Individual Differences in Attentional Bias Associated with Cocaine Dependence Are Related to Varying Engagement of Neural Processing Networks

Cocaine and other drug dependencies are associated with significant attentional bias for drug use stimuli that represents a candidate cognitive marker of drug dependence and treatment outcomes. We explored, using fMRI, the role of discrete neural processing networks in the representation of individual differences in the drug attentional bias effect associated with cocaine dependence (AB-coc) using a word counting Stroop task with personalized cocaine use stimuli (cocStroop). The cocStroop behavioral and neural responses were further compared with those associated with a negative emotional word Stroop task (eStroop) and a neutral word counting Stroop task (cStroop). Brain–behavior correlations were explored using both network-level correlation analysis following independent component analysis (ICA) and voxel-level, brain-wide univariate correlation analysis. Variation in the attentional bias effect for cocaine use stimuli among cocaine-dependent men and women was related to the recruitment of two separate neural processing networks related to stimulus attention and salience attribution (inferior frontal–parietal–ventral insula), and the processing of the negative affective properties of cocaine stimuli (frontal–temporal–cingulate). Recruitment of a sensory–motor–dorsal insula network was negatively correlated with AB-coc and suggested a regulatory role related to the sensorimotor processing of cocaine stimuli. The attentional bias effect for cocaine stimuli and for negative affective word stimuli were significantly correlated across individuals, and both were correlated with the activity of the frontal–temporal–cingulate network. Functional connectivity for a single prefrontal–striatal–occipital network correlated with variation in general cognitive control (cStroop) that was unrelated to behavioral or neural network correlates of cocStroop- or eStroop-related attentional bias. A brain-wide mass univariate analysis demonstrated the significant correlation of individual attentional bias effect for cocaine stimuli with distributed activations in the frontal, occipitotemporal, parietal, cingulate, and premotor cortex. These findings support the involvement of multiple processes and brain networks in mediating individual differences in risk for relapse associated with drug dependence.     

Neural Correlates of Reward-Based Spatial Learning in Persons with Cocaine Dependence

Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus-response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory.     

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-HT_2C receptor (5-HT_2CR) 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-HT_2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT_2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT_2CR 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.     

Disruption of dopamine D1 receptor phosphorylation at serine 421 attenuates cocaine-induced behaviors in mice

Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.     

Citicoline in addictive disorders: a review of the literature

Background: Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders such as stroke and dementia. Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of neuronal membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse. Objectives: To review the literature on citicoline’s use in addictive disorders. Methods: Using PubMed we conducted a narrative review of the clinical literature on citicoline related to addictive disorders from the years 1900–2013 using the following keywords: citicoline, CDP-choline, addiction, cocaine, alcohol, substance abuse, and substance dependence. Out of approximately 900 first hits, nine clinical studies have been included in this review. Results: Most addiction research investigated citicoline for cocaine use. The findings suggest that it is safe and well tolerated. Furthermore, citicoline appears to decrease craving and is associated with a reduction in cocaine use, at least at high doses in patients with both bipolar disorder and cocaine dependence. Limited data suggest citicoline may also hold promise for alcohol and cannabis dependence and in reducing food consumption. Conclusions: Currently, there is limited research on the efficacy of citicoline for addictive disorders, but the available literature suggests promising results. Future research should employ larger sample sizes, increased dosing, and more complex study designs.     

Stochastic dynamic causal modeling of working memory connections in cocaine dependence

Although reduced working memory brain activation has been reported in several brain regions of cocaine‐dependent subjects compared with controls, very little is known about whether there is altered connectivity of working memory pathways in cocaine dependence. This study addresses this issue by using functional magnetic resonance imaging‐based stochastic dynamic causal modeling (DCM) analysis to study the effective connectivity of 19 cocaine‐dependent subjects and 14 healthy controls while performing a working memory task. Stochastic DCM is an advanced method that has recently been implemented in SPM8 that can obtain improved estimates, relative to deterministic DCM, of hidden neuronal causes before convolution with the hemodynamic response. Thus, stochastic DCM may be less influenced by the confounding effects of variations in blood oxygen level‐dependent response caused by disease or drugs. Based on the significant regional activation common to both groups and consistent with previous working memory activation studies, seven regions of interest were chosen as nodes for DCM analyses. Bayesian family level inference, Bayesian model selection analyses, and Bayesian model averaging (BMA) were conducted. BMA showed that the cocaine‐dependent subjects had large differences compared with the control subjects in the strengths of prefrontal–striatal modulatory (B matrix) DCM parameters. These findings are consistent with altered cortical–striatal networks that may be related to reduced dopamine function in cocaine dependence. As far as we are aware, this is the first between‐group DCM study using stochastic methodology. Hum Brain Mapp 35:760–778, 2014. © 2012 Wiley Periodicals, Inc.     

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anticocaine antibodies, none of the hapten was successfully designed, which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl norcocaine (HNC), bromoacetamido butyl norcocaine (BNC), and succinyl butyl norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anticocaine antibodies for better cocaine recognition. Mice immunized with these haptens conjugated to immunogenic proteins produced high titre anticocaine antibodies. However, during chemical conjugation of HNC and BNC haptens to carrier proteins, the 2β methyl ester group is hydrolyzed, and immunizing mice with these conjugate vaccines in mice produced antibodies that bound both cocaine and the inactive benzoylecgonine metabolite. While in the case of the SBNC conjugate, vaccine hydrolysis of the methyl ester did not appear to occur, leading to antibodies with high specificity to cocaine over BE. Although we observed similar specificity with a SNC hapten, the striking difference is that SBNC carries a positive charge on the tropane nitrogen atom, and therefore, it is expected to have better binding of cocaine. The 50% cocaine inhibitory concentration (IC₅₀) value for SBNC antibodies (2.8 μm ) was significantly better than the SNC antibodies (9.4 μm ) when respective hapten–BSA was used as a substrate. In addition, antibodies from both sera had no inhibitory effect from BE. In contrast to BNC and HNC, the SBNC conjugate was also found to be highly stable without any noticeable hydrolysis for several months at 4 °C and 2–3 days in pH 10 buffer at 37 °C.