Predictors of cocaine use disorder treatment outcomes: a systematic review.

BACKGROUND: Psychosocial approaches are the first-line treatments for cocaine dependence, although they still present high dropout and relapse rates. Thus, there is a pressing need to understand which variables influence treatment outcomes to improve current treatments and prevent dropout and relapse rates. The aim of this study is to explore predictors of treatment retention and abstinence in CUD. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched three databases-PubMed, PsychINFO and Web of Science-for randomized clinical trials (RCTs) published in English and Spanish from database inception through April 1, 2023. We selected all studies that met the inclusion criteria (adults aged ≥ 18, outpatient treatment, CUD as main addiction, and no severe mental illness) to obtain data for the narrative synthesis addressing cocaine abstinence and treatment retention as main outcome variables. After data extraction was completed, risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB-2). RESULTS: A total of 566 studies were screened, and, of those, 32 RCTs were included in the synthesis. Younger age, more years of cocaine use, and craving levels were significant predictors of relapse and treatment dropout. Fewer withdrawal symptoms, greater baseline abstinence, greater treatment engagement, and more self-efficacy were all predictors of longer duration of abstinence. The role of impulsivity as a predictor of CUD is unclear due to conflicting data, although the evidence generally suggests that higher impulsivity scores can predict more severe addiction and withdrawal symptoms, and earlier discontinuation of treatment. CONCLUSION: Current evidence indicates which variables have a direct influence on treatment outcomes, including well-studied cocaine use-related variables. However, additional variables, such as genetic markers, appear to have a high impact on treatment outcomes and need further study. SYSTEMATIC REVIEW REGISTRATION: This systematic review is registered at PROSPERO (ID: CRD42021271847). This study was funded by the Spanish Ministry of Science, Innovation and Universities, Instituto Carlos III (ISCIII) (FIS PI20/00929) and FEDER funds and Fundació Privada Hospital de la Santa Creu i Sant Pau (Pla d'acció social 2020).

Nucleus accumbens neuronal ensembles vary with cocaine reinforcement in male and female rats.

Neuronal ensembles in the medial prefrontal cortex mediate cocaine self-administration via projections to the nucleus accumbens. We have recently shown that neuronal ensembles in the prelimbic cortex form rapidly to mediate cocaine self-administration. However, the role of neuronal ensembles within the nucleus accumbens in initial cocaine-seeking behaviour remains unknown. Here, we sought to expand the current literature by testing the necessity of the cocaine self-administration ensemble in the nucleus accumbens core (NAcCore) 1 day after male and female rats acquire cocaine self-administration by using the Daun02 inactivation procedure. We found that disrupting the NAcCore ensembles after a no-cocaine reward-seeking test increased subsequent cocaine seeking, while disrupting NAcCore ensembles following a cocaine self-administration session decreased subsequent cocaine seeking. We then characterized neuronal cell type in the NAcCore using RNAscope in situ hybridization. In the no-cocaine session, we saw reduced dopamine D1 type neuronal activation, while in the cocaine self-administration session, we found preferential dopamine D1 type neuronal activity in the NAcCore.

Neonatal outcomes associated with tobacco, alcohol, and crack use during pregnancy in three Neonatal Intensive Care Units.

Despite the prevalence of substance use during pregnancy, studies focusing exclusively on Neonatal Intensive Care Units (NICU) admissions remain limited. This study investigates the impact of maternal use of tobacco, alcohol, and/or crack, on neonatal outcomes among infants admitted to three Brazilian NICUs. Additionally, the investigation explores the impact of substance use on DNA damage in newborns. Over a one-year period, data from 254 newborns were collected through medical records, accompanied by blood samples. Findings revealed that 16.1% of newborns had mothers reporting substance use during pregnancy. Significant associations were found between maternal substance use and adverse neonatal outcomes, including low birth weight, preterm birth, and sexually transmitted infections. Maternal variables linked to substance use encompassed non-white skin color, low education, non-masonry housing, lower income, diseases in other children, and fewer prenatal consultations. Notably, neonatal DNA damage showed no significant association with substance use. Our results underscore the substantial impact of maternal substance use on NICU-admitted infants, emphasizing the necessity for targeted interventions that address both neonatal health and maternal well-being, thereby underscoring the crucial role of comprehensive care in NICU settings.

Alterações sistêmicas e bucais em pacientes usuários de cocaína: uma revisão integrativa da literatura / Cambios sistémicos y orales em pacientes consumidores de cocaína: una revisión bibliográfica integradora / Systemic and oral changes in cocaína-using patients: an integrative literature review

Introdução: A utilização de cocaína é bastante associada ao surgimento de algumas manifestações sistêmicas e também de algumas alterações orais. Objetivo: Identificaras alterações sistêmicas e bucais mais comuns a pacientes usuários de cocaína. Metodologia: Trata-se de uma revisão sistemática da literatura, considerando artigos com texto completo, com restrição de idioma em Português ou Inglês e que tenham sido publicados entre os anos de 2017 a 2022. Usou-se as bases de dados LiLaCS, MedLine e BBO, por via portal Biblioteca Virtual de Saúde, e SciELO. Os artigos excluídosf oram aqueles que não apresentaram relação explícita do uso de cocaína com alguma manifestação sistêmica e/ou bucal. Resultados: Após o processo de triagem,10 artigos foram salvos para serem analisados e 111 foram descartados por não atenderem aos critérios de inclusão. Dos 10 artigosselecionados,40% deles (n=4) trouxeram informações identificando possíveis riscos de desenvolvimento de doenças cardiovasculares sofridas pelos usuários de cocaína, 10%(n=1) identificou problemas cognitivos associados ao uso da cocaína,30% dos artigos (n=3) mostrou as alterações bucais associadas à utilização abusiva de cocaína. Conclusões: Houve a predominância de algumas manifestações sistêmicas e bucais nos indivíduos usuários de cocaína, como doenças cardiovasculares, xerostomia, perfurações no palato, etc. A partir disso, há algumas alterações sistêmicas e bucais provocadas por esse uso. Mediante o risco considerável, faz-se necessário que o Cirurgião-Dentista se atualize sobre essas alterações em pacientes usuários de cocaína visando promover um trabalho transdisciplinare multiprofissional para atender adequadamente às suas necessidades (AU).

Introduction: The use of cocaine is closely associated with the appearance of some systemic manifestations and also some oral alterations.Objective: To identify the most common systemic and oral alterations in cocaine-using patients.Methodology:This is a systematic review of the literature, considering full-text articles, with a language restriction of "Portuguese" or "English" and published between 2017 and 2022. We used the LiLaCS, MedLine and BBO databases, via the Virtual Health Library (VHL) portal, and SciELO.The articles excluded were those that did not explicitly relate cocaine use to some systemic and/or oral manifestation.Results: After the screening process, 10 articles were saved for analysis and 111 were discarded because they did not meet the inclusion criteria. Of the 10 articles selected, 40% (n=4) provided information identifying possible risks of developing cardiovascular diseases suffered by cocaine users, 10% (n=1)identified cognitive problems associated with cocaine use, 30% of the articles (n=3) showed oral alterations associated with cocaine abuse.Conclusions: There has been a predominance of some systemic and oral manifestations in cocaine users, such as cardiovascular diseases, xerostomia, perforations in the palate, etc. Based on this, there are some systemic and oral alterations caused by this use. Given the considerable risk, it is necessary for dentists to be up-to-date on these alterations in cocaine-using patients in order to promote transdisciplinary and multi-professional work to adequately meet their needs (AU).

Introducción: El consumo de cocaína está estrechamente asociado a la aparición de algunas manifestaciones sistémicas y también de algunas alteraciones orales. Objetivo:Identificar las alteraciones sistémicas y bucales más frecuentes en los consumidores de cocaína. Metodología: Se trata de una revisión sistemática de la literatura, considerando artículos a texto completo, con restricción de idioma en "portugués" o "inglés" y publicados entre 2017 y 2022. Se utilizaron las bases de datos LiLaCS, MedLine y BBO, a través del portal Biblioteca Virtual en Salud (BVS) y SciELO. Los artículos excluidos fueron aquellos que no mostraban una relación explícita entre el consumo de cocaína y alguna manifestación sistémica y/o oral. Resultados: Tras el proceso de cribado, se guardaron10 artículos para el análisis y se descartaron 111 por no cumplir los criterios de inclusión. De los 10 artículos seleccionados, el 40% (n=4) proporcionaba información que identificaba posibles riesgos de desarrollar enfermedades cardiovasculares sufridaspor consumidores de cocaína, el 10% (n=1) identificaba problemas cognitivos asociados al consumo de cocaína, el 30% de los artículos (n=3) mostraban alteraciones orales asociadas al abuso de cocaína.Conclusiones:Ha habido un predominio de algunas manifestaciones sistémicas y orales en los consumidores de cocaína, como enfermedades cardiovasculares, xerostomía, perforaciones en el paladar, etc. De acuerdo con esto, existen algunas alteraciones sistémicas y orales causadas por este uso. Dado el considerable riesgo, es necesario que los odontólogos estén al día sobre estas alteraciones en los pacientes consumidores de cocaína, con el fin de promover el trabajo transdisciplinar y multiprofesional para atender adecuadamente sus necesidades (AU).

Granulomatosis with polyangiitis or its mimic? A case report.

Differentiation between granulomatosis with polyangiitis (GPA) limited to the upper airways and cocaine-induced midline destructive lesion (CIMDL) may be particularly difficult because of their common histopathologic features and antineutrophil cytoplasmic antibody (ANCA) profiles. We herein present a case involving a young woman with an initial diagnosis of GPA based on upper and lower airway manifestations and constitutional symptoms, histopathologic evidence of granulomas, a positive cytoplasmic ANCA indirect immunofluorescent test result, and proteinase 3 positivity by enzyme-linked immunosorbent assay (ELISA). CIMDL was confirmed based on the appearance of a hard palate perforation, positivity for methylecgonine on urine toxicology, a positive perinuclear ANCA indirect immunofluorescent test result, and subsequent human neutrophil elastase (HNE) ANCA positivity by ELISA. Finally, based on the coexistence of CIMDL, constitutional symptoms, and lower airway manifestations, the diagnosis was modified to cocaine-induced GPA mimic. Urine toxicology for cocaine and HNE ELISA are indicated in young patients with GPA who develop limited airway disease to check for the presence of CIMDL and cocaine-/levamisole-induced ANCA-associated vasculitis. Continued abstinence from cocaine is the first-choice therapy for both CIMDL and cocaine-induced GPA mimic.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

Prior cocaine self-administration does not impair the ability to delay gratification in rats during diminishing returns.

Previous exposure to drugs of abuse produces impairments in studies of reversal learning, delay discounting and response inhibition tasks. While these studies contribute to the understanding of normal decision-making and how it is impaired by drugs of abuse, they do not fully capture how decision-making impacts the ability to delay gratification for greater long-term benefit. To address this issue, we used a diminishing returns task to study decision-making in rats that had previously self-administered cocaine. This task was designed to test the ability of the rat to choose to delay gratification in the short-term to obtain more reward over the course of the entire behavioral session. Rats were presented with two choices. One choice had a fixed amount of time delay needed to obtain reward [i.e. fixed delay (FD)], while the other choice had a progressive delay (PD) that started at 0 s and progressively increased by 1 s each time the PD option was selected. During the 'reset' variation of the task, rats could choose the FD option to reset the time delay associated with the PD option. Consistent with previous results, we found that prior cocaine exposure reduced rats' overall preference for the PD option in post-task reversal testing during 'no-reset' sessions, suggesting that cocaine exposure made rats more sensitive to the increasing delay of the PD option. Surprisingly, however, we found that rats that had self-administered cocaine 1-month prior, adapted behavior during 'reset' sessions by delaying gratification to obtain more reward in the long run similar to control rats.

The Mexican dataset of a repetitive transcranial magnetic stimulation clinical trial on cocaine use disorder patients: SUDMEX TMS.

Cocaine use disorder (CUD) is a global health problem with severe consequences, leading to behavioral, cognitive, and neurobiological disturbances. While consensus on treatments is still ongoing, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising approach for medication-resistant disorders, including substance use disorders. In this context, here we present the SUDMEX-TMS, a Mexican dataset from an rTMS clinical trial involving CUD patients. This longitudinal dataset comprises 54 CUD patients (including 8 females) with data collected at five time points: baseline (T0), two weeks (T1), three months (T2), six months (T3) follow-up, and twelve months (T4) follow-up. The clinical rTMS treatment followed a double-blinded randomized clinical trial design (n = 24 sham/30 active) for 2 weeks, followed by an open-label phase. The dataset includes demographic, clinical, and cognitive measures, as well as magnetic resonance imaging (MRI) data collected at all time points, encompassing structural (T1-weighted), functional (resting-state fMRI), and multishell diffusion-weighted (DWI-HARDI) sequences. This dataset offers the opportunity to investigate the impact of rTMS on CUD participants, considering clinical, cognitive, and multimodal MRI metrics in a longitudinal framework.

Attentional ERPs in consumers of smoked and insufflated cocaine associated with neuropsychological performance.

BACKGROUND: Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced amplitude of the P3a, while both SCD and IC dependent (ICD) would show reduced amplitude of the P3b. METHODS: We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks. RESULTS: At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. The amplitude of P3a and P3b was lower in Users groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down. CONCLUSIONS: Different routes of administration lead to distinct attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance Dependence.

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens.

Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain's reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders.

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

Sequencing hour-level temporal patterns of polysubstance use among persons who use cocaine, alcohol, and cannabis: A back-translational approach.

BACKGROUND: Polysubstance use is highly prevalent among persons who use cocaine; however, little is known about how alcohol and cannabis are used with cocaine. We identified temporal patterns of cocaine+alcohol and cocaine+cannabis polysubstance use to inform more translationally relevant preclinical models. METHODS: Participants who used cocaine plus alcohol and/or cannabis at least once in the past 30 days (n=148) were interviewed using the computerized Substance Abuse Module and the newer Polysubstance Use-Temporal Patterns Section. For each day in the past 30 days, participants reported whether they had used cocaine, alcohol, and cannabis; if any combinations of use were endorsed, participants described detailed hourly use of each substance on the most "typical day" for the combination. Sequence analysis and hierarchical clustering were applied to identify patterns of timing of drug intake on typical days of cocaine polysubstance use. RESULTS: We identified five temporal patterns among the 180 sequences of reported cocaine polysubstance use: 1) limited cocaine/cocaine+alcohol use (53%); 2) extensive cannabis then cocaine+alcohol+cannabis use (22%); 3) limited alcohol/cannabis then cocaine+alcohol use (13%); 4) extensive cocaine+cannabis then cocaine+alcohol+cannabis use (4%); and 5) extensive cocaine then cocaine+alcohol use (8%). While drug intake patterns differed, prevalence of use disorders did not. CONCLUSIONS: Patterns were characterized by cocaine, alcohol, and cannabis polysubstance use and by the timing, order, duration, and quantity of episode-level substance use. The identification of real-world patterns of cocaine polysubstance use represents an important step toward developing laboratory models that accurately reflect human behavior.

Tmod2 Is a Regulator of Cocaine Responses through Control of Striatal and Cortical Excitability and Drug-Induced Plasticity.

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 (Tmod2) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance abuse and intellectual disability in humans. Here, we mine the KOMP2 data and find that Tmod2 knock-out mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping shows that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knock-outs, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole-brain MR imaging shows differences in brain volume across multiple regions, although transcriptomic experiments did not reveal perturbations in gene coexpression networks. Detailed electrophysiological characterization of Tmod2 KO neurons showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data, collected from both males and females, provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine.

Cocaine Gut: A Rare Case of Cocaine-Induced Esophageal, Gastric, and Small Bowel Necrosis.

Cocaine is an indirect-acting sympathomimetic drug that inhibits norepinephrine and dopamine reuptake in the adrenergic presynaptic cleft. Cocaine use has been associated with strokes, angina, arrhythmias, and agitation. Data on gastrointestinal complications such as mesenteric ischemia, bowel necrosis, ulceration, and perforation are scarce. Here, we present a rare case of cocaine-induced esophageal, gastric, and small bowel necrosis that contributes to the limited literature on this subject. Diagnosis of cocaine-induced gastrointestinal complications involves a combination of imaging studies, laboratory assessments, and histopathological examinations. Timely surgical resection, supported by intravenous fluids, antibiotics, and pain management, is the mainstay of treatment. The prognosis varies but is significantly influenced by the promptness and effectiveness of the intervention, underscoring the importance of vigilant clinical care in such cases.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

A narrative systematic review of associations and temporality between use of methamphetamine, ecstasy/MDMA, or cocaine with anxiety or depressive symptoms.

OBJECTIVE: Anxiety and depression are prevalent mental health problems in people who use illicit stimulants. Improved understanding of the temporal relationship between methamphetamine, ecstasy/MDMA, or cocaine use with anxiety or depression informs public health interventions and treatment options for those experiencing this co-occurrence. This narrative systematic review sought to examine associations and temporality between the use of methamphetamine, ecstasy/MDMA, or cocaine, with anxiety or depressive symptoms. Method Systematic searches of 4 electronic databases were conducted up to August 2023. Study eligibility included the measurement of anxiety and/or depressive symptoms, and frequency of illicit stimulant use (methamphetamine, cocaine, or ecstasy/MDMA) at two separate time points, with data analysis of the association between these variables. The Joanna Briggs Critical Appraisal Checklist was utilised to assess quality. Data was extracted, and a narrative synthesis incorporating an eight-criteria framework to assess associations was conducted. Results 4432 studies were screened for eligibility; 11 studies (3 RCTs and 8 prospective cohort studies) were included. Evidence for an association between depressive symptoms and methamphetamine use was demonstrated in six studies, with temporal evidence in three studies supporting methamphetamine use preceding depressive symptoms. Three studies reported an association between cocaine use and depressive symptoms. Evidence for associations with any of the illicit stimulants and anxiety symptoms was lacking. CONCLUSIONS: There was some evidence to support a case for temporality, particularly for methamphetamine use and depressive symptoms. Investing in longitudinal studies is pivotal to understanding the dynamic and reciprocal relationship between illicit stimulant use and anxiety or depressive symptoms. A limitation of the study was the variation in the measurement and analysis of outcomes.

Preliminary investigation of the administration of biperiden to reduce relapses in individuals with cocaine/crack user disorder: A randomized controlled clinical trial.

BACKGROUND: Several studies have demonstrated that ACh modulates the dopaminergic circuit in the nucleus accumbens, and its blockade appears to be associated with the inhibition of the reinforced effect or the increase in dopamine caused by cocaine use. The objective of this study was to evaluate the effect of biperiden (a muscarinic receptor antagonist with a relatively higher affinity for the M1 receptor) on crack/cocaine use relapse compared to a control group that received placebo. METHODS: This study is a double-blind, randomized, placebo-controlled clinical trial. The intervention group received 2 mg of biperiden, 3 times a day, for a period of 3 months. The control group received identical placebo capsules, at the same frequency and over the same period. All participants were followed for a period of six months. RESULTS: The sample comprised 128 people, with 61 in the control group and 67 in the biperiden group. Lower substance consumption was observed in the group that received biperiden treatment two (bT2 = -2.2 [-3.3; -1.0], p < 0.001) and six months (bT4 = -6, 2 [-8.6; -3.9], p < 0.001) after the beginning of the intervention. The biperiden group had a higher latency until a possible first day of consumption, in the same evaluation periods (bT2 = 0.26 [0.080; 0.44], p = 0.004; bT4 = 0.63 [0.32; 0.93], p < 0.001). CONCLUSIONS: Despite the major limitations of the present study, the group that received biperiden reduced the number of days of cocaine/crack use and showed an increase in the latency time for relapse. More studies are needed to confirm the utility of this approach.