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1.  GABA Levels in The Dorsal Anterior Cingulate Cortex Associated with Difficulty Ignoring Smoking-Related Cues in Tobacco-Dependent Volunteers 
Neuropsychopharmacology  2013;38(6):1113-1120.
Substance abusers have difficulty ignoring drug-related cues, which is associated with relapse vulnerability. This ‘attentional bias' towards drug cues translates into an inability to ignore drug-related stimuli and may reflect deficits in the brain regions, such as the dorsal anterior cingulate cortex (dACC)—a key region in cognitive control and adaptive decision making. Quantifying relationships between attentional biases to drug cues and dACC neurochemistry could aid in identifying neurobiological mechanisms associated with increased relapse vulnerability precipitated by drug cues. As gamma-aminobutyric acid (GABA) deficits have been linked to impaired cognition and addictive disorders, we hypothesized that reduced GABA in the dACC would be associated with increased attentional biases towards smoking-related cues. We confirmed this hypothesis among nicotine-dependent tobacco smokers by combining an offline behavioral measure of attentional bias with magnetic resonance spectroscopy. Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal. Findings revealed a relationship between heightened reactivity to drug cues, and both decreasing dACC GABA and early withdrawal symptoms. Because reduced GABA function in frontal brain regions disrupt cognitive function, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore highly salient distractors such as tobacco-related stimuli and therefore might be more prone to cue-induced relapse. This newly discovered relationship between dACC GABA and attentional bias provides evidence for a neurochemical target, which may aid smoking cessation in highly cue-reactive individuals.
doi:10.1038/npp.2013.10
PMCID: PMC3629395  PMID: 23306182
addiction & substance abuse; attentional bias; dACC; GABA; imaging; clinical or preclinical; negative affect; neurochemistry; nicotine dependence; tobacco; GABA; dACC; negative affect; attentional bias; tobacco; nicotine dependence
2.  Natural Rewards, Neuroplasticity, and Non-Drug Addictions 
Neuropharmacology  2011;61(7):1109-1122.
There is a high degree of overlap between brain regions involved in processing natural rewards and drugs of abuse. “Non-drug” or “behavioral” addictions have become increasingly documented in the clinic, and pathologies include compulsive activities such as shopping, eating, exercising, sexual behavior, and gambling. Like drug addiction, non-drug addictions manifest in symptoms including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse. These alterations in behavior suggest that plasticity may be occurring in brain regions associated with drug addiction. In this review, I summarize data demonstrating that exposure to non-drug rewards can alter neural plasticity in regions of the brain that are affected by drugs of abuse. Research suggests that there are several similarities between neuroplasticity induced by natural and drug rewards and that, depending on the reward, repeated exposure to natural rewards might induce neuroplasticity that either promotes or counteracts addictive behavior.
doi:10.1016/j.neuropharm.2011.03.010
PMCID: PMC3139704  PMID: 21459101
novelty seeking; addiction; motivation; reinforcement; behavioral addiction; plasticity
3.  Corticotropin-releasing Factor in the Dorsal Raphe Nucleus: Linking Stress Coping and Addiction 
Brain research  2009;1314C:29.
Addiction and stress are linked at multiple levels. Drug abuse is often initiated as a maladaptive mechanism for coping with stress. It is maintained in part by negative reinforcement to prevent the aversive consequences of stress associated with abstinence. Finally, stress is a major factor leading to relapse in subjects in which drug seeking behavior has extinguished. These associations imply overlapping or converging neural circuits and substrates that underlie the processes of addiction and the expression of the stress response. Here we discuss the major brain serotonin (5-HT) system, the dorsal raphe nucleus (DRN)-5-HT system as a point of convergence that links these processes and how the stress-related neuropeptide, corticotropin-releasing factor (CRF) directs this by a bimodal regulation of DRN neuronal activity. The review begins by describing a structural basis for CRF regulation of the DRN-5-HT system. This is followed by a review of the effects of CRF and stress on DRN function based on electrophysiological and microdialysis studies. The concept that multiple CRF receptor subtypes in the DRN facilitate distinct coping behaviors is reviewed with recent evidence for a unique cellular mechanism by which stress history can determine the type of coping behavior. Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT-dopamine interactions in addiction.
doi:10.1016/j.brainres.2009.09.100
PMCID: PMC2819581  PMID: 19800322
serotonin; dorsal raphe nucleus; corticotropin-releasing factor; stress; receptor trafficking; drug abuse
4.  Impaired Prefrontal Cortical Function and Disrupted Adaptive Cognitive Control in Methamphetamine Abusers: An fMRI Study 
Biological psychiatry  2009;65(8):706-709.
Background
Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in chronic MA abuse.
Methods
In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event related fMRI design to examine trial to trial reaction time (RT) adjustments in 12 chronic MA abusers who met DSM-IV criteria for MA dependence and 16 non-substance abusing controls. A variant of the Stroop task was employed to contrast the groups on error rates, RT Stroop conflict effect and the level of trial-to-trial adjustments seen after incongruent trials.
Results
The MA abusers exhibited reduced RT adjustments along with reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. MA abusers did not differ from controls on accuracy rates or within-trial Stroop conflict effects.
Conclusions
The observed deficits in trial to trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. Such adjustments are critical to everyday functioning and deficits in modifying behavior based on prior events may reflect a key deficit that contributes to maladaptive drug seeking behavior.
doi:10.1016/j.biopsych.2008.11.026
PMCID: PMC2678684  PMID: 19136097
Methamphetamine; prefrontal; attention; fMRI; imaging
5.  An Evaluation of the Evidence that Methamphetamine Abuse Causes Cognitive Decline in Humans 
Neuropsychopharmacology  2012;38(2):259-274.
Methamphetamine (MA) is one of the most commonly abused illicit substances worldwide. Among other problems, abuse of the drug has been associated with reduced cognitive function across several domains. However, much of the literature has not attempted to differentiate cognitive difficulties caused by MA abuse from preexisting cognitive difficulties that are likely caused by other factors. Here, we address this question, evaluating evidence for a priori hypotheses pertaining to six lines of research: (a) animal studies; (b) cross-sectional human studies; (c) a twin study; (d) studies of changes in cognition with abstinence from MA; (e) studies of changes in brain structure and function with abstinence from MA; and (f) studies of the relationship between the severity of MA abuse and the extent of cognitive deficits observed. Overall the findings were mixed, with some support for a causal relationship between MA abuse and cognitive decline, and other findings suggesting that there is no relationship. The preponderance of the data, however, does support the possibility that MA abuse causes cognitive decline, of unknown duration, in at least some users of the drug. When averaged across individuals, this decline is likely to be mild in early-to-middle adulthood. However, moderator variables are likely to contribute to the presence and/or severity of cognitive decline exhibited by a given individual.
doi:10.1038/npp.2012.179
PMCID: PMC3527116  PMID: 22948978
methamphetamine; stimulant; cognition; review; cognitive; neuropsychology; Addiction & Substance Abuse; Animal models; cognitive; Learning & Memory; methamphetamine; Neuropharmacology; neuropsychology; review; stimulant
6.  Prefrontal Cortical Dysfunction in Abstinent Cocaine Abusers 
The anterior cingulate cortex (ACC) and lateral prefrontal (LPFC) cortex are brain regions important to executive cognitive functions (ECF). We determined ACC and LPFC function in 23-day abstinent cocaine abusers using positron emission tomography (PET H215O) during performance of a modified version of the Stroop Task. Cocaine abusers showed less activation than non-drug-using comparison subjects in the left ACC and the right LPFC and greater activation in the right ACC. Average amount of cocaine used per week was negatively correlated with activity in the rostral ACC and right LPFC. Disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction.
doi:10.1176/appi.neuropsych.16.4.456
PMCID: PMC2771441  PMID: 15616172
7.  Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling 
PLoS ONE  2007;2(11):e1187.
The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine “rush”. Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.
doi:10.1371/journal.pone.0001187
PMCID: PMC2063513  PMID: 18000554
8.  Behavioral and Neurological Foundations for the Moral and Legal Implications of Intoxication, Addictive Behaviors and Disinhibition 
Behavioral sciences & the law  2009;27(2):237-259.
Disinhibition and addictive behaviors are related and carry moral implications. Both typically involve diminished consideration of negative consequences, which may result in harm to oneself or others. Disinhibition may occur on state and trait levels, and addictive substances may elicit disinhibitory states, particularly when intoxication is reached. Data suggest that trait disinhibition and addictions may be conceptualized as involving misdirected motivation with underlying biological bases including genetic factors, alterations in neurotransmitter systems and differences in regional brain function. The influences of intoxication on the brain share similarities with cognitive impairments in individuals with chronic substance abuse and those with trait disinhibition related to frontal lobe injuries. These findings raise questions about volitional impairment and morality. Although impaired volition related to disinhibition and addictive behaviors has been studied from multiple perspectives, additional research is needed to further characterize mechanisms of impairment. Such findings may have important implications in multiple legal and psychiatric domains.
doi:10.1002/bsl.855
PMCID: PMC2748412  PMID: 19241397
addiction; alcohol; disinhibition; impulsivity; intoxication; morality
9.  Overlapping Cognitive Patterns in Schizophrenia and Methamphetamine Dependence 
Objective
To examine whether overlapping cognitive deficits exist in currently drug-abstinent chronic methamphetamine (MA) abusers and schizophrenia (SZ) patients.
Background
Both SZ and chronic MA abuse are associated with frontostriatal disruption as well as deficits in cognitive control such as selective attention. To identify overlapping cognitive profiles, we compared performance of the two groups on the Stroop attention task.
Method
Data were analyzed from 69 MA abusers who had been MA-abstinent for differing periods of time and from 23 SZ patients and 38 non-substance-abusing controls.
Results
The MA abusers in early abstinence displayed more Stroop interference than the SZ patients (p= 0.004), long-term abstinent MA abusers (p= 0.009), and controls (p = 0.002). In the MA abusers, the magnitude of Stroop interference correlated positively with longer drug use [p = 0.01] and negatively with longer drug abstinence [p= 0.04]. No correlations were found between psychotic symptoms and task performance.
Conclusions
On this task of attentional selection, only the MA abusers in early stages of abstinence showed performance deficits compared to controls. More research is needed to further elucidate overlapping patterns between MA abuse and SZ.
doi:10.1097/WNN.0b013e31823fc1d0
PMCID: PMC3269832  PMID: 22123586
schizophrenia; methamphetamine; selective attention; Stroop; cognition
10.  Nicotine and Hippocampus-Dependent Learning 
Molecular neurobiology  2006;34(2):93-107.
Addiction is a complex disorder because many factors contribute to the development and maintenance of addiction. One factor is learning. For example, drug–context associations that develop during drug use could facilitate drug craving upon re-exposure to contexts previously associated with drugs. Additionally, deficits in cognitive processes associated with withdrawal could precipitate relapse in attempts to ameliorate those deficits. Because addiction and learning involve common neural areas and cell signaling cascades, addiction-related changes in processes underlying plasticity may contribute to addiction. This article examines similarities between addiction and learning at the behavioral, neural, and cellular levels, with emphasis on the neural substrates underlying the effects of acute nicotine, chronic nicotine, and withdrawal from chronic nicotine on hippocampus-dependent contextual learning.
doi:10.1385/MN:34:2:93
PMCID: PMC2716133  PMID: 17220532
Learning; addiction; acetylcholine; nicotine; hippocampus; contextual fear conditioning; CREB; MAPK; withdrawal; plasticity
11.  Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex 
The American journal of psychiatry  2002;159(10):1642-1652.
Objective
Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction.
Method
An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction.
Results
The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses.
Conclusions
These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward.
PMCID: PMC1201373  PMID: 12359667
12.  Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction 
European journal of pharmacology  2010;639(1-3):47-58.
Glutamate plays a pivotal role in regulating drug self-administration and drug-seeking behavior, and the past decade has witnessed a substantial surge of interest in the role of Group I metabotropic glutamate receptors (mGlu1 and mGlu5 receptors) in mediating these behaviors. As will be reviewed here, Group I mGlu receptors are involved in normal and drug-induced synaptic plasticity, drug reward, reinforcement and relapse-like behaviors, and addiction-related cognitive processes such as maladaptive learning and memory, behavioral inflexibility, and extinction learning. Animal models of addiction have revealed that antagonists of Group I mGlu receptors, particularly the mGlu5 receptor, reduce self-administration of virtually all drugs of abuse. Since inhibitors of mGlu5 receptor function have now entered clinical trials for other medical conditions and appear to be well-tolerated, a key question that remains unanswered is - what changes in cognition are produced by these compounds that result in reduced drug intake and drug-seeking behavior? Finally, in contrast to mGlu5 receptor antagonists, recent studies have indicated that positive allosteric modulation of mGlu5 receptors actually enhances synaptic plasticity and improves various aspects of cognition, including spatial learning, behavioral flexibility, and extinction of drug-seeking behavior. Thus, while inhibition of Group I mGlu receptor function may reduce drug reward, reinforcement, and relapse-related behaviors, positive allosteric modulation of the mGlu5 receptor subtype may actually enhance cognition and potentially reverse some of the cognitive deficits associated with chronic drug use.
doi:10.1016/j.ejphar.2010.01.029
PMCID: PMC2891107  PMID: 20371237
drug addiction; rodent models; glutamate; metabotropic glutamate receptor; allosteric modulators; learning; memory; cognition; extinction
13.  Differences in Early Maladaptive Schemas between a Sample of Young Adult Female Substance Abusers and a Non-clinical Comparison Group 
Early maladaptive schemas, defined as cognitive and behavioural patterns of viewing oneself and the world that cause considerable distress, are increasingly being recognized as an important underlying correlate of mental health problems. Recent research has begun to examine early maladaptive schemas among individuals seeking treatment for substance abuse. Unfortunately, there is limited research on whether substance abusers score higher on early maladaptive schemas than non-clinical controls. Thus, the current study examined whether a sample of young adult female substance abuse treatment seekers (n = 180) scored higher than a non-clinical group of female college students (n = 284) on early maladaptive schemas. Results demonstrated that the substance abuse group scored higher than the non-clinical group on 16 of the 18 early maladaptive schemas. In addition, a number of differences in early maladaptive schemas were large in effect size. Implications of these findings for future research and substance abuse treatment programmes are discussed.
doi:10.1002/cpp.1803
PMCID: PMC3463747  PMID: 22615132
Early Maladaptive Schemas; Substance Use; Female; Clinical
14.  Dysregulation of D2-Mediated Dopamine Transmission in Monkeys after Chronic Escalating Methamphetamine Exposure 
The Journal of Neuroscience  2012;32(17):5843-5852.
Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability, and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.
doi:10.1523/JNEUROSCI.0029-12.2012
PMCID: PMC3353813  PMID: 22539846
Addiction; methamphetamine; dopamine; D2-like receptor; inhibitory control; feedback sensitivity
15.  Effects of cocaine rewards on neural representations of cognitive demand in nonhuman primates 
Psychopharmacology  2010;213(1):105-118.
Rationale
Investigations of the neural consequences of the effects of cocaine on cognition have centered on specific brain circuits including prefrontal cortex, medial temporal lobe and striatum and their roles in controlling drug dependent behavior and addiction. These regions are critical to many aspects of drug abuse; however recent investigations in addicted individuals have reported possible cognitive deficits that impact recovery and other therapeutic interventions.
Objectives
Therefore a direct assessment of the effects of cocaine as a reward for cognitive function provides a means of determining how brain systems involved such as prefrontal cortex are affected under normal vs. conditions of acute drug exposure as a precursor to the final impaired function in the addicted state.
Methods
Nonhuman primates (NHPs) were tested in a delayed-match-to-sample decision making task to determine effects of high vs. low cognitive load trials on single neuron activity and fluorodeoxyglucose-positron emission tomography (FDG-PET) determined metabolic activation of prefrontal cortex when juice vs. intravenous cocaine were employed as rewards for successful performance.
Results
Cognitive processing in prefrontal cortex was altered primarily on high load trials in which cocaine was randomly presented as the signaled and delivered reward on particular trials. The detrimental actions of cocaine rewards were also shown to persist and impair task performance on subsequent juice rewarded trials.
Conclusions
The findings indicate that one of the ways in which cocaine use may disrupt performance of a cognitive task is to alter neural processing in prefrontal cortex when involved in discriminating circumstances on the basis of low vs. high cognitive demand.
doi:10.1007/s00213-010-2017-2
PMCID: PMC3126099  PMID: 20865250
Prefrontal Cortex; Neural recording; PET Imaging; Cocaine rewards; Decision processes
16.  The detrimental effects of emotional process dysregulation on decision-making in substance dependence 
Substance dependence is complex and multifactorial, with many distinct pathways involved in both the development and subsequent maintenance of addictive behaviors. Various cognitive mechanisms have been implicated, including impulsivity, compulsivity, and impaired decision-making. These mechanisms are modulated by emotional processes, resulting in increased likelihood of initial drug use, sustained substance dependence, and increased relapse during periods of abstinence. Emotional traits, such as sensation-seeking, are risk factors for substance use, and chronic drug use can result in further emotional dysregulation via effects on reward, motivation, and stress systems. We will explore theories of hyper and hypo sensitivity of the brain reward systems that may underpin motivational abnormalities and anhedonia. Disturbances in these systems contribute to the biasing of emotional processing toward cues related to drug use at the expense of natural rewards, which serves to maintain addictive behavior, via enhanced drug craving. We will additionally focus on the sensitization of the brain stress systems that result in negative affect states that continue into protracted abstinence that is may lead to compulsive drug-taking. We will explore how these emotional dysregulations impact upon decision-making controlled by goal-directed and habitual action selections systems, and, in combination with a failure of prefrontal inhibitory control, mediate maladaptive decision-making observed in substance dependent individuals such that they continue drug use in spite of negative consequences. An understanding of the emotional impacts on cognition in substance dependent individuals may guide the development of more effective therapeutic interventions.
doi:10.3389/fnint.2012.00101
PMCID: PMC3491319  PMID: 23162443
addiction; emotion; cognition; reward; stress; decision-making
17.  Relationship between craving and personality in treatment-seeking women with substance-related disorders 
BMC Psychiatry  2003;3:1.
Background
Individual differences may impact susceptibility to addiction. The impact of personality features on drug craving, however, has not been studied, particularly in women.
Methods
Ninety-five treatment-seeking women with substance dependence, abstinent for at least 5 and no more than 21 days, were investigated regarding the correlation between personality factors and craving. Personality was assessed using the Temperament and Character Inventory (TCI), the NEO Personality Inventory Revised (NEO-PI-R), and the Barratt Impulsiveness Scale version 11 (BIS-11). Cravings were assessed through the Pennsylvania Craving Scale (PCS), and the Craving Questionnaire (CQ). Anxiety and depressive symptomatology were also recorded.
Results
Craving scores were positively correlated with depression and negatively correlated with number of days abstinent from substance use. Also, craving scores were positively associated with the novelty-seeking factor from the TCI and the total score on the BIS-11, and negatively associated with the conscientiousness and agreeableness facets of the NEO-PI-R.
Conclusion
Findings suggest that personality features, particularly impulsiveness, can be important predictors of craving in women, which has important implications for treatment planning.
doi:10.1186/1471-244X-3-1
PMCID: PMC140309  PMID: 12525264
18.  The Mean and the Individual: Integrating Variable-Centered and Person-Centered Analyses of Cognitive Recovery in Patients with Substance Use Disorders 
Neuropsychological and cognitive deficits are observed in the majority of persons with alcohol and drug use disorders and may interfere with treatment processes and outcomes. Although, on average, the brain and cognition improve with abstinence or markedly reduced substance use, better understanding of the heterogeneity in the time-course and extent of cognitive recovery at the individual level is useful to promote bench-to-bedside translation and inform clinical decision making. This study integrated a variable-centered and a person-centered approach to characterize diversity in cognitive recovery in 197 patients in treatment for a substance use disorder. We assessed executive function, verbal ability, memory, and complex information processing speed at treatment entry, and then 6, 26, and 52 weeks later. Structural equation modeling was used to define underlying ability constructs and determine the mean level of cognitive changes in the sample while minimizing measurement error and practice effects on specific tests. Individual-level empirical growth plots of latent factor scores were used to explore prototypical trajectories of cognitive change. At the level of the mean, small to medium effect size gains in cognitive abilities were observed over 1 year. At the level of the individual, the mean trajectory of change was also the modal individual recovery trajectory shown by about half the sample. Other prototypical cognitive change trajectories observed in all four cognitive domains included Delayed Gain, Loss of Gain, and Continuous Gain. Together these trajectories encompassed between 86 and 94% of individual growth plots across the four latent abilities. Further research is needed to replicate and predict trajectory membership. Replication of the present findings would have useful implications for targeted treatment planning and the new cognitive interventions being developed to enhance treatment outcomes.
doi:10.3389/fpsyt.2013.00177
PMCID: PMC3870950  PMID: 24399976
cognitive recovery; neuropsychological impairment; longitudinal; person-centered; variable-centered; treatment; substance use disorders; alcohol use disorders
19.  Neurobiology of the incubation of drug craving 
Trends in neurosciences  2011;34(8):411-420.
It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the last decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine, and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering our understanding of brain mechanisms and circuits that underlie drug craving in human addicts.
doi:10.1016/j.tins.2011.06.001
PMCID: PMC3152666  PMID: 21764143
20.  The Role of Guanfacine as a Therapeutic Agent to Address Stress-related Pathophysiology in Cocaine Dependent Individuals 
The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence.
doi:10.1016/B978-0-12-420118-7.00006-8
PMCID: PMC4017947  PMID: 24484979
21.  The Obsessive Compulsive Cocaine Use Scale: Development and initial validation of a self-rated instrument for the quantification of thoughts about cocaine use 
Drug and alcohol dependence  2011;120(1-3):250-254.
BACKGROUND
Craving is a hallmark of addiction and characterized by obsessive thoughts about, and compulsive urges to use, a substance. While craving is frequently thought of as primarily being a feature of acute withdrawal, there is evidence to suggest that it increases in strength over extended periods of abstinence. While several measures are available to assess acute craving states, there remains a lack of clinical measures appropriate for capturing the enduring cognitive aspects of urges to use drugs. The present study was designed to develop and validate a measure of obsessive-compulsive thoughts in cocaine-dependent individuals.
METHODS
The proposed 14-item Obsessive Compulsive Cocaine Use Scale (OCCUS) was administered to 107 individuals; 55 participants meeting diagnostic criteria for cocaine dependence and 52 recreational users of cocaine. In addition to the OCCUS, participants also completed the Drug Abuse Screening Test, Cocaine Craving Questionnaire-Now, and Social Desirability Scale of the California Personality Inventory.
RESULTS
Results of confirmatory factor analysis indicated that the OCCUS fit the two-factor structure of the Obsessive Compulsive Drinking Scale on which it was based, independently assessing the “obsessive” and “compulsive” aspects of cocaine dependence. The OCCUS demonstrated good internal consistency reliability and convergent, discriminant, and criterion validity.
CONCLUSION
The proposed measure is a promising step towards the successful capture of the long-term cognitive features of craving for cocaine via self-report, and should represent a useful tool for clinical and research use.
doi:10.1016/j.drugalcdep.2011.07.024
PMCID: PMC3245789  PMID: 21890282
cocaine dependence; obsessive; compulsive; craving; substance abuse; psychometric properties
22.  Effects of galanin on monoaminergic systems and HPA axis: potential mechanisms underlying the effects of galanin on addiction- and stress-related behaviors 
Brain research  2009;1314C:206.
Like a number of neuropeptides, galanin can alter neural activity in brain areas that are important for both stress-related behaviors and responses to drugs of abuse. Accordingly, drugs that target galanin receptors can alter behavioral responses to drugs of abuse and can modulate stress-related behaviors. Stress and drug-related behaviors are interrelated: stress can promote drug-seeking, and the behavioral signs of drug withdrawal result from increased activity in brain circuits involved in the stress response. We review here what is known about the ability of galanin and galanin receptors to alter neuronal activity, and we discuss potential mechanisms that may underlie the effects of galanin on behaviors involved in responses to stress and addictive drugs. Understanding the mechanisms underlying galanin's effects on neuronal function in brain regions related to stress and addiction may be useful in developing novel therapeutics for the treatment of stress- and addiction-related disorders.
doi:10.1016/j.brainres.2009.08.033
PMCID: PMC2819596  PMID: 19699187
galanin; drug abuse; opiates; psychostimulants; addiction; stress; locus coeruleus; mesolimbic dopamine system; HPA axis; dorsal raphe; opiate withdrawal
23.  Dynorphin and the Pathophysiology of Drug Addiction 
Pharmacology & therapeutics  2007;116(2):306-321.
Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/κ-opioid receptor system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/κ-opioid receptor system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.
doi:10.1016/j.pharmthera.2007.06.011
PMCID: PMC2939016  PMID: 17868902
dynorphin; kappa opioid receptor; glutamate; dopamine; drug and alcohol addiction
24.  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.
doi:10.1016/j.nlm.2011.02.014
PMCID: PMC3138832  PMID: 21376820
addiction; extinction; reconsolidation; cue; reinstatement; memory; neuroadaptation
25.  Adaptive plasticity of NMDA-receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction 
It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty-seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, “fix” the addictive behavior in the adolescent and young adult brain.
doi:10.1016/j.pbb.2007.01.016
PMCID: PMC2662130  PMID: 17291572
NMDA receptors; dendritic spines; experience-dependent plasticity; adolescence; ethanol

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