Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine's discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors.     

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine‐related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5‐day withdrawal period. In addition, c‐Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c‐Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Synapse 67:553–567, 2013. © 2013 Wiley Periodicals, Inc.     

Specific blockade of morphine- and cocaine-induced reinforcing effects in conditioned place preference by nitrous oxide in mice

Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, the following day mice were given saline. This sequence alternated during the next 4 days. Control animals received saline every day. The behavior of animals was evaluated on day 8. N(2)O did not induce CPP but impaired the acquisition of morphine-induced CPP and blocked the expression of cocaine- and morphine-induced CPP. The effects of the gas were long lasting and persist 4 days following the exposure. Moreover no behavioral modifications in tests usually used to investigated emotional state as compared with control mice were observed in animals exposed to N(2)O, ruling out an effect of this gas on attention, anxiety, depression, locomotion and anhedonia. These studies raise the possibility that N(2)O could have a clinical benefit in the management of morphine and cocaine addiction.     

Inhibitory Control and Impulsivity Levels in Women Crack Users

Objective: investigate impulsivity levels and inhibitory control in women crack users and explore the relationships between impulsivity and inhibitory control. Method and Design: 52 healthy women (M = 32.83 years; SD = 9.54) and 46 crack cocaine users (M = 31.02 years; SD = 7.73), in abstinence, performed the assessment protocol included a Sociodemographic Data Questionnaire, Mini-Mental State Examination (MMSE), a GO/No-Go Task and the Barratt Impulsiveness Scale–11 (BIS-11). It was a quantitative research with cross-sectional design and control group. Results: crack group showed higher levels of impulsivity in all domains when compared to the control group (crack group M = 76.39, SD = 11.39, control group M = 58.53, SD = 10.76, p <.01). Participants from the crack group presented a significantly higher total reaction time in the Go-NoGo task (F(1,93) = 9.93, p =.002; effect size =.09, observed power =.87) and significantly more commission (F(1,93) = 7.20, p =.009; effect size =.07, observed power =.75) and omission errors (F(1,93) = 6.04, p =.01; effect size =.06, observed power =.68), in Go/NoGo Task. Groups did also significantly differ on total standard deviations suggesting that variability in total reaction time was significantly greater in the crack group. Results showed that only in the crack group there were significant correlations between Go-NoGo parameters and Barratt Impulsiveness Scale. Conclusions: Our findings are consistent that impulsivity and inhibitory control are closely linked to crack use in women. Future studies should consider to evaluate crack users in different withdrawal times, controlling the impact of abstinence time in the variables studied.     

An overview of non-cardiac cocaine toxicity

Cocaine use in the United States continues to be a significant problem. Cocaine use is responsible for approximately 143,000 Emergency Department visits annually. The cardiac effects of cocaine are well known and much is written on this topic; this is beyond the scope of this article. Cocaine use is also responsible for a variety of non-cardiac, systemic complications, which it is our purpose to review. Multiple systemic effects of cocaine are seen with both acute and chronic use. These systems include: psychological and psychiatric, neurological, renal, pulmonary, gastrointestinal, obstetrical, and otolaryngological.     

NF-κB调控可卡因行为敏化的BDNF机制简

目的獉獉：探讨脑源性神经营养因子（BDNF）是否作为核因子NF-κB的靶基因,参与NF-κB对可卡因行为敏化的影响。方法獉獉：建立NF-κB抑制剂DDTC作用下的小鼠可卡因诱导行为敏化模型,用Real-time PCR检测海马、前额叶皮质、伏隔核中Bdnf的表达。结果獉獉：可卡因可诱导伏隔核和海马（而非前额叶皮质）中Bdnf的上调,而在DDTC的作用下,总Bdnf及BdnfⅣ在伏隔核、海马和前额叶皮质中分别表达下调、不变和上调。结论獉獉：在不同的脑区NF-κB作用的机制可能不同,在伏隔核中,Bdnf可能作为NF-κB的靶基因参与可卡因行为敏化的形成。     

Parenting under the influence: The effects of opioids,alcohol and cocaine on mother–child interaction

Nearly 20% of adults receiving treatment for a substance use disorder live with their minor children (Stanger et al., 1999) and women in drug use treatment are twice as likely as men to have children in their household (Wechsberg et al., 1998). Parental drug use impacts the family through reduced family resources such as money and food, and researchers consistently note parenting deficits among substance users (Solis, Shadur, Burns, & Hussong, 2012). Little is known about differences in parenting and mother–child interaction among mothers with different drugs of choice or among mothers of older children, between 8 and 16 years. This study reports the findings from a sample of treatment seeking opioid, alcohol and cocaine using mothers and their 8–16-year-old child. Findings from a mother–child observational task and self-reported parenting measure indicated less undermining autonomy and higher mother maternal acceptance among opioid compared to alcohol addicted mothers. African American mothers were observed to have fewer negative interactional behaviors than Whites and both African American mothers and children self-reported higher firm control and maternal acceptance. Overall, mothers appeared to struggle with effective discipline with older versus younger children. Findings offer useful information to clinicians seeking to effectively tailor their interventions to women and children who present with different drugs of abuse, race/culture and developmental stage of child.     

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)–basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, {"type":"entrez-protein","attrs":{"text":"SKF81297","term_id":"1156277425","term_text":"SKF81297"}}SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC–BLA functional interactions. Thus, a VTA–OFC–BLA neural circuit promotes drug context-induced motivated behavior.     

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.