Cocaine Abuse Research Articles

Psilocybin-assisted psychotherapy for methamphetamine dependence: a case report involving daily methamphetamine use

Methamphetamine (MA) dependence leads to severe physical and psychological issues. Current treatments, including psychosocial therapies and residential rehabilitation, face limitations such as high relapse rates, cost, and accessibility issues. As a result, there is an urgent need for novel approaches to treat MA dependence that are effective, affordable, and accessible to patients. Psilocybin, the active component in numerous mushrooms of the Psilocybe genus, has shown potential for enhancing psychotherapy for various addiction and mental health issues due to its effects on perception, cognition, and affect. Psilocybin-assisted psychotherapy (PAT) has demonstrated initial safety and efficacy in treating alcohol, cocaine, and nicotine dependence. The case presented here describes a 36-year-old transwoman and daily MA user, who participated in a single-arm open-label clinical trial assessing feasibility and safety of PAT for MA dependence at St. Vincent’s Hospital, Sydney. Following inpatient withdrawal management and one session of psilocybin-assisted therapy, she experienced significant cognitive and emotional shifts and sustained MA abstinence. She reported improved mental health over 3 months following treatment completion. She also noted increased self-esteem, mindfulness, and distress tolerance. This study suggests that PAT (following inpatient MA withdrawal management) may offer a scalable, safe, and effective approach for treating MA dependence. However, further research is required to confirm the generalisability and efficacy of PAT for broader populations of people using MA. It is encouraging that this participant, a daily MA user, showed improvements in mood and cognition, in addition to abstinence from MA.

Long- vs short-access cocaine alters behavioral inhibition for cocaine in male rats

Impulsivity and behavioral inhibition are measures commonly associated with substance misuse, particularly cocaine use disorder. However, patterns of impulsive behaviors have been shown to differ based on cocaine use history and level of cocaine dependence. Extended cocaine access, which more closely models neural and behavioral changes that take place during the development of problematic cocaine use, has been shown to decrease behavioral inhibition in comparison to limited cocaine access. However, previous preclinical studies investigating these relationships have been mostly correlational and only utilize non-drug rewards. This study aims to utilize a differential rates of low reinforcement (DRL) schedule to investigate the impact of extended access to cocaine on behavioral inhibition toward a cocaine reinforcer. Male Sprague Dawley rats first self-administered intravenous cocaine infusions on a DRL schedule of reinforcement before being split into two groups: one given 6-h extended cocaine access (LgA) and one given 1-h short cocaine access (ShA) for 10 daily sessions. Following a washout period, the rats were placed back on DRL cocaine self-administration sessions. Results revealed that LgA rats showed impaired performance on the behavioral inhibition measure during the DRL self-administration sessions compared to baseline DRL performance and compared to ShA post-access behavioral inhibition measures. These results indicate that extended cocaine access impairs an organism's behavioral inhibition toward future cocaine use, indicating that those individuals with a history of heavy cocaine use will have impaired behavioral inhibition toward future cocaine use.

Astrocytic Regulation of Cocaine Locomotor Sensitization in EcoHIV Infected Mice

Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model in male and female mice to assess changes in locomotor responses after repeated cocaine (10mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.

Barriers and facilitators to medication-assisted treatment for cocaine use disorder among men who have sex with men: a qualitative study

BackgroundRates of cocaine use disorder (CUD) among men who have sex with men (MSM) are high and rising. Among MSM, cocaine use is associated with negative socioeconomic, medical, and psychological outcomes. There are no FDA-approved pharmacotherapy options to treat CUD, and psychosocial interventions demonstrate limited efficacy. While there have been numerous trials evaluating possible medications for CUD, there is a scarcity of qualitative data on the barriers and facilitators of medication-assisted treatment.MethodsSemi-structured interviews were conducted with 16 participants enrolled in a phase II randomized control trial evaluating extended-release lorcaserin among MSM with CUD. Participants were asked about their motivations for enrolling in the study, attitudes towards taking a medication for CUD, barriers and facilitators of study pill adherence, and their general study experience. Interviews were analyzed using an inductive and exploratory approach to thematic analysis.ResultsParticipants were highly motivated to reduce cocaine use and viewed pharmacotherapy as a viable and desirable treatment option. Pharmacotherapy was seen as having fewer access and adherence structural barriers compared to existing psychosocial therapies. Medication reminders facilitated pill taking, while side effects, travel, and active substance use presented barriers to study pill adherence. Disclosure of study participation within social networks was variable pointing to anticipated substance use and treatment stigma.ConclusionsOur study highlights important factors affecting the acceptability and uptake of medication-assisted treatment for CUD among a diverse sample of MSM. These findings can help guide the development and implementation of future pharmacotherapy options for CUD and other substance use disorders in this key population.

RDS04-010: A novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals.

Cocaine use disorder (CUD) is a severe public health problem, and currently, there is no FDA-approved medication for its treatment. Atypical dopamine (DA) transporter (DAT) inhibitors display low addictive liability by themselves and may have therapeutic potential for treatment of psychostimulant use disorders. Here, we report that RDS04-010, a novel atypical DAT inhibitor that binds to an inward-facing conformation of DAT due to its sulfoxide moiety, displayed distinct pharmacological profiles in animal models of addiction from its sulfide analog, RDS03-094, a DAT inhibitor that binds to a more outward-facing conformation. Systemic administration of RDS04-010 dose-dependently inhibited cocaine self-administration (SA), shifted the cocaine SA dose-response curve downward, decreased motivation for cocaine seeking under progressive ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. In contrast, RDS03-094 displayed more cocaine-like reinforcing effects. Its pretreatment upward-shifted both the cocaine self-administration dose-response and optical brain-stimulation reward curves. RDS03-094 alone was able to reinstate extinguished cocaine-seeking behavior and sustain self-administration during a substitution test. Collectively, these findings suggest that RDS04-010 is a novel atypical DAT inhibitor with favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. Moreover, this extensive behavioral evaluation further confirms the role DAT binding conformation plays in the distinctive profiles of atypical DAT inhibitors that prefer the inward facing conformation.

Deux cents ans d’histoire des usages et mésusages du protoxyde d’azote

Deux cents ans d’histoire des usages et mésusages du protoxyde d’azote

Integration of pharmacochemistry, pharmacodynamics and metabolomics to reveal active ingredients and mechanism of Nan Bao detox capsule alleviating methamphetamine addiction.

Nan Bao detox capsule (NBDC), derived from ancient Chinese opioid detox protocols, shows promising therapeutic potential in substance abuse disorders, particularly for attenuating methamphetamine (MA) addiction. This study aimed to identify active ingredients, evaluate therapeutic efficacy in an MA addiction rat model and delineate pharmacodynamic mechanisms using metabolomics. In vitro phytochemical profiling characterized 258 drug-related compounds, with 87 prototype entities mainly identified in rat plasma. NBDC significantly attenuated METH-induced behavioural anomalies and modulated neurotransmitter levels, notably increasing brain DA and serotonin (5-HT) content with concomitant upregulation of D1 dopamine receptor (DRD1) and 5-HT1A receptor (5-HT1AR) expression, ameliorating hippocampal pathology. Metabolomic analysis identified histamine receptor as a potential target and revealed the involvement of NBDC in metabolic pathways associated with cocaine addiction, amphetamine abuse and Parkinson's disease. Conclusively, NBDC presents a promising therapeutic agent for mitigating MA addiction through a synergistic interplay of multiple constituents, pharmacological targets and metabolic pathways.

Melatonin Protects Against Cocaine-Induced Blood-Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression.

Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.

Associations Between Self-Reported Cocaine Use Patterns and Cocaine and Its Metabolites in Hair: Implications for Clinical and Forensic Practices.

In forensic toxicology, it has been debated if hair testing allows an estimation of the intensity of cocaine use-an assumption that may have risen because self-reports in a forensic setting are of uncertain validity per se. We therefore investigated the relationship between self-reported cocaine use and cocaine hair concentrations (including its main metabolites benzoylecgonine and norcocaine) in chronic cocaine users voluntary participating in psychiatric study settings. Additionally, we tested whether hair testing can distinguish between individuals with and without a diagnosis of cocaine dependency. Cocaine users (N = 195) from three independent experimental studies reported their average powder cocaine consumption in g/week over the last 3-4 months in an interview and provided a 3- to 4-cm hair sample assayed with liquid chromatography tandem-mass spectrometry. Moreover, study participants were assessed with the Structured Clinical Interview (SCID-IV) for psychiatric diagnoses. Using linear regression models, we found a robust correlation between cocainetotal (sum of cocaine and metabolites) hair concentration and self-reported cocaine use in g/week (rcocainetotal = 0.47, p < 0.001), indicating that 1000 pg/mg cocainetotal corresponded to a use of 0.80 g/week (confidence interval [95%]: 0.56-1.07 g/week). In logistic regression models, cocainetotal hair concentration predicted cocaine dependency with a sensitivity of 0.79 and a specificity of 0.65 (threshold 0.5), suggesting its acceptable capacity to distinguish dependent from non-dependent cocaine users. The findings may have significant implications for forensic and clinical practices, encouraging the use of hair analysis as a potential tool for monitoring cocaine use and dependence.

The Mechanism of the Nucleus Accumbens-Ventral Pallidum Pathway Mediated by Drug Withdrawal-Induced High-Seeking Motivation in Cocaine Addiction.

The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse.

Dopamine D1-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats.

Previous studies indicated differing effects of dopamine D1-like and D2-like receptor (D1R and D2R, respectively) agonists on cocaine self-administration. Leftward shifts by D2R agonists in the cocaine self-administration dose-effect function contrast with decreases by D1R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D1R agonists are due to actions at D1Rs has not been determined possibly due to the difficulty in separating the blockade by a D1R antagonist of the effects of the D1R agonists and those of cocaine. In the present study, pretreatment with the D1R agonists R(+)-SKF-81297 (0.1-1.0 mg/kg) and ({plus minus})-SKF-82958 (0.032-0.32 mg/kg) dose-dependently decreased maximal cocaine self-administration at doses below those affecting food-reinforced responding. In contrast, pretreatment with the D2R agonists R(-)-NPA (0.001-0.01 mg/kg) and (-)-quinpirole (0.01-0.1 mg/kg) dose-dependently left shifted the cocaine self-administration dose-effect function. The decreases by D1R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D1R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D1R agonists on cocaine self-administration were like those that shifted self-administration of D1R agonists to the right but had no effects on self-administration of D2R agonists. Self-administration of the D2R agonists was dose-dependently shifted to the right by the preferential D2R antagonist, L-741,626, but not by SCH-39166. These results demonstrate that the decreases by the D1R agonists in cocaine self-administration are selectively D1R-mediated, and support findings suggesting fundamentally distinct roles of the D1Rs and D2Rs in cocaine reinforcement. Significance Statement Dopamine D1-like (D1R) agonists decrease maximal cocaine self-administration, whereas D2-like (D2R) agonists shift the cocaine self-administration dose-effect function leftward with mechanisms for those different effects unclear. The present study demonstrates blockade by the selective D1R antagonist SCH-39166 of decreases in maximal cocaine self-administration at doses that blocked other D1R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D1-like and D2-like receptors in cocaine reinforcement and development of D1R agonists as potential treatments for cocaine-use disorder.

Cervical kyphoscoliosis due to substance abuse: a case series on introduction and neurosurgical treatment.

A prospective case series. To investigate the possible associations of multi-directional cervical kyphoscoliosis (CKS) with substance abuse and evaluate treatment outcomes. CKS is a rare medical situation without a well-established pathology. Still there are many obscurities in treatment paradigms and outcomes. To our knowledge, there is no published report on the association between CKS with addiction. Besides the novel report of such a rare etiology for CSK, the complexity of the neurosurgical treatment makes this report the first of its kind. In this series, we presented three patients with a history of crack cocaine addiction who suffered CKS due to prolonged hand-over-neck posture and treated all of them with a complex neurosurgical protocol. All cases were operated on and restored their normal spine alignment. Their long-term outcomes showed independent neurological status with no major surgical complications. Crack cocaine addiction might be associated with CKS in long-term cocaine abuse. A complex neurosurgical approach can achieve a sustainable clinical outcome.

The Mental Suffering of Cocaine-Addicted Patients: A Retrospective Analysis of Personality Disorders' Prevalence and Their Association with Psychopathological Symptoms.

(1) Background: The observational retrospective study aimed to investigate the prevalence of personality disorders (PDs) and their association with psychopathological symptoms in a group of patients with cocaine addiction. (2) Methods: Ninety-five medical records of the Pathological Addictions Service of the National Health Service of Lecce (Italy) were analyzed. PDs were diagnosed using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) and psychopathological symptoms were investigated through the Symptom Checklist 90-Revised (SCL-90-R). (3) Results: Ninety-two out of ninety-five patients met the criteria for at least one PD (96.8%), almost 35% had two Cluster B PDs, and over 25% had three Cluster B PDs. Nine out of ninety-five people met the criteria for all Cluster B PDs. Among the Cluster B PDs, it emerged that the most frequent diagnosis was that of narcissistic-borderline-antisocial (over 20% of the total sample). The analysis highlighted that mental suffering is prevalent in those with multiple comorbid Cluster B PDs. Specifically, depression and psychoticism exceed the clinical cut-off (T score > 63) in all patient groups. At the same time, anxiety and obsessions-compulsions are complained of only by those with more than two PDs as well as the level of general distress. Furthermore, anxiety, hostility, and paranoid ideation are significantly higher in the group of patients with more than three PDs. (4) Conclusions: Further studies should better investigate the relationship between the two aspects and describe the causal effects of PDs on psychopathological symptoms or, on the contrary, the effects of the substance on mental health and the worsening of personality alterations.

Oxytocin moderates fMRI connectivity and response to implicit threat processing in cocaine use disorder

Stressful social experiences play an important role in increasing vulnerability to substance use, including cocaine. Oxytocin (OXT), known for its anxiolytic properties and involvement in social functioning, has been suggested as a potential therapeutic for cocaine use disorder (CUD). However, limited research has explored OXT’s influence on social stress in CUD, and no study has examined its effects on neural response to subconscious (implicit) social threat cues in this population. To address this gap, the present study administered intranasal OXT (24 IU) or placebo (PBO) to participants with CUD (CUD+, N = 76) or without CUD (CUD-, N = 61) in a randomized parallel design. Participants then completed a functional magnetic resonance imaging (fMRI) task involving briefly presented facial fear and anger (i.e., threat) cues, followed by neutral face stimuli. Whole-brain activation and amygdala functional connectivity (using psychophysiological interaction modeling) were examined in response to the facial threat cues. OXT reduced activation in the thalamus and pontine reticular formation in response to fear cues, and in the supplementary motor area for both fear and anger cues, regardless of CUD status. Additionally, under PBO, amygdala-medial prefrontal cortex connectivity to fear stimuli was negative for the CUD+ group, but under OXT, this coupling was positive, similar to the positive coupling observed for the CUD- group under both PBO and OXT administration. The finding of OXT-mediated reversal of amygdala-prefrontal coupling was specific to CUD+ and suggests that OXT alters circuitry related to threat surveillance and implicit emotion regulation in CUD. However, additional research is needed to determine whether these alterations due to OXT have clinical significance in CUD.

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

Artificial intelligence-based analysis of behavior and brain images in cocaine-self-administered marmosets

BackgroundThe sophisticated behavioral and cognitive repertoires of non-human primates (NHPs) make them suitable subjects for studies involving cocaine self-administration (SA) schedules. However, ethical considerations, adherence to the 3Rs principle (replacement, reduction and refinement), and other factors make it challenging to obtain NHPs individuals for research. Consequently, there is a need for methods that can comprehensively analyze small datasets using artificial intelligence (AI). New methodsWe employed AI to identify cocaine dependence patterns from collected data. First, we collected behavioral data from cocaine SA marmosets (Callithrix jacchus) to develop a dependence prediction model. SHapley Additive exPlanations (SHAP) values were used to demonstrate the importance of various variables. Additionally, we collected positron emission tomographic (PET) images showing dopamine transporter (DAT) binding potential and developed an algorithm for PET image segmentation. ResultsThe prediction model indicated that the Random Forest (RF) algorithm performed best, with an area under the curve (AUC) of 0.92. The top five variables influencing the model were identified using SHAP values. The PET image segmentation model achieved an accuracy of 0.97, a mean squared error of 0.02, an intersection over union (IoU) of 0.845, and a Dice coefficient of 0.913. Comparison with existing methods and conclusionUtilizing data from the marmoset SA experiment, we developed an ML-based dependence prediction model and analyzed variable importance rankings using SHAP. AI-based imaging segmentation methods offer a valuable tool for evaluating DAT availability in NHPs following chronic cocaine administration.

Psychopathy traits explain variance shared between features of substance use disorders and violence.

There is a substantial research literature on identifying risk and protective factors for violence perpetration. Substance use disorders have long been identified as constituting a significant predictor of violent behaviour. Psychopathy traits have also been similarly recognised, but inter-relationships between psychopathy traits, features of substance use disorders and violence have been little explored. To determine the degree to which shared variance between substance dependence symptoms and violence, as indicated by criminal charges for violent offences, among jailed men can be explained by psychopathy traits. Features of dependence on substances in three drug classes (alcohol, cannabis and cocaine) were assessed in a sample of 682 men in a county jail awaiting trial on criminal charges, many for violent offences. Statistical comparisons of zero-order and partial correlations tested whether accounting for psychopathy total and facet scores, assessed by the Psychopathy Checklist-Revised (PCL-R), affected associations between substance dependence symptoms and violent charges. Total PCL-R scores accounted for a significant proportion of the shared variance between the history of criminal charges for violence offences and lifetime substance dependence symptoms in all three drug classes. At the facet level, controlling for ratings on the interpersonal and modified antisocial facets reduced the association between criminal charges for violent offences and symptoms of cocaine dependence; controlling for ratings on a modified antisocial facetalso attenuated links between alcohol and cannabis dependence symptoms and history of charges for violent offences. These findings build on the sparse literature to date on the role of psychopathy traits on relationships between features of substance use disorders and violence. Given that the observed connection between substance dependence symptoms and charges for violent offences is partly accounted for by individual differences in psychopathy traits, it follows that effective treatment for those traits may be useful, perhaps essential to reducing links between features of some substance use disorders and violent offending.

Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity

Cocaine use disorder (CUD) is a chronic neuropsychiatric disorder estimated to effect 1–3% of the population. Activity-dependent neuroprotective protein (ADNP) is essential for brain development and functioning, shown to be protective in fetal alcohol syndrome and to regulate alcohol consumption in adult mice. The goal of this study was to characterize the role of ADNP, and its active peptide NAP (NAPVSIPQ), which is also known as davunetide (investigational drug) in mediating cocaine-induced neuroadaptations. Real time PCR was used to test levels of Adnp and Adnp2 in the nucleus accumbens (NAc), ventral tegmental area (VTA), and dorsal hippocampus (DH) of cocaine-treated mice (15 mg/kg). Adnp heterozygous (Adnp+/−)and wild-type (Adnp+/−) mice were further tagged with excitatory neuronal membrane-expressing green fluorescent protein (GFP) that allowed for in vivo synaptic quantification. The mice were treated with cocaine (5 injections; 15 mg/kg once every other day) with or without NAP daily injections (0.4 µg/0.1 ml) and sacrificed following the last treatment. We analyzed hippocampal CA1 pyramidal cells from 3D confocal images using the Imaris x64.8.1.2 (Oxford Instruments) software to measure changes in dendritic spine density and morphology. In silico ADNP/NAP/cocaine structural modeling was performed as before. Cocaine decreased Adnp and Adnp2 expression 2 h after injection in the NAc and VTA of male mice, with mRNA levels returning to baseline levels after 24 h. Cocaine further reduced hippocampal spine density, particularly synaptically weaker immature thin and stubby spines, in male Adnp+/+) mice while increasing synaptically stronger mature (mushroom) spines in Adnp+/−) male mice and thin and stubby spines in females. Lastly, we showed that cocaine interacts with ADNP on a zinc finger domain identical to ketamine and adjacent to a NAP-zinc finger interaction site. Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD.

Astrocytic Regulation of Cocaine Locomotor Sensitization in EcoHIV Infected Mice.

Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model to assess changes in locomotor responses after repeated cocaine (10mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.

Predictors of abstinence maintenance after cocaine inpatient detoxification: A prospective study.

Cocaine is a highly addictive substance, and with no approved medication for cocaine use disorder (CUD), leading to a heavy burden. Despite validated psychosocial treatments, relapse rates after detoxification are very high in CUD. Few consistent factors can predict abstinence after detoxification. Our study, therefore, aimed at identifying factors predicting abstinence among CUD patients after inpatient detoxification. Eighty-one CUD inpatients were included during detoxification and characterized for clinical and sociodemographic data at baseline and at a follow-up of 3 months after discharge, including a standard measure of their abstinence duration from cocaine. We performed Cox univariate analyzes to determine the factors associated with abstinence maintenance, followed by a multivariate Cox regression to identify independent predictors. Abstinence maintenance was shorter in patients injecting cocaine (hazard ratio [HR] = 5.16, 95% confidence interval [CI]: 2.01-13.27, p < .001) and using cocaine heavily in the month before inclusion (HR = 1.03, 95% CI: 1.00-1.06, p = .046). Conversely, abstinence maintenance was longer in patients with longer inpatient detoxification stays (HR = 0.96, 95% CI: 0.94-0.99, p = .015) and prescribed with selective serotonin reuptake inhibitors (SSRIs) (HR = 0.30, 95% CI: 0.16-0.56, p < .001). Patients with severe CUD may require longer inpatient stays to achieve abstinence. Regarding SSRI prescription, more specific studies are needed to provide stronger recommendations about their use in clinical practice. Our findings suggest several modifiable factors to improve inpatient treatment response in CUD. As there are no specific recommendations about the optimal duration of inpatient stay, our results could pave the way for evidence-based guidelines.