Neurometabolic profile of the amygdala in smokers assessed with 1H-magnetic resonance spectroscopy.

Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored. A novel non-water-suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (≥15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1-3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t-tests or Mann-Whitney-U tests. Smoking state differences were investigated by repeated-measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations. Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack-years and smoking duration. In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction.

Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density.

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

Accumbal-thalamic connectivity and associated glutamate alterations in human cocaine craving: A state-dependent rs-fMRI and 1H-MRS study.

Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm3) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.

Disentangling craving- and valence-related brain responses to smoking cues in individuals with nicotine use disorder.

Tobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behaviour is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex and ventral striatum. However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-related brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments.

Neurometabolic alterations in the nucleus accumbens of smokers assessed with 1 H magnetic resonance spectroscopy: The role of glutamate and neuroinflammation.

Tobacco use is one of the leading causes of premature death and morbidity worldwide. For smokers trying to quit, relapse rates are high, even after prolonged periods of abstinence. Recent findings in animal models highlight the role of alterations in glutamatergic projections from the prefrontal cortex onto the nucleus accumbens (NAc) in relapse vulnerability. Moreover, inflammatory responses in the NAc have been reported during withdrawal. A novel proton magnetic resonance spectroscopy (1 H-MRS) protocol was applied in humans to measure molar concentrations for glutamate, its sum with glutamine (Glx), and myoinositol plus glycine (mI + Gly) in the NAc (19 smokers, 20 matched controls). Smokers were measured at baseline and during withdrawal and satiation. No difference between groups or smoking states was found for glutamate or Glx, but, in smokers, stronger craving and more severe nicotine dependence were associated with lower baseline glutamate and Glx levels, respectively. Interestingly, mI + Gly concentrations were higher during withdrawal than baseline and correlated negatively with nicotine dependence severity and pack years of smoking. The lack of glutamatergic changes between groups and smoking states may imply that glutamate homeostasis is not significantly altered in smokers or that changes are too small for detection by 1 H-MRS. Moreover, the observed increase in mI + Gly may imply that neuroinflammatory processes occur in the NAc during nicotine withdrawal. These findings shed light on neurobiological relapse mechanisms in smokers and may provide the opportunity to develop more effective treatment options targeting the glutamate and neuroinflammation system.

Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction.

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behavior. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared with healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared with baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on 2 days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalized medicine approach in addiction.

Dextromethorphan Abuse Among Opioid-Dependent Patients.

BACKGROUND: Among opioid-dependent patients on maintenance therapy, concomitant drug abuse is a serious problem. Dextromethorphan, an over-the-counter antitussive agent that can be purchased without prescription, is a drug with a high potential for misuse, especially when consumed in high doses.The objective of this study was to investigate possible abuse of dextromethorphan among substituted opioid-dependent patients and comparison of subjective and objective findings.Due to its ability to increase serotonin levels, opioid-dependent patients may be particularly susceptible to dextromethorphan misuse. Dextromethorphan misuse may have side effects, including psychiatric symptoms and serotonin syndrome, and may induce assault, suicide, or homicide. METHODS: A total of 104 opioid-dependent patients in maintenance treatment were included in this cross-sectional study conducted in the outpatient department of the Psychiatric Hospital, University of Zurich. Study participants were divided into 2 groups based on laboratory results: dextromethorphan abusers (n = 12) and nonabusers (n = 92). The objective use and concentrations of dextromethorphan was detected using 3-month hair toxicology analysis.Statistical analysis was performed by using χ test, Student t test, Mann-Whitney U test, and Barnard exact test. RESULTS: Dextromethorphan was abused by 12 (11.5%) patients, 11 (91.7%) of whom did not report concomitant abuse of dextromethorphan but were identified through hair analysis. In general, there were significant differences among patients abusing dextromethorphan compared with nondextromethorphan consumers in terms of trauma due to sexual maltreatment/violence, multiple traumas, or harmful use of hallucinogenic drugs. CONCLUSIONS: Further studies are necessary to examine dextromethorphan and its impact on patients with psychiatric comorbidities and psychiatric medication. According to literature, there is a significant drug interaction risk due to the impact of dextromethorphan misuse on serotonin syndrome and psychiatric symptoms.1-3 We recommend active inquiry into and testing for concomitant drug abuse among substituted opioid-dependent patients to reduce the risk of drug interactions and side effects in this especially vulnerable group of patients.

Social and Non-Social Cognitive Enhancement in Cocaine Users-A Closer Look on Enhancement Motives for Cocaine Consumption.

BACKGROUND: Cognitive disturbances of chronic cocaine users (CU) have been repeatedly investigated. However, it is yet unknown how CU using cocaine for cognitive or social enhancement differ from stimulant-naïve controls and CU that do not have these motives. More precisely, we assumed that CU with an enhancement motive self-medicate deficits in specific cognitive abilities, i.e., they use cocaine to enhance their performance in either social (social motive) or non-social cognitive situations (cognitive motive). METHODS: Forty-two CU were categorized according to their motives for cocaine consumption into social and non-social motive groups as well as cognitive and non-cognitive motive groups, respectively. Subsequently, CU motive groups were compared to 48 stimulant-naïve controls in their social and non-social cognitive functioning applying a comprehensive neuropsychological test battery. RESULTS: The social motive group showed deficits in cognitive empathy compared to controls (Cohen's d = 0.65) and the non-social motive group (d = 0.60). No mentionable effects were found for emotional empathy and Theory-of-Mind. Cognitive and non-cognitive motive groups both showed general cognitive deficits but with different patterns of impairments compared to controls: the cognitive motive group had deficits mainly in working memory (d = 0.84) and declarative memory (d = 0.60), whereas the non-cognitive motive group also had deficits in working memory (d = 0.61) but additionally in executive functions (d = 0.67). For the domains declarative memory and executive functions, the respective other CU group displayed intermediate performance. CONCLUSIONS: This study demonstrates that cocaine is partially instrumentalized by CU with specific enhancement motives to counteract related cognitive impairments.

Concomitant Heroin and Cocaine Use among Opioid-Dependent Patients during Methadone, Buprenorphine or Morphine Opioid Agonist Therapy.

BACKGROUND: Among all the treatment methods developed so far, opioid agonist treatment (OAT) is the most effective therapy for opioid dependence. While methadone (MTD) is the most commonly used, fewer data are available on alternative opioid agonist. The aim of this study was to assess the efficacy of buprenorphine (BUP) and slow-released morphine compared to MTD with regard to the reduction of concomitant heroin and cocaine use. METHODS: This cross-sectional study included 105 patients receiving MTD, BUP, or slow-release morphine as opioid agonist therapy at the Psychiatric Hospital of Zurich. Illicit drug use was assessed using a retrospective 3-month hair toxicology analysis to quantify concentrations of heroin degradation products and metabolites, as well as cocaine and cocaine metabolites. We have also collected self-reports, but in the data of the study, only the results of the hair analysis were considered. RESULTS: BUP-treated patients showed lower rates of illicit opiate consumption in comparison to the group treated with MTD or slow-released morphine (p < 0.05). The proportion of heroin-positive hair samples associated with slow-release morphine treatment was similar to the proportion associated with MTD treatment. Neither the MTD vs. slow-released morphine groups nor the BUP vs. MTD groups showed significant differences in the number of patients consuming cocaine although patients in the BUP group had significantly lower concentrations of cocaine in hair testing compared to the patients in the MTD group. Prevalence of cocaine consumption was also significantly lower in the BUP group compared to patients in the slow-release morphine group (p < 0.05). CONCLUSION: This study suggests that BUP OAT is associated with reduced additional opiate co-use.

Improvement of Emotional Empathy and Cluster B Personality Disorder Symptoms Associated With Decreased Cocaine Use Severity.

Aims: Chronic cocaine users display impaired social cognitive abilities, reduced prosocial behavior, and pronounced cluster B personality disorder (PD) symptoms all contributing to their social dysfunctions in daily life. These social dysfunctions have been proposed as a major factor for maintenance and relapse of stimulant use disorders in general. However, little is known about the reversibility of social cognitive deficits and socially problematic personality facets when stimulant use is reduced or ceased. Therefore, we examined the relation between changing intensity of cocaine use and the development of sociocognitive functioning and cluster B PD symptomatology over the course of 1 year. Methods: Social cognition, social decision-making, and cluster B PD symptoms were assessed in 38 cocaine users (19 with increased and 19 with decreased use) and 48 stimulant-naive healthy controls at baseline and at 1-year follow-up. Cocaine use severity was objectively determined by quantitative 6-month hair analyses. The categorization of the two cocaine user groups was based on a combination of absolute (± 0.5 ng/mg) and relative (± 10%) changes in the cocaine hair concentration between baseline and the 1-year follow-up. Social cognition was assessed using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). A combined Distribution/Dictator Game was applied for assessing social decision-making. Cluster B PD symptoms were measured by a Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) PD questionnaire according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Results: Increased cocaine use was linked to worsened empathy, while decreased cocaine use went along with improved emotional empathy. Moreover, whereas decreased cocaine use was associated with reduced severity of self-reported cluster B PD symptoms, these symptoms remained largely stable in increasers. In contrast to a significant reduction of prosocial behavior at baseline in the combined cocaine user group, specifically decreasers were not statistically distinguishable from controls at the follow-up. Conclusions: Sociocognitive deficits and cluster B PD symptoms of chronic cocaine users are adaptable over time as they covary with the increase or decrease in cocaine use. Hence, abstinence orientation and training of social cognition and interaction might improve social functioning, and should therefore be important therapeutic elements in cocaine addiction treatment.

Longitudinal changes in cocaine intake and cognition are linked to cortical thickness adaptations in cocaine users.

BACKGROUND: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake. METHODS: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes. RESULTS: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period. CONCLUSIONS: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible.

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use.

Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.

Cognitive and neuroanatomical impairments associated with chronic exposure to levamisole-contaminated cocaine.

Currently, levamisole is the most common cocaine adulterant worldwide and it is known to induce a variety of adverse side effects. Animal studies and human case reports suggest potential neurotoxicity of the compound but neither neuroanatomical nor cognitive effects of levamisole have been systematically investigated in cocaine users so far. We examined cognitive performance and cortical structural differences between chronic cocaine users with low and high recent exposure to levamisole objectively determined by quantitative toxicological hair analyses. In Study 1, we compared 26 chronic cocaine users with low levamisole exposure (lowLevCU), 49 matched cocaine users with high levamisole exposure (highLevCU), and 78 matched stimulant-naive controls regarding cognitive functioning employing a comprehensive neuropsychological test battery. In Study 2, we investigated cortical thickness by use of T1-weighted MRI in a subgroup of 12 lowLevCU, 17 highLevCU, and 38 stimulant-naive controls. In Study 1, both cocaine user groups showed significant impairments in the cognitive domains of attention and working memory as well as in the global cognitive index. However, highLevCU showed significantly worse executive functions compared to lowLevCU although both groups did not differ in severity of cocaine consumption and other clinical dimensions. Study 2 revealed that highLevCU, displayed reduced cortical thickness specifically in the middle frontal gyrus compared to both controls and lowLevCU. Our results suggest that levamisole exposure during the last months in cocaine users is associated with increased executive function impairments and pronounced thinning of the lateral prefrontal cortex. Consequently, prevention and drug policy-making should aim to reduce levamisole contamination of street cocaine.

Socio-cognitive functioning in stimulant polysubstance users.

BACKGROUND: Using more than one psychotropic substance is accompanied by increased risks for psychiatric and physical disorders. Accordingly, deficits in basal cognitive functions have been consistently associated with polysubstance use (PSU), whereas little is known about potential impairments in more complex socio-cognitive skills, which are relevant for daily-life functioning. Therefore, we investigated the effects of toxicological validated stimulant PSU on social cognition under consideration of potential cumulative effects. METHODS: We compared socio-cognitive performances of 47 individuals with stimulant PSU with 59 matched stimulant-naïve controls using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). Additionally, social network size was assessed by the Social Network Questionnaire (SNQ). Hair and urine testing was employed to categorize three PSU subgroups (3, 4, and ≥5 substances used) and to ensure drug abstinence in controls. RESULTS: Individuals with stimulant PSU showed lower emotional empathy (MET) and a smaller social network (SNQ) compared to controls (both with linear trends for increasing number of used substances: p < .05). In contrast, cognitive empathy (MET and MASC) was largely unaffected by PSU. Additional linear regression analyses within PSU individuals revealed number of used substances as the best predictor for inferior performance in emotional empathy (p < .01), while severity of the use of single substances or substance-classes did not show a significant impact. CONCLUSION: These findings demonstrate cumulative adverse effects of stimulant PSU on an important facet of socio-cognitive functioning. Therefore, emotional empathy deficits should be targeted in future interventions and rehabilitations for individuals with PSU.

Stable self-serving personality traits in recreational and dependent cocaine users.

Chronic cocaine use has been associated with impairments in social cognition, self-serving and antisocial behavior, and socially relevant personality disorders (PD). Despite the apparent relationship between Machiavellianism and stimulant use, no study has explicitly examined this personality concept in cocaine users so far. In the frame of the longitudinal Zurich Cocaine Cognition Study, the Machiavellianism Questionnaire (MACH-IV) was assessed in 68 recreational and 30 dependent cocaine users as well as in 68 psychostimulant-naïve controls at baseline. Additionally, three closely related personality dimensions from the Temperament and Character Inventory (TCI)-cooperativeness, (social) reward dependence, and self-directedness-and the screening questionnaire of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) were acquired. At the one-year follow-up, 57 cocaine users and 48 controls were reassessed with the MACH-IV. Finally, MACH-IV scores were correlated with measures of social cognition and interaction (cognitive/emotional empathy, Theory-of-Mind, prosocial behavior) and with SCID-II PD scores assessed at baseline. Both recreational and dependent cocaine users showed significantly higher Machiavellianism than controls, while dependent cocaine users additionally displayed significantly lower levels of TCI cooperativeness and self-directedness. During the one-year interval, MACH-IV scores showed high test-retest reliability and also the significant gap between cocaine users and controls remained. Moreover, in cocaine users, higher Machiavellianism correlated significantly with lower levels of cooperativeness and self-directedness, with less prosocial behavior, and with higher cluster B PD scores. However, Machiavellianism was not correlated with measures of cocaine use severity (r<-.15). Both recreational and dependent cocaine users display pronounced and stable Machiavellian personality traits. The lack of correlations with severity of cocaine use and its temporal stability indicates that a Machiavellian personality trait might represent a predisposition for cocaine use that potentially serves as a predictor for stimulant addiction.

α2A -Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users.

Cocaine users characteristically display preferences for smaller immediate rewards over larger delayed rewards, and this delay discounting (DD) has been proposed as an endophenotype of cocaine addiction. Recent evidence suggests that the norepinephrine system and more specifically the α2A -adrenergic receptor (ADRA2A) are impacted by chronic cocaine use while also being potentially involved in the neural mechanisms underlying DD. Hence, we investigated the effects of ADRA2A polymorphisms and ADRA2A mRNA expression levels on DD of cocaine users and stimulant-naïve controls. Two hundred and twenty-three participants (129 cocaine users and 94 stimulant-naïve healthy controls) completed a computerized DD paradigm and were genotyped for three single nucleotide polymorphisms (SNPs; rs1800544, rs521674 and rs602618) in the ADRA2A gene, while their peripheral ADRA2A mRNA expression was quantified in whole blood samples. The three SNPs were in near-perfect linkage disequilibrium. Accordingly, significant group*genotype interactions were found for all three ADRA2A variants revealing steeper DD in cocaine users (but not in controls) carrying the G-allele of SNP rs1800544, the T-allele of rs521674 and the C-allele of rs602618. Similarly, high ADRA2A mRNA expression levels were significantly associated with a reduced tendency to choose smaller more immediate rewards (over larger delayed rewards) in cocaine users but not in controls. As the relationship between DD and cocaine use was moderated by ADRA2A SNPs and by peripheral ADRA2A gene expression, we propose that the norepinephrine system is involved in DD deficits observed in cocaine using individuals. Consequently, pharmacological compounds targeting ADRA2As might be considered for the symptom-specific treatment of delay aversion in stimulant addiction.

Risky Decisions in a Lottery Task Are Associated with an Increase of Cocaine Use.

Cocaine use disorder is associated with maladaptive decision-making behavior, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk-taking behavior, 31 chronic cocaine users and 26 stimulant-naïve healthy controls who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT) with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of 1 year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder.

Cognitive and emotional impairments in adults with attention-deficit/hyperactivity disorder and cocaine use.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an important modulator of cognitive and social functioning in cocaine addiction but it is unclear whether ADHD symptoms and cocaine use display mutually aggravating interaction effects on cognition, social functioning, and depressive symptoms. Therefore, we investigated the interaction of cocaine use and adult ADHD on social and non-social cognition and depressive symptoms. METHODS: Twenty-four cocaine users with (CU+ADHD) and 30 without ADHD (CU-ADHD), 29 cocaine-naïve ADHD patients, and 40 cocaine-naïve healthy controls underwent comprehensive neuropsychological testing including assessment of social cognition (cognitive/emotional empathy and Theory-of-Mind). Additionally, depressive symptoms were measured with the Beck Depression Inventory. RESULTS: The effect size of global cognitive impairment was largest in CU+ADHD (d=1.22 vs. controls) followed by CU-ADHD (d=0.74), and cocaine-naïve ADHD patients (d=0.33). A similar pattern appeared regarding depressive symptoms (CU+ADHD: d=1.47; CU-ADHD: d=0.49, ADHD: d=0.34). In the measures of Theory-of-Mind (CU+ADHD: d=0.76; CU-ADHD: d=0.06, ADHD: d=0.01) and cognitive empathy (CU+ADHD: d=0.80; CU-ADHD: d=0.39, ADHD: d=-0.11) only CU+ADHD showed moderate to large impairments. Moreover, two-way analyses of covariance revealed a significant interaction effect of the factors ADHD and cocaine use on depressive symptoms (p<0.05) and Theory-of-Mind (p<0.05) but not on global cognitive performance (p=0.64). CONCLUSIONS: When occurring together, cognitive impairments associated with both ADHD and cocaine use are largely additive, whereas both factors seem to mutually potentiate one another with respect to mood and mental perspective-taking disturbances. Given the high comorbidity between ADHD and cocaine use, longitudinal studies are needed to investigate the origin of these potentiated impairments.

Glutamatergic and neurometabolic alterations in chronic cocaine users measured with (1) H-magnetic resonance spectroscopy.

Cocaine addiction is a chronically relapsing disorder that is associated with harmful consequences. Relapses occur frequently and effective pharmacotherapies are currently sparse. Preclinical studies suggest that altered glutamatergic signaling is crucial for the maintenance of cocaine self-administration. However, the translational validity of these models is currently unknown. Therefore, we investigated potential differences of glutamate, glutamine and further metabolite levels in the pregenual anterior cingulate cortex (pgACC) and the right dorsolateral prefrontal cortex (rDLPFC) of chronic cocaine users and controls using the PRior knOwledge FITting 2.0 tool in combination with two-dimensional J-resolved single-voxel (1) H-magnetic resonance spectroscopy at 3T and voxel tissue composition and relaxation correction. Glutamate and glutamine levels did not differ between cocaine users and controls, but higher weekly cocaine use and higher cocaine hair concentrations were associated with lower glutamine/creatine ratios in the pgACC. Interestingly, cocaine users exhibited higher glucose/total creatine ratios than controls in the pgACC and higher choline/creatine ratios in the pgACC and rDLPFC. These results imply that cocaine use is associated with altered cortical glucose metabolism and membrane turnover. Finally, cocaine use over the past 6 months appears to decrease cortical glutamine levels indicating changes in glutamate cycling.

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users.

Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.