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.

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.

Contingency management plus acceptance and commitment therapy for initial cocaine abstinence: Results of a sequential multiple assignment randomized trial (SMART).

BACKGROUND: This study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. METHOD: For Phase 1 of treatment, participants (N=118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. RESULTS: Phase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. DISCUSSION: Adding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy.

Percentage of negative urine drug screens as a clinically meaningful endpoint for RCTs evaluating treatment for cocaine use.

BACKGROUND: This study examined a threshold based on the percentage of cocaine-negative (CN) urine drug screens (UDS) collected during treatment as a potential meaningful endpoint for clinical trials. We hypothesized that individuals providing at least 75% CN UDS would have better long-term outcomes than those providing less than 75% CN UDS. METHODS: Two separate pooled datasets of randomized clinical trials conducted at different institutions were used for analyses: one composed of eight trials (N = 760) and the other composed of three trials (N = 416), all evaluating behavioral and/or pharmacological treatments for cocaine use. UDS were collected at least once per week (up to three times per week) during the 8- or 12-week treatment period across all trials, with substance use and psychosocial functioning measured up to 12 months following treatment. Chi-squares and ANOVAs compared within-treatment and follow-up outcomes between the groups. RESULTS: Compared to those who did not achieve the threshold, participants who achieved the 75%-CN threshold were retained in treatment longer and had a longer period of continuous abstinence, and were more likely to report problem-free functioning. Additionally, participants who achieved the 75%-CN threshold were more likely to report sustained abstinence and better psychosocial functioning throughout a follow-up period up to 12 months than those who did not achieve the threshold. CONCLUSIONS: A threshold of 75%-CN UDS is associated with short- and long-term clinical benefits. Future clinical trials may consider this a meaningful threshold for defining treatment responders.

Impulsivity and Treatment Outcomes in Individuals with Cocaine Use Disorder: Examining the Gap between Interest and Adherence.

Background: Impulsivity is implicated in the development and maintenance of Cocaine Use Disorder (CUD). Less work has examined impulsivity's role on interest in initiating treatment, treatment adherence, or treatment response. No pharmacotherapies are approved for CUD, so efforts to understand and bolster the effects of psychotherapy are important in guiding and refining treatment. The present study examined the impact of impulsivity on interest in treatment, treatment initiation, treatment adherence, and treatment outcomes in individuals with CUD. Methods: Following the completion of a larger study on impulsivity and CUD participants were offered 14 sessions of (12 weeks) Cognitive Behavioral Relapse Prevention (CBT-RP). Before starting treatment, participants completed seven self-report and four behavioral measures of impulsivity. Sixty-eight healthy adults (36% female) with CUD (aged 49.4 ± 7.9) expressed an interest in treatment. Results: Greater scores on several self-report measures of impulsivity, and fewer difficulties with delayed gratification were associated with increased interest in treatment in both males and females. 55 participants attended at least 1 treatment session, while 13 participants did attend a single session. Individuals who attended at least one treatment session scored lower on measures of lack of perseverance and procrastination. Still, measures of impulsivity did not reliably predict session attendance nor the frequency of cocaine-positive urine samples throughout treatment. Males attended nearly twice as many treatment sessions as females despite nonsignificant associations between impulsivity in males and the number of sessions attended. Conclusions: Greater impulsivity in individuals with CUD was associated with expressing an interest in treatment, but not treatment adherence or response.

Cocaine Use May Moderate the Associations of HIV and Female Sex with Neurocognitive Impairment in a Predominantly African American Population Disproportionately Impacted by HIV and Substance Use.

HIV-associated neurocognitive disorders (HAND) remain a major challenge for people with HIV in the antiretroviral therapy era. Cocaine use may trigger/exacerbate HAND among African American (AA) adults, especially women. Between 2018 and 2019, 922 adults, predominantly AAs, with/without HIV and with/without cocaine use in Baltimore, Maryland, were enrolled in a study investigating the association of HIV and cocaine use with neurocognitive impairment (NCI). Neurocognitive performance was assessed with the NIH Toolbox Cognition Battery (NIHTB-CB). NCI was considered to be present if the fully adjusted standard score for at least two cognitive domains was 1.0 standard deviation below the mean. Although the overall analysis showed HIV and female sex were associated with NCI, the associations were dependent on cocaine use. Neither HIV [adj prevalence ratio (PR): 1.12, confidence interval (95% CI): 0.77-1.64] nor female sex (adj PR: 1.07, 95% CI: 0.71-1.61) was associated with NCI among cocaine nonusers, while both HIV (adj PR: 1.39, 95% CI: 1.06-1.81) and female sex (adj PR: 1.53, 95% CI: 1.18-1.98) were associated with NCI in cocaine users. HIV was associated with two NIHTB-CB measures overall. In addition, HIV was associated with a lower dimensional change card sort score (an executive function measure) in cocaine users and not in nonusers. Cognitive performance was poorer in female than in male cocaine users. The adverse effect of HIV on cognitive performance predominantly affected cocaine users. However, cocaine use may moderate the impact of HIV and female sex on cognitive performance, highlighting the importance of reducing cocaine use in NCI prevention among the AA population.

Transgenerational Cycle of Traumatization and HIV Risk Exposure among Crack Users.

The aim of this manuscript is to understand the impact of childhood sexual abuse on the development of Post-Traumatic Stress Disorder (PTSD), Human Immunodeficiency Virus (HIV) exposure. and parental neglect in crack cocaine users, considering the role of gender. This study is a secondary database analysis of a sample from a multicenter cross-sectional study with 715 crack cocaine users receiving outpatient treatment in public mental health networks in six Brazilian capitals. Prevalence ratios were estimated by Poisson regression. In crack cocaine users with childhood sexual abuse, traumatic experiences seem to remain fixed through the development of Post Traumatic Stress Disorder (PTSD) in adulthood. Crack cocaine users with childhood abuse and PTSD in adulthood showed more sexual risk behaviors, including outcomes such as HIV (PR = 3.6 p < 0.001 for childhood abuse and PR = 3.7 p < 0.001 for PTSD). Furthermore, this traumatic trajectory affects the functional ability of crack cocaine users, especially women, to work thus impacting their inclusion and sense of social belonging. Such a chain seems to be reflected in the establishment of a circle of transgenerational transmission, to the extent that subjects with a history of abuse and PTSD reported more parental neglect towards their children. This study reinforces the importance of preventive public policies regarding early socio-emotional vulnerabilities and the need to support families, especially women, to avoid HIV and self-destructive outcomes such as crack cocaine use.

Cuidado em saúde mental com gestantes usuárias de crack / Mental health care with pregnant crack users / Cuidadode salud mental con mujeres embarazadas que utilizan crack

Neste manuscrito, apresentamos uma pesquisa cujo objetivo foi o de compreender como vem sendo produzidas as práticas de cuidado às gestantes usuárias de crack nos serviços de saúde de um município do interior do Rio Grande do Sul. Este estudo de abordagem qualitativa, foi realizado junto a dois serviços públicos, o Programa de Redução de Danos (PRD) e o Centro de Atenção Psicossocial para Álcool e outras Drogas (CAPSad III), com cinco mulheres voluntárias para a pesquisa. As histórias de vida foram reconstruídas a partir de suas narrativas e também de profissionais da saúde que proveram algum tipo de cuidado às participantes. Após a exposição das histórias, refletimos sobre três pistas importantes para pensarmos as práticas de cuidado às gestantes usuárias de crack: saúde mental, uso de drogas e interseccionalidade; direitos humanos, hierarquias reprodutivas e concepções de maternidade; e as práticas de cuidado em saúde. Observamos que as concepções dos profissionais acerca da maternidade direcionam as práticas de cuidado em saúde, caracterizando-se como um cuidado no espectro da saúde materno-infantil, e não um cuidado direcionado à saúde da mulher. Conhecer as demandas de cuidado dessas mulheres é essencial para que possamos pensar em práticas de saúde pautadas pela clínica ampliada. (AU)

In this manuscript, we present a research whose objective was to understand how the practicesof care to the pregnant women users of crack have been being produced in the services of health in a town of Rio Grande do Sul. This study of qualitative approach it was developed jointly to two public services, the Program of Reduction of Harms (PRH) andPsychosocial Care Centers Alcohol and other Drugs (CAPSad), with five voluntary women for the research. The life histories were rebuilt starting from their narratives and also of health's professionals that provided some care to the participants.After exposing the stories, we reflected on three important clues to think about care practices for pregnant women who use crack: mental health, drug use and intersectionality; human rights, reproductive hierarchies and conceptions of motherhood; and health care practices. We observed that the professionals' conceptions about maternity guide health care practices, characterized as care in the spectrum of maternal and child health, and not care directed at women's health.Knowing the care demands of these women is essential for us to think about health practices guided by the expanded clinic. (AU)

En este manuscrito presentamos una investigación cuyoobjetivo fue comprender cómo se ha producidolas prácticas de atención a las embarazadas usuarias de crack en los servicios de salud de una ciudad del interior de Rio Grande do Sul. Este estudio cualitativo se realizó con dos servicios públicos, el Programa de Reducción de Daños (PRD) y el Centro de Atención Psicosocial de Alcohol y Otras Drogas (CAPSad III), con cinco mujeres voluntarias para la investigación. Las historias de vida fueron reconstruidas a partir de sus narrativas y también de profesionalesde la salud que brindaron algún tipo de atención a los participantes. Luego de exponer las historias, reflexionamos sobre tres claves importantes para pensar en las prácticas de cuidado de las embarazadas que consumen crack: salud mental, consumo de drogas y interseccionalidad; derechos humanos, jerarquías reproductivas y concepciones de la maternidad; y prácticas de atención de la salud.Observamos que las concepciones de los profesionales sobre la maternidad orientan las prácticas de atención de la salud, caracterizadas como cuidados en el espectro de la salud maternoinfantil, y no cuidados dirigidos a la salud de la mujer. Conocer las demandas de atención de estas mujeres es fundamental para que pensemos en las prácticas de salud guiadas por la clínica ampliada. (AU)

The complexity of cortical folding is reduced in chronic cocaine users.

Cocaine use is a worldwide health problem with psychiatric, somatic and socioeconomic complications, being the second most widely used illicit drug in the world. Despite several structural neuroimaging studies, the alterations in cortical morphology associated with cocaine use and addiction are still poorly understood. In this study, we compared the complexity of cortical folding (CCF), a measure that aims to summarize the convoluted structure of the cortex between patients with cocaine addiction (n = 52) and controls (n = 36), and correlated it with characteristics of addiction and impulsivity. We found that patients with cocaine addiction had greater impulsivity and showed reduced CCF in a cluster that encompassed the left insula and the supramarginal gyrus (SMG) and in one in the left medial orbitofrontal cortex. Finally, the CCF in the left medial orbitofrontal cortex was correlated with the age of onset of cocaine addiction and with attentional impulsivity. Overall, our findings suggest that chronic cocaine use is associated with changes in the cortical surface in the fronto-parieto-limbic regions that underlie emotional regulation and these changes are associated with earlier cocaine use. Future longitudinal studies are warranted to unravel the association of these changes with the diathesis for the disorder and with the chronic use of this substance.

Towards a machine-learning assisted diagnosis of psychiatric disorders and their operationalization in preclinical research: Evidence from studies on addiction-like behaviour in individual rats.

Over the last few decades, there has been a progressive transition from a categorical to a dimensional approach to psychiatric disorders. Especially in the case of substance use disorders, interest in the individual vulnerability to transition from controlled to compulsive drug taking warrants the development of novel dimension-based objective stratification tools. Here we drew on a multidimensional preclinical model of addiction, namely the 3-criteria model, previously developed to identify the neurobehavioural basis of the individual's vulnerability to switch from controlled to compulsive drug taking, to test a machine-learning assisted classifier objectively to identify individual subjects as vulnerable/resistant to addiction. Datasets from our previous studies on addiction-like behaviour for cocaine or alcohol were fed into a variety of machine-learning algorithms to develop a classifier that identifies resilient and vulnerable rats with high precision and reproducibility irrespective of the cohort to which they belong. A classifier based on K-median or K-mean-clustering (for cocaine or alcohol, respectively) followed by artificial neural networks emerged as a highly reliable and accurate tool to predict if a single rat is vulnerable/resilient to addiction. Thus, each rat previously characterized as displaying 0-criterion (i.e., resilient) or 3-criteria (i.e., vulnerable) in individual cohorts was correctly labelled by this classifier. The present machine-learning-based classifier objectively labels single individuals as resilient or vulnerable to developing addiction-like behaviour in a multisymptomatic preclinical model of addiction-like behaviour in rats. This novel dimension-based classifier increases the heuristic value of these preclinical models while providing proof of principle to deploy similar tools for the future of diagnosis of psychiatric disorders.

Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users.

Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response.

Effects of Human Immunodeficiency Virus Infection and Former Cocaine Dependence on Neuroanatomical Measures and Neurocognitive Performance.

Evidence from animal research, postmortem analyses, and magnetic resonance imaging (MRI) investigations indicate substantial morphological alteration in brain structure as a function of human immunodeficiency virus (HIV) or cocaine dependence (CD). Although previous research on HIV+ active cocaine users suggests the presence of deleterious morphological effects in excess of either condition alone, a yet unexplored question is whether there is a similar deleterious interaction in HIV+ individuals with CD who are currently abstinent. To this end, the combinatorial effects of HIV and CD history on regional brain volume, cortical thickness, and neurocognitive performance was examined across four groups of participants in an exploratory study: healthy controls (n = 34), HIV-negative individuals with a history of CD (n = 21), HIV+ individuals with no history of CD (n = 20), HIV+ individuals with a history of CD (n = 15). Our analyses revealed no statistical evidence of an interaction between both conditions on brain morphometry and neurocognitive performance. While descriptively, individuals with comorbid HIV and a history of CD exhibited the lowest neurocognitive performance scores, using Principle Component Analysis of neurocognitive testing data, HIV was identified as the primary driver of neurocognitive impairment. Higher caudate volume was evident in CD+ participants relative to CD- participants. Findings indicate no evidence of compounded differences in neurocognitive function or structural measures of brain integrity in HIV+ individuals in recovery from CD relative to individuals with only one condition.

Differential expression of miR-1249-3p and miR-34b-5p between vulnerable and resilient phenotypes of cocaine addiction.

Cocaine addiction is a complex brain disorder involving long-term alterations that lead to loss of control over drug seeking. The transition from recreational use to pathological consumption is different in each individual, depending on the interaction between environmental and genetic factors. Epigenetic mechanisms are ideal candidates to study psychiatric disorders triggered by these interactions, maintaining persistent malfunctions in specific brain regions. Here we aim to study brain-region-specific epigenetic signatures following exposure to cocaine in a mouse model of addiction to this drug. Extreme subpopulations of vulnerable and resilient phenotypes were selected to identify miRNA signatures for differential vulnerability to cocaine addiction. We used an operant model of intravenous cocaine self-administration to evaluate addictive-like behaviour in rodents based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria to diagnose substance use disorders. After cocaine self-administration, we performed miRNA profiling to compare two extreme subpopulations of mice classified as resilient and vulnerable to cocaine addiction. We found that mmu-miR-34b-5p was downregulated in the nucleus accumbens of vulnerable mice with high motivation for cocaine. On the other hand, mmu-miR-1249-3p was downregulated on vulnerable mice with high levels of motor disinhibition. The elucidation of the epigenetic profile related to vulnerability to cocaine addiction is expected to help find novel biomarkers that could facilitate the interventions to battle this devastating disorder.

A preliminary investigation of schedule parameters on cocaine abstinence in contingency management.

Contingency management (CM) interventions are the most effective psychosocial interventions for substance use disorders. However, further investigation is needed to create the most robust intervention possible. This study investigated the effects of 1) reinforcer magnitude; and 2) fixed and escalating and resetting incentives on cocaine abstinence in an outpatient trial. In this analysis, 34 treatment-seeking individuals with Cocaine Use Disorder received either high or low value incentives for providing a benzoylecgonine-negative urine sample or were in a control condition and received incentives for providing a urine sample regardless of the results. Participants received either escalating and resetting incentives, wherein the value of each incentive increased with consecutive negative samples and reset to the initial level upon a positive sample (Experiment 1), or fixed incentives, wherein they received the same value incentive for each negative urine sample they provided (Experiment 2). Large incentives produced more abstinence, although escalating and resetting reinforcer values did not have a differential effect. Large, fixed incentives promoted abstinence faster than other reinforcers, whereas smaller incentives resulted in poor abstinence and took many visits to achieve initial abstinence. Future research comparing different schedules on cocaine abstinence in a randomized control trial with a larger sample size is required.

Effects of ketosis on cocaine-induced reinstatement in male mice.

In recent years, the benefits of the ketogenic diet (KD) on different psychiatric disorders have been gaining attention, but the substance abuse field is still unexplored. Some studies have reported that palatable food can modulate the rewarding effects of cocaine, but the negative metabolic consequences rule out the recommendation of using it as a complementary treatment. Thus, the main aim of this study was to evaluate the effects of the KD on cocaine conditioned place preference (CPP) during acquisition, extinction, and reinstatement. 41 OF1 male mice were employed to assess the effects of the KD on a 10 mg/kg cocaine-induced CPP. Animals were divided into three groups: SD, KD, and KD after the Post-Conditioning test. The results revealed that, while access to the KD did not block CPP acquisition, it did significantly reduce the number of sessions required to extinguish the drug-associated memories and it blocked the priming-induced reinstatement.

Exploring protective associations between the use of classic psychedelics and cocaine use disorder: a population-based survey study.

Cocaine Use Disorder (CUD) is a significant public health problem associated with elevated morbidity and mortality within the United States. Current behavioral treatments have limited efficacy and there are currently no FDA approved pharmacological treatments for CUD. Classic psychedelics might be associated with lowered odds of substance misuse and may effectively treat various forms of addiction. Thus, the goal of this study is to assess protective associations that lifetime use of classic psychedelics may share with CUD within a nationally representative sample of the U.S. We used data from The National Survey on Drug Use and Health (NSDUH) (2015-2019) and conducted survey-weighted multivariable logistic regression to test whether each of four classic psychedelics (peyote, mescaline, psilocybin, LSD) conferred lowered odds of CUD and its related 11 sub-criteria. Participants were 214,505 adults in the NSDUH (2015-2019) aged 18 and older. Peyote conferred lowered odds of CUD, reducing the odds of CUD by over 50% (aOR: 0.47). All other substances (including other classic psychedelics) either shared no association to CUD or conferred increased odds of CUD. Furthermore, sensitivity analyses revealed peyote to confer sharply lowered odds of the majority (seven of 11) of CUD criteria as well (aOR range: 0.26-0.47). Peyote use is associated with lowered odds of CUD. Future inquiries into third variable factors (i.e., demographic/personality profiles of individuals who use peyote, motivational/contextual factors surrounding peyote use) that may underlie our observed associations may reveal protective factors that can inform treatment development for CUD. Additionally, future longitudinal studies can shed further light on whether there is a temporal link between peyote use and lowered odds of CUD.

Peer presence and familiarity as key factors to reduce cocaine intake in both rats and humans: an effect mediated by the subthalamic nucleus.

RATIONALE: Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Although the importance of social influence in the context of drug addiction is known, there is a need for studies assessing its neurobiological substrate and for translational research. OBJECTIVES: Here, we explored the influence of peer presence and familiarity on cocaine intake and its neurobiological basis. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigated its role on such influence of social context on cocaine intake. METHODS: We first compared cocaine consumption in various conditions (with no peer present or with peers with different characteristics: abstinent peer or drug-taking peer, familiar or not, cocaine-naive or not, dominant or subordinate) in rats (n = 90). Then, with a translational approach, we assessed the influence of the social context (alone, in the group, in a dyad with familiar or non-familiar peers) on drug intake in human drug users (n = 77). RESULTS: The drug consumption was reduced when a peer was present, abstinent, or drug-taking as well, and further diminished when the peer was non-familiar. The presence of a non-familiar and drug-naive peer represents key conditions to diminish cocaine intake. The STN lesion by itself reduced cocaine intake to the level reached in presence of a non-familiar naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Then, the human study confirmed the beneficial effect of social presence, especially of non-familiar peers. CONCLUSION: Our results indirectly support the use of social interventions and harm reduction strategies and position the STN as a key cerebral structure to mediate these effects.

Assessing combinatorial effects of HIV infection and former cocaine dependence on cognitive control processes: A functional neuroimaging study of response inhibition.

Individuals with a diagnosis of co-morbid HIV infection and cocaine use disorder are at higher risk of poor health outcomes. Active cocaine users, both with and without HIV infection, show clear deficits in response inhibition and other measures of executive function that are instrumental in maintaining drug abstinence, factors that may complicate treatment. Neuroimaging and behavioral evidence indicate normalization of executive control processes in former cocaine users as a function of the duration of drug abstinence, but it is unknown to what extent co-morbid diagnosis of HIV affects this process. To this end, we investigate the combinatorial effects of HIV and cocaine dependence on the neural substrates of cognitive control in cocaine-abstinent individuals with a history of cocaine dependence. Blood-oxygen level dependent signal changes were measured as 86 participants performed a Go/NoGo response inhibition task while undergoing functional magnetic resonance imaging (fMRI). Four groups of participants were selected based on HIV and cocaine-dependence status. Participants affected by both conditions demonstrated the lowest response accuracy of all participant groups. In a region of interest analysis, hyperactivation in the left putamen and midline-cingulate hyperactivation was observed in individuals with both HIV and cocaine dependence relative to individuals with only one condition. Results of a whole-brain analysis indicate response inhibition-related hyperactivation in the bilateral supplementary motor area, bilateral hippocampi, bilateral primary somatosensory areas, right dorsal anterior cingulate, and left insula in the CD+/HIV+ group relative to all other groups. These results indicate complex and interactive alterations in neural activation during response inhibition and highlight the importance of examining the neurocognitive effects of co-morbid conditions.

Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats.

BACKGROUND: Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD). OBJECTIVE: Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated. METHODS: Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 µs pulse width and 130 Hz frequency) stimulation with a constant current of 150 µA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated. RESULTS: Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions. CONCLUSIONS: These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.

Emotion recognition in individuals with cocaine use disorder: the role of abstinence length and the social brain network.

RATIONALE: Emotion recognition is impaired in drug addiction. However, research examining the effects of cocaine use on emotion recognition yield mixed evidence with contradictory results potentially reflecting varying abstinence durations. OBJECTIVES: Therefore, we investigated emotion recognition and its neural correlates in individuals with cocaine use disorder (CUD) parsed according to abstinence duration. METHODS: Emotion recognition performance was compared between current cocaine users (CUD + , n = 28; cocaine-positive urine), short-term abstainers (CUD-ST, n = 23; abstinence < 6 months), long-term abstainers (CUD-LT, n = 20; abstinence ≥ 6 months), and controls (n = 45). A sample subset (n = 73) underwent structural magnetic resonance imaging to quantify regional gray matter volume (GMV) using voxel-based morphometry. RESULTS: CUD + demonstrated greater difficulty recognizing happiness than CUD-ST and controls, and sadness and fear compared to controls (p < 0.01). For fear, CUD-ST also performed worse than controls (p < 0.01), while no differences emerged between CUD-LT and controls. Whole-brain analysis revealed lower GMV in the bilateral cerebellum in CUD + compared to CUD-LT and controls; a similar pattern was observed in the amygdala (CUD + < CUD-LT) (pFWE < 0.01). Collapsed across all participants, poorer recognition for happiness was associated with lower right cerebellar GMV (pFWE < 0.05). CONCLUSIONS: Emotion recognition is impaired with current cocaine use, and selective deficits (in fear) may persist with up to 6 months of abstinence. Lower cerebellar GMV may underlie deficits in positive emotion recognition. Interventions targeting emotional-social-cognitive deficits, especially among active users, may enhance treatment success for individuals with CUD.