Shijing Liu

Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared with non-drug-using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alterations of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections.

Relationship between attentional bias to cocaine-related stimuli and impulsivity in cocaine-dependent subjects

Background: Cocaine-dependent subjects show attentional bias to cocaine-related stimuli, increased impulsivity on questionnaires, and impaired inhibitory control (one component of impulsivity on behavioral tasks). However, the relationship between attentional bias, impulsivity, and inhibitory control in cocaine-dependent subjects is unknown. Objective: To investigate the relationship between attentional bias to cocaine-related stimuli, impulsivity, and inhibitory control in cocaine dependence. Methods: This study employed the cocaine Stroop task to measure attentional bias to cocaine-related stimuli, immediate memory task (IMT) to measure inhibitory control, and Barratt Impulsiveness Scale version 11 to measure impulsivity. Thirty-two controls and 37 cocaine-dependent subjects were recruited through newspaper advertisement. Results: Cocaine-dependent subjects had higher attentional bias to cocaine-related words, higher scores for Barratt Impulsiveness Scale, and higher commission error rate on the IMT than controls. The attentional bias was positively correlated with the commission error rate on the IMT in the cocaine-dependent subjects but not in control subjects. Conclusions: Cocaine-dependent subjects showed attentional bias to cocaine-related words, increased impulsivity, and poor inhibitory control compared with controls. The attentional bias was associated with inhibitory control in cocaine-dependent subjects but not in control subjects. Scientific Significance: Our findings suggest that cocaine-dependent subjects with poor inhibitory control may show higher attentional bias to cocaine-related words compared with controls and those with better inhibitory control.

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity’) that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.

Increased intra-individual reaction time variability in cocaine-dependent subjects: role of cocaine-related cues.

Neuroimaging data suggest that impaired performance on response inhibition and information processing tests in cocaine-dependent subjects is related to prefrontal and frontal cortical dysfunction and that dysfunction in these brain areas may underlie some aspects of cocaine addiction. In subjects with attention-deficit hyperactivity disorder and other psychiatric disorders, the Intra-Individual Reaction Time Variability (IIRTV) has been associated with frontal cortical dysfunction. In the present study, we evaluated IIRTV parameters in cocaine-dependent subjects vs. controls using a cocaine Stroop task. Fifty control and 123 cocaine-dependent subjects compiled from three studies completed a cocaine Stroop task. Standard deviation (SD) and coefficient of variation (CV) for reaction times (RT) were calculated for both trials with neutral and trials with cocaine-related words. The parameters mu, sigma, and tau were calculated using an ex-Gaussian analysis employed to characterize variability in RTs. The ex-Gaussian analysis divides the RTs into normal (mu, sigma) and exponential (tau) components. Using robust regression analysis, cocaine-dependent subjects showed greater SD, CV and Tau on trials with cocaine-related words compared to controls (p<0.05). However, in trials with neutral words, there was no evidence of group differences in any IIRTV parameters (p>0.05). The Wilcoxon matched-pairs signed-rank test showed that for cocaine-dependent subjects, both SD and tau were larger in trials with cocaine-related words than in trials with neutral words (p<0.05). The observation that only cocaine-related words increased IIRTV in cocaine-dependent subjects suggests that cocaine-related stimuli might disrupt information processing subserved by prefrontal and frontal cortical circuits.

The influence of dopamine β-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study.

Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy. Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine &bgr;-hydroxylase (D&bgr;H). Seventy-one cocaine-dependent patients who participated in a 12-week randomized double-blind placebo-controlled trial of levodopa/carbidopa were genotyped for the D&bgr;H gene (DBH) polymorphism rs1611115. Our results showed that for patients with the low D&bgr;H activity genotypes (CT/TT) who received levodopa, the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes (P=0.004). Individuals with the normal D&bgr;H activity genotype (CC) showed no differential response to levodopa. These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism.

Attentional Bias in Adults with Cannabis Use Disorders.

ABSTRACT There has been modest examination of attentional bias in individuals with cannabis use disorders. Clinical implications of this work are directly relevant to better informing extant evidence-based treatment for substance use disorders (e.g., relapse prevention) and/or developing novel interventions. The overarching aim of this investigation was to examine a novel attentional bias task in adults with cannabis use disorders. Participants were comprised of 25 adults (8 women: M age = 31, SD = 6.8; range = 22–45) with cannabis use disorders (n = 12) and controls (n = 13) without any current (past month) psychopathology. Relative to controls, adults with cannabis use disorders had greater attentional bias scores. These differences were present only at the 125-ms probe time, where the cannabis use disorders group showed greater attentional bias to cannabis cues than the control group (adjusted p = .001, cannabis use disorders mean = 59.9, control mean = −24.8, Cohens d-effect size for 125 ms = 1.03). The cannabis use disorders group also reported significantly greater perceived stress and post-task stress scores than the control group, but stress was not related to attentional bias. This study informs understanding of the influence of cannabis cues on visual detection and reaction time under different cue-target onset times, as attentional bias was most prevalent under time pressure to detect the probe.

Effects of escitalopram on attentional bias to cocaine-related stimuli and inhibitory control in cocaine-dependent subjects

Key characteristics of cocaine dependence include attentional bias to cocaine cues and impaired inhibitory control. Studies suggest that serotonin modulates both cocaine cue reactivity and inhibitory control. We investigated effects of the selective serotonin reuptake inhibitor escitalopram on cocaine cue reactivity and inhibitory processes in cocaine-dependent subjects. In a double-blind placebo-controlled design, cocaine-dependent subjects received placebo (n=12) or escitalopram (n=11; 10 mg on days 1–3, 20 mg on days 4–24 and 10 mg on days 25–28) orally, once daily for 4 weeks. The cocaine Stroop and immediate memory task (IMT) were administered at baseline, days 1, 4, 11, 18 and 25 after placebo or escitalopram initiation. There were no significant between-group differences in baseline performance on the cocaine Stroop task or the IMT. On day 1 (acute phase), escitalopram produced a significantly greater decrease from baseline than placebo in attentional bias measured by cocaine Stroop task 5 hours post-dose. No significant changes from baseline in attentional bias were observed on subsequent test days (chronic phase). Inhibitory control as measured by IMT commission error rate was not significantly different between two groups in either the acute or chronic phase. Consistent with preclinical data, serotonin-modulating drugs like escitalopram may have acute effects on cocaine cue reactivity in human cocaine users.

Serotonin transporter gene promoter polymorphism predicts relationship between years of cocaine use and impulsivity

Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Departments of Pediatrics, Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas and Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA