From a cycle to a period: the potential role of BDNF as plasticity and phase-specific biomarker in cocaine use disorder

Cocaine Use Disorder (CUD) is one of the diseases with the greatest social and health impact, due to the high cost of rehabilitation management and the high risk of dangerous behavior and relapse. This pathology frequently leads to unsuccessful attempts to interrupt the consumption, resulting in relapses and a vicious circle binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving). The alternation of these phases in addictions was well illustrated by Koob and colleagues in the so-called “addictive cycle”, which nowadays represents a landmark in the addiction field. Recently, there has been an increased interest in the international literature for biomarkers able to explain the several phases of addiction, and one of the most studied biomarkers is undoubtedly Brain-derived Neurotrophic Factor (BDNF). In this perspective article, we discuss the potential role of BDNF as biomarker of the CUD phases described in the “Addictive Cycle”, speculating about the close relationship between BDNF fluctuations and the clinical course of CUD. Furthermore, we discuss BDNF potential role as “staging” biomarker, able to predict disease worsening. Finding valuable biomarkers of CUD severity and disease stage could shift clinicians' attention from the perspective of behavioral symptomatic treatment to a novel brain-based approach, allowing more effective and targeted therapeutic strategies to be developed, thus determining major benefits for CUD patients.

Infants of Mothers with Cocaine Use: Review of Clinical and Medico-Legal Aspects

Illicit drug use is a global problem that also affects pregnant women. Substance use and alcohol abuse during pregnancy may have various harmful consequences for both mothers and foetuses. Intrauterine exposure to illicit substances can be investigated through maternal reports and toxicological tests on mothers’ and/or newborns’ samples. While the negative effects of alcohol and opioid use on pregnancy, the foetus, and/or newborn are well established, the effects of cocaine use remain controversial. We performed a review of the literature to evaluate the current state of knowledge of the effects of intrauterine cocaine exposure on newborns’ and children’s long-term development and to highlight possible implications for health professionals dealing with women who use cocaine during pregnancy. Although intrauterine cocaine exposure has been associated with reduced infant measurements, no specific amount of cocaine use exerting such effects has been determined, and no long-term effects have been confirmed. The evidence of cocaine use during pregnancy justifies a clinical and social takeover of the mother and newborn without assuming that there will certainly be long-term damage related to intrauterine cocaine exposure, but also considering other possible associated factors.

Mean corrected generalized estimating equations for longitudinal binary outcomes with report bias

Cocaine addiction is an important public health problem worldwide. Cognitive-behavioral therapy is a counseling intervention for supporting cocaine-dependent individuals through recovery and relapse prevention. It may reduce patients’ cocaine uses by improving their motivations and enabling them to recognize risky situations. To study the effect of cognitive behavioral therapy on cocaine dependence, the self-reported cocaine use with urine test data were collected at the Primary Care Center of Yale-New Haven Hospital. Its outcomes are binary, including both the daily self-reported drug uses and weekly urine test results. To date, the generalized estimating equations are widely used to analyze binary data with repeated measures. However, due to the existence of significant self-report bias in the self-reported cocaine use with urine test data, a direct application of the generalized estimating equations approach may not be valid. In this paper, we proposed a novel mean corrected generalized estimating equations approach for analyzing longitudinal binary outcomes subject to reporting bias. The mean corrected generalized estimating equations can provide consistently and asymptotically normally distributed estimators under true contamination probabilities. In the self-reported cocaine use with urine test study, accurate weekly urine test results are used to detect contamination. The superior performances of the proposed method are illustrated by both simulation studies and real data analysis.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

D-amphetamine maintenance therapy reduces cocaine use in female rats

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats) After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine-treated rats showed reduced motivation to take and seek cocaine, responding less for cocaine both under progressive ratio and extinction conditions. In contrast, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. Thus, d-amphetamine treatment reduces both the development and expression of addiction-relevant patterns of cocaine use in female animals.

Prevalence of crack cocaine use and its associated factors in patients treated in a specialized outpatient service

Background Despite the advance in studies addressing the use of crack cocaine, knowledge about the characteristics of users that seek treatment in the different modalities of care for substance use disorders is important to plan the operationalization of these services. Objective To analyze the prevalence and factors associated with the use of crack cocaine in outpatients. Method Cross-sectional study consisting in the analysis of the medical records of outpatients of a chemical dependency clinic located in the south of Brazil from 1999 to 2015. The Fisher’s exact test and the Poisson regression model were used to analyze the data. Results Medical records from 1,253 patients were analyzed, and 1,196 (95.5%) of them contained information on the use of crack cocaine. Use of this substance was reported by 47% (95% CI [44, 50]) of the outpatients. The risk group was composed of adults aged 20-39 years, with no income, who had three or more children, did not consume alcohol or marijuana, had continuous family assistance, spontaneously looked for the service, and had already been hospitalized or assisted at a therapeutic community or psychosocial center. Conclusion There is great demand for the outpatient care of crack cocaine users. It is crucial that the risk factors guide treatment planning.

Dimensionality and homogeneity of the Colombian version of the Cocaine Craving Questionnaire (CCQ-N-10)

Background and aimIt is essential to have a validated instrument to measure craving for cocaine use. However, in Colombia, there is no instrument to screen cocaine craving. The study aimed to determine the homogeneity and dimensionality of the CCQ-N-10 in patients with cocaine use disorder in Colombia.Materials and methodsAn adaptation and subsequent analysis of the psychometric properties of the CCQ-N-10 scale was carried out with 102 hospitalized or outpatient adults diagnosed with substance use disorders in addiction units in Bucaramanga, Colombia. Internal consistency and construct validity were estimated by confirmatory factor analysis and correlation analysis with scales with similar objectives.ResultsAn omega coefficient of 0.93 was obtained, and adjustment indicators of the confirmatory model were acceptable (RMSEA of 0.08, CFI and TLI of 0.99) when two of the original scale items were removed from the original scale analysis.ConclusionsThis study shows that the craving scale reduced to eight items can be helpful to assess the construct in the Colombian population; However, the small sample size makes it challenging to carry out other analyzes to corroborate its psychometric properties.