355
Spirit possession; Uganda; Explanatory models; Help-seeking; Dissociative disorders; Traditional healing; Traumatic experiences
6.  Assessing treatment fidelity in a cultural adaptation of motivational interviewing 
The efficacy of Motivational Interviewing (MI) for addictions is well-documented. Grounding MI in social/cultural priorities may enhance treatment response. We evaluate the method of assessing competence using the Motivational Interviewing Treatment Integrity system (MITI) for standard (MI) and culturally-adapted MI (CAMI) delivered to Latino heavy drinkers. Twenty audiotapes (MI, n=10; CAMI, n=10) were MITI coded by two raters unaware of treatment assignment. Inter-rater reliabilities were excellent (.78–.99) except for CAMI Complex Reflections, Global ratings of empathy and MI spirit. The MITI reliably evaluates MI and CAMI treatment fidelity. Future research should investigate lower reliabilities for MI Global and complex reflections cross-culturally.
PMCID: PMC4594845  PMID: 25984959
Motivational Interviewing; alcohol; treatment integrity; cultural adaptation; Latinos
7.  “Old Dogs” and New Skills: How Clinician Characteristics Relate to Motivational Interviewing Skills Before, During, and After Training 
The relationships between the occupational, educational, and verbal-cognitive characteristics of health care professionals and their Motivational Interviewing (MI) skills before, during, and after training were investigated.
Fifty-eight community-based addiction clinicians (M = 42.1 yrs., SD =10.0; 66% Female) were assessed prior to enrolling in a two-day MI training workshop and being randomized to one of three post-workshop supervision programs: live supervision via tele-conferencing (TCS), standard tape-based supervision (Tape), or workshop training alone. Audiotaped sessions with clients were rated for MI skillfulness with the Motivational Interviewing Treatment Integrity (MITI) coding system v 2.0 at pre-workshop and 1, 8, and 20 weeks post-workshop. Correlation coefficients and generalized linear models were used to test the relationships between clinician characteristics and MI skill at each assessment point.
Baseline MI skill levels were the most robust predictors of pre- and post-supervision performances. Clinician characteristics were associated with MI Spirit and reflective listening skill throughout training and moderated the effect of post-workshop supervision method on MI skill. TCS, which provided immediate feedback during practice sessions, was most effective for increasing MI Spirit and reflective listening among clinicians with no graduate degree and stronger vocabulary performances. Tape supervision was more effective for increasing these skills among clinicians with a graduate degree. Further, TCS and Tape were most likely to enhance MI Spirit among clinicians with low average to average verbal and abstract reasoning performances.
Clinician attributes influence the effectiveness of methods used to promote the acquisition of evidence-based practices among community-based practitioners.
PMCID: PMC3928150  PMID: 22563640
Motivational Interviewing; Clinician Training; Clinical Supervision
8.  Cancer risk assessment of ethyl carbamate in alcoholic beverages from Brazil with special consideration to the spirits cachaça and tiquira 
BMC Cancer  2010;10:266.
Ethyl carbamate (EC) is a multi-site carcinogen in experimental animals and probably carcinogenic to humans (IARC group 2A). Traces of EC below health-relevant ranges naturally occur in several fermented foods and beverages, while higher concentrations above 1 mg/l are regularly detected in only certain spirits derived from cyanogenic plants. In Brazil this concerns the sugarcane spirit cachaça and the manioc (cassava) spirit tiquira, which both regularly exceed the national EC limit of 0.15 mg/l. This study aims to estimate human exposure in Brazil and provide a quantitative risk assessment.
The human dietary intake of EC via alcoholic beverages was estimated based on WHO alcohol consumption data in combination with own surveys and literature data. This data comprises the EC contents of the different beverage groups cachaça, tiquira, other spirits, beer, wine, and unrecorded alcohol (as defined by the WHO; including alcohol which is not captured in routine government statistics nor taxed). The risk assessment was conducted using the margin of exposure (MOE) approach with benchmark doses obtained from dose-response modelling of animal experiments. Lifetime cancer risk was calculated using the T25 dose descriptor.
Considering differences between pot-still and column-still cachaça, its average EC content would be 0.38 mg/l. Tiquira contained a considerably higher average EC content of 2.34 mg/l. The whole population exposure from all alcoholic beverages was calculated to be around 100 to 200 ng/kg bw/day, with cachaça and unrecorded alcohol as the major contributing factors. The MOE was calculated to range between 400 and 2,466, with the lifetime cancer risk at approximately 3 cases in 10,000. An even higher risk may exist for binge-drinkers of cachaça and tiquira with MOEs of up to 80 and 15, respectively.
According to our risk assessment, EC poses a significant cancer risk for the alcohol-drinking population in Brazil, in addition to that of alcohol alone. Model calculations show that the implementation of the 0.15 mg/l limit for cachaça would be beneficial, including an increase of the MOE by a factor between 3 to 6. The implementation of policy measures for tiquira and unrecorded alcohol also appears to be advisable.
PMCID: PMC2892455  PMID: 20529350
9.  Traumatic Experience and Somatoform Dissociation Among Spirit Possession Practitioners in the Dominican Republic 
Recent studies in African contexts have revealed a strong association between spirit possession and severe trauma, with inclusion into a possession cult serving at times a therapeutic function. Research on spirit possession in the Dominican Republic has so far not included quantitative studies of trauma and dissociation. This study evaluated demographic variables, somatoform dissociative symptoms, and potentially traumatizing events in the Dominican Republic with a group of Vodou practitioners that either do or do not experience spirit possession. Inter-group comparisons revealed that in contrast to non-possessed participants (n = 38), those experiencing spirit possession (n = 47) reported greater somatoform dissociation, more problems with sleep, and previous exposure to mortal danger such as assaults, accidents, or diseases. The two groups did not differ significantly in other types of trauma. The best predictor variable for group classification was somatoform dissociation, although those items could also reflect the experience of followers during a possession episode. A factor analysis across variables resulted in three factors: having to take responsibility early on in life and taking on a professional spiritual role; traumatic events and pain; and distress/dissociation. In comparison with the non-possessed individuals, the possessed ones did not seem to overall have a remarkably more severe story of trauma and seemed to derive economic gains from possession practice.
PMCID: PMC4735242  PMID: 26427849
Spirit possession; Somatoform dissociation; Traumatic experience; Dominican Republic
10.  Could masked conceptual primes increase recollection? The subtleties of measuring recollection and familiarity in recognition memory 
Neuropsychologia  2012;50(13):3027-3040.
We begin with a theoretical overview of the concepts of recollection and familiarity, focusing, in the spirit of this special issue, on the important contributions made by Andrew Mayes. In particular, we discuss the issue of when the generation of semantically-related information in response to a retrieval cue might be experienced as recollection rather than familiarity. We then report a series of experiments in which two different types of masked prime, presented immediately prior to the test cue in a recognition memory paradigm, produced opposite effects on Remember vs. Know judgments. More specifically, primes that were conceptually related to the test item increased the incidence of Remember judgments, though only when intermixed with repetition primes (which increased the incidence of Know judgments instead, as in prior studies). One possible explanation—that the fluency of retrieval of item–context associations can be experienced as recollection, even when the source of that fluency is unknown—is counter to conventional views of recollection and familiarity, though it was anticipated by Andrew in his writings nearly two decades ago.
► We review the estimation of recollection and familiarity, inspired by Andrew Mayes. ► In a recognition memory experiment, masked primes were shown before test cue words. ► Repetition primes increased ‘familiar’ responses, both hits and false alarms. ► Conceptual primes increased remember' responses (recollection), for hits only.
PMCID: PMC3500693  PMID: 22898644
Remember/know; Source memory; Context; Episodic; Priming
11.  Serotonergic Mechanisms in Addiction-Related Memories 
Behavioural brain research  2008;195(1):39-53.
Drug-associated memories are a hallmark of addiction and a contributing factor in the continued use and relapse to drugs of abuse. Repeated association of drugs of abuse with conditioned stimuli leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. A greater understanding of the mechanisms underlying the formation and retrieval of drug-associated memories may shed light on potential therapeutic approaches to effectively intervene with drug use-associated memory. There is evidence to support the involvement of serotonin (5-HT) neurotransmission in learning and memory formation through the families of the 5-HT1 receptor (5-HT1R) and 5-HT2R which have also been shown to play a modulatory role in the behavioral effects induced by many psychostimulants. While there is a paucity of studies examining the effects of selective 5-HT1AR ligands, the available dataset suggests that 5-HT1BR agonists may inhibit retrieval of cocaine-associated memories. The 5-HT2AR and 5-HT2CR appear to be integral in the strong conditioned associations made between cocaine and environmental cues with 5-HT2AR antagonists and 5-HT2CR agonists possessing potency in blocking retrieval of cocaine-associated memories following cocaine self-administration procedures. The complex anatomical connectivity between 5-HT neurons and other neuronal phenotypes in limbic-corticostriatal brain structures, the heterogeneity of 5-HT receptors (5-HTXR) and the conflicting results of behavioral experiments which employ non-specific 5-HTXR ligands contribute to the complexity of interpreting the involvement of 5-HT systems in addictive-related memory processes. This review briefly traces the history of 5-HT involvement in retrieval of drug-cue associations and future targets of serotonergic manipulation that may reduce the impact that drug cues have on addictive behavior and relapse.
PMCID: PMC2630382  PMID: 18639587
Serotonin receptors; cocaine; self-administration; memory retrieval; extinction; conditioned stimuli
12.  Attentional Bias for Non-drug Reward is Magnified in Addiction 
Attentional biases for drug-related stimuli play a prominent role in addiction, predicting treatment outcome. Attentional biases also develop for stimuli that have been paired with non-drug reward in adults without a history of addiction, the magnitude of which is predicted by visual working memory capacity and impulsiveness. We tested the hypothesis that addiction is associated with an increased attentional bias for non-drug (monetary) reward relative to that of healthy controls, and that this bias is related to working memory impairments and increased impulsiveness. Seventeen patients receiving methadone maintenance treatment for opioid dependence and seventeen healthy controls participated. Impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11), visual working memory capacity was measured as the ability to recognize briefly presented color stimuli, and attentional bias was measured as the magnitude of response time slowing caused by irrelevant but previously reward-associated distractors in a visual search task. The results showed that attention was biased toward the distractors across all participants, replicating previous findings. Importantly, this bias was significantly greater in the patients than in the controls and was negatively correlated with visual working memory capacity. Patients were also significantly more impulsive than controls as a group. Our findings demonstrate that patients in treatment for addiction experience greater difficulty ignoring stimuli associated with non-drug reward. This non-specific reward-related bias could mediate the distracting quality of drug-related stimuli previously observed in addiction.
PMCID: PMC3934504  PMID: 24128148
attention; reward; learning; working memory; impulsiveness
13.  Bernard Lerer: Recipient of the 2014 Inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics) 
This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21st century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry—pharmacoepigenetics—that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way to cultivate transgenerational capacity and broader cognizance of the concept and practice of responsible innovation as an important criterion of 21st century omics science and personalized medicine. A new call is presently in place for the 2016 PRACP Werner Kalow prize. Nominations can be made in support of an exceptional individual interdisciplinary scholar, or alternatively, an entire research team, from any region in the world with a record of highly innovative contributions to global omics science and/or personalized medicine, in the spirit of responsible innovation. The application process is straightforward, requiring a signed, 1500-word nomination letter (by the applicant or sponsor) submitted not later than May 31, 2015.
Wanderer, your footsteps are
the road, and nothing more;
wanderer, there is no road,
the road is made by walking.
By walking one makes the road,
and upon glancing behind
one sees the path
that never will be trod again.
Wanderer, there is no road –
Only wakes upon the sea.
“The real voyage of discovery consists not in seeking new landscapes but in having new eyes.”
PMCID: PMC3976589  PMID: 24649998
14.  Psychosocial stress after reactivation of drug-related memory impairs later recall in abstinent heroin addicts 
Psychopharmacology  2008;203(3):599-608.
Stress and stress hormone are known to play important roles in modulating different stages of memory including reconsolidation. In a previous study, we found that treatment with stress or corticosterone after a single memory reactivation disrupted reconsolidation of a drug-related memory in rats. Here we presumed that stress after memory reactivation can effectively inhibit drug-related memory by disrupting its reconsolidation in abstinent heroin addicts.
Materials and methods
In the present study, 21 abstinent heroin addicts learned a word list (containing ten neutral, ten heroin-related negative, and ten heroin-related positive words) on day 1; retrieval of a word list (learned 24 h earlier) was made on day 2; and immediately after retrieval, they were exposed to either a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control condition in a crossover manner. On day 3, free recall of the word list and other psychological and physical responses were assessed.
The stressor induced a significant increase in salivary free cortisol and a decrease in mood. Memory recall was significantly impaired after the stress condition. Follow-up analysis revealed that heroin-related negative and positive words (i.e., heroin-related words) were affected, whereas no effect was observed for neutral words. No changes were detected for cued recall, working memory, or attention. Stress after drug-related memory retrieval significantly decreased its subsequent recall, likely through impaired drug-related memory reconsolidation process.
Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.
PMCID: PMC3683960  PMID: 19020867
Stress; Glucocorticoids; Heroin-related memory; Reconsolidation
15.  Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects 
Neuropsychopharmacology  2010;35(7):1485-1499.
Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.
PMCID: PMC3055466  PMID: 20393457
addiction and substance abuse; imaging; clinical or preclinical; acetylcholine; biological psychiatry; cocaine addiction; Acetylcholine; Addiction & Substance Abuse; Biological Psychiatry; cocaine addiction; Imaging; Clinical or Preclinical
16.  Neurocognitive Characterizations of Russian Heroin Addicts without a Significant History of Other Drug Use 
Drug and alcohol dependence  2007;90(1):25-38.
Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol\heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered.
PMCID: PMC1991277  PMID: 17382488
heroin addiction; cognition; neuropsychology; alcoholism; Russia
17.  Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction 
Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis - the hippocampus - is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat i.v. cocaine self-administration in rodents, a clinicall-relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation or locomotion, as sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Further, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.
PMCID: PMC2844797  PMID: 20053911
dentate gyrus; hippocampus; subgranular zone; SGZ; irradiation; self-administration
18.  Internet Addictive Individuals Share Impulsivity and Executive Dysfunction with Alcohol-Dependent Patients 
Internet addiction disorder (IAD) should belong to a kind of behavioral addiction. Previous studies indicated that there are many similarities in the neurobiology of behavior and substance addictions. Up to date, although individuals with IAD have difficulty in suppressing their excessive online behaviors in real life, little is known about the patho-physiological and cognitive mechanisms responsible for IAD. Neuropsychological test studies have contributed significantly to our understanding of the effect of IAD on the cognitive function. The purpose of the present study was to examine whether Internet addictive individuals share impulsivity and executive dysfunction with alcohol-dependent individuals. Participants include 22 Internet addictive individuals, 22 patients with alcohol dependence (AD), and 22 normal controls (NC). All participants were measured with BIS-11, go/no-go task, Wisconsin Card Sorting Test, and Digit span task under the same experimental condition. Results showed that Barratt impulsiveness scale 11 scores, false alarm rate, the total response errors, perseverative errors, failure to maintain set of IAD and AD group were significantly higher than that of NC group, and hit rate, percentage of conceptual level responses, the number of categories completed, forwards scores, and backwards scores of IAD and AD group were significantly lower than that of NC group, however, no differences in above variables between IAD group and AD group were observed. These results revealed that the existence of impulsivity, deficiencies in executive function and working memory in an IAD and an AD sample, namely, Internet addictive individuals share impulsivity and executive dysfunction with alcohol-dependent patients.
PMCID: PMC4142341  PMID: 25202248
Internet addiction disorder; alcohol dependence; impulsivity; executive function; working memory
19.  Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study 
Gut  2003;52(6):861-867.
Background: There may be a weak association between total alcohol intake and colorectal cancer but the effect of different types of alcohol and effect on colon subsites have not been investigated satisfactorily.
Aims: To investigate the relationship between amount and type of alcohol and the risk of colon and rectal cancer.
Subjects: A population based cohort study with baseline assessment of weekly intake of beer, wine, and spirits, smoking habits, body mass index, educational level, and leisure time physical activity in Copenhagen, Denmark. The study included a random sample of 15 491 men and 13 641 women, aged 23–95 years. Incident cases of colorectal cancer were identified in the nationwide Danish Cancer Register.
Results: During a mean follow up of 14.7 years, we observed 411 colon cancers and 202 rectal cancers. We observed a dose-response relationship between alcohol and rectal cancer. Drinkers of more than 41 drinks a week had a relative risk of rectal cancer of 2.2 (95% confidence limits 1.0–4.6) compared with non-drinkers. Drinkers of more than 14 drinks of beer and spirits a week, but not wine, had a risk of 3.5 (1.8–6.9) of rectal cancer compared with non-drinkers, while those who drank the same amount of alcohol but including more than 30% of wine had a risk of 1.8 (1.0–3.2) of rectal cancer. No relation between alcohol and colon cancer was found when investigating the effects of total alcohol, beer, wine, and spirits, and percentage of wine of total alcohol intake.
Conclusion: Alcohol intake is associated with a significantly increased risk of rectal cancer but the risk seems to be reduced when wine is included in the alcohol intake.
PMCID: PMC1773681  PMID: 12740343
alcohol; colon cancer; rectal cancer; population based study
20.  Non-Coding RNAs Regulating Morphine Function: With Emphasis on the In vivo and In vitro Functions of miR-190 
Frontiers in Genetics  2012;3:113.
Non-coding RNAs (ncRNAs), especially microRNAs, are reported to be involved in a variety of biological processes, including several processes related to drug addiction. It has been suggested that the biological functions of opioids, one typical type of addictive drugs, are regulated by ncRNAs. In the current review, we examine a variety of mechanisms through which ncRNAs could regulate μ-opioid receptor (OPRM1) activities and thereby contribute to the development of opioid addiction. Using miR-23b as an example, we present the possible ways in which ncRNA-mediated regulation of OPRM1 expression could impact opioid addiction. Using miR-190 as an example, we demonstrate the critical roles played by ncRNAs in the signal cascade from receptor to systemic responses, including the possible modulation of adult neurogenesis and in vivo contextual memory. After discussing the possible targets of ncRNAs involved in the development of opioid addiction, we summarize the mechanisms underlying the interaction between ncRNAs and opioid addiction and present suggestions for further study.
PMCID: PMC3375446  PMID: 22715342
microRNA; miR-190; non-coding RNA; opioid addiction
21.  Cognitive Enhancement as a Treatment for Drug Addictions 
Neuropharmacology  2012;64(1):452-463.
Drug addiction continues to be an important public health problem, with an estimated 22.6 million current illicit drug users in the United States alone. For many addictions, including cocaine, methamphetamine, and marijuana addiction, there are no approved pharmacological treatments. Behavioral treatments are effective but effects vary widely across individuals. Treatments that are effective across multiple addictions are greatly needed, and accumulating evidence suggests that one such approach may be pharmacological or behavioral interventions that enhance executive inhibitory control in addicts. Current evidence indicates that most forms of chronic drug use may be associated with significant cognitive impairments, especially in attention, working memory, and response inhibition functions. In some studies, these impairments predict poor treatment retention and outcome. A number of cognitive enhancing agents, including galantamine, modafinil, atomoxetine, methylphenidate, and guanfacine, have shown promising findings in human studies. Specific behavioral interventions, including cognitive remediation, also show promise. However, whether improvement of selective cognitive functions reduces drug use behavior remains to be determined. Cognitive enhancement to improve treatment outcomes is a novel strategy worthy of future research, as are related questions such as whether these approaches may be broadly beneficial to most addicts or best reserved for substance users with specific demonstrated cognitive impairments.
PMCID: PMC3445733  PMID: 22735770
22.  Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories – indications for novel treatments of addiction* 
The European Journal of Neuroscience  2014;40(1):2163-2182.
This review discusses the evidence for the hypothesis that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental learning and memory mechanisms in the brain that underlie the seeking and taking of drugs. It is argued that these behaviours initially are goal-directed, but increasingly become elicited as stimulus–response habits by drug-associated conditioned stimuli that are established by Pavlovian conditioning. It is further argued that compulsive drug use emerges as the result of a loss of prefrontal cortical inhibitory control over drug seeking habits. Data are reviewed that indicate these transitions from use to abuse to addiction depend upon shifts from ventral to dorsal striatal control over behaviour, mediated in part by serial connectivity between the striatum and midbrain dopamine systems. Only some individuals lose control over their drug use, and the importance of behavioural impulsivity as a vulnerability trait predicting stimulant abuse and addiction in animals and humans, together with consideration of an emerging neuroendophenotype for addiction are discussed. Finally, the potential for developing treatments for addiction is considered in light of the neuropsychological advances that are reviewed, including the possibility of targeting drug memory reconsolidation and extinction to reduce Pavlovian influences on drug seeking as a means of promoting abstinence and preventing relapse.
PMCID: PMC4145664  PMID: 24935353
cocaine; compulsion; habits; reconsolidation; relapse; striatum
23.  Memory Extinction Entails the Inhibition of the Transcription Factor NF-κB 
PLoS ONE  2008;3(11):e3687.
In contextual memories, an association between a positive or negative reinforcement and the contextual cues where the reinforcement occurs is formed. The re-exposure to the context without reinforcement can lead to memory extinction or reconsolidation, depending on the number of events or duration of a single event of context re-exposure. Extinction involves the temporary waning of the previously acquired conditioned response. The molecular processes underlying extinction and the mechanisms which determine if memory will reconsolidate or extinguish after retrieval are not well characterized, particularly the role of transcription factors and gene expression. Here we studied the participation of a transcription factor, NF-κB, in memory extinction. In the crab context-signal memory, the activation of NF-κB plays a critical role in consolidation and reconsolidation, memory processes that are well characterized in this model. The administration of a NF-κB inhibitor, sulfasalazine prior to extinction session impeded spontaneous recovery. Moreover, reinstatement experiments showed that the original memory was not affected and that NF-κB inhibition by sulfasalazine impaired spontaneous recovery strengthening the ongoing memory extinction process. Interestingly, in animals with fully consolidated memory, a brief re-exposure to the training context induced neuronal NF-κB activation and reconsolidation, while prolonged re-exposure induced NF-κB inhibition and memory extinction. These data constitutes a novel insight into the molecular mechanisms involved in the switch between memory reconsolidation and extinction. Moreover, we propose the inhibition of NF-κB as the engaged mechanism underlying extinction, supporting a novel approach for the pharmacological enhancement of this memory process. The accurate description of the molecular mechanisms that support memory extinction is potentially useful for developing new strategies and drug candidates for therapeutic treatments of the maladaptive memory disorders such as post-traumatic stress, phobias, and drug addiction.
PMCID: PMC2577885  PMID: 18997870
24.  Cholinergic Functioning in Stimulant Addiction: Implications for Medications Development 
CNS drugs  2009;23(11):939-952.
Acetylcholine (ACh), the first neurotransmitter discovered, participates in many CNS functions including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic (nAChR) and muscarinic (mAChR) type cholinergic receptors. The goal of this review is to synthesize a growing literature that supports the potential role of ACh as a treatment target for stimulant addiction. ACh interacts with the dopaminergic reward system in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). In the VTA, both nAChR and mAChR stimulate the dopaminergic system. In the NAc, cholinergic interneurons integrate cortical and subcortical information related to reward. In the PFC, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic agonists in the development of stimulant addiction. Muscarinic agonists seem to have an inhibitory role depending on the subtype of mAChR. In human studies acetylcholine esterase (AChE) inhibitors, which increase synaptic ACh levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted.
PMCID: PMC2778856  PMID: 19845415
acetylcholine; dopamine; nicotinic; muscarinic; stimulant addiction; brain reward system
25.  Cellular, Molecular, and Genetic Substrates Underlying the Impact of Nicotine on Learning 
Neurobiology of learning and memory  2013;107:10.1016/j.nlm.2013.08.004.
Addiction is a chronic disorder marked by long-lasting maladaptive changes in behavior and in reward system function. However, the factors that contribute to the behavioral and biological changes that occur with addiction are complex and go beyond reward. Addiction involves changes in cognitive control and the development of disruptive drug-stimuli associations that can drive behavior. A reason for the strong influence drugs of abuse can exert on cognition may be the striking overlap between the neurobiological substrates of addiction and of learning and memory, especially areas involved in declarative memory. Declarative memories are critically involved in the formation of autobiographical memories, and the ability of drugs of abuse to alter these memories could be particularly detrimental. A key structure in this memory system is the hippocampus, which is critically involved in binding multimodal stimuli together to form complex long-term memories. While all drugs of abuse can alter hippocampal function, this review focuses on nicotine. Addiction to tobacco products is insidious, with the majority of smokers wanting to quit; yet the majority of those that attempt to quit fail. Nicotine addiction is associated with the presence of drug-context and drug-cue associations that trigger drug seeking behavior and altered cognition during periods of abstinence, which contributes to relapse. This suggests that understanding the effects of nicotine on learning and memory will advance understanding and potentially facilitate treating nicotine addiction. The following sections examine: 1) how the effects of nicotine on hippocampus-dependent learning change as nicotine administration transitions from acute to chronic and then to withdrawal from chronic treatment and the potential impact of these changes on addiction, 2) how nicotine usurps the cellular mechanisms of synaptic plasticity, 3) the physiological changes in the hippocampus that may contribute to nicotine withdrawal deficits in learning, and 4) the role of genetics and developmental stage (i.e., adolescence) in these effects.
PMCID: PMC3873373  PMID: 23973448
Acetylcholine; Hippocampus; Addiction; LTP; Cognition; Adolescence

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