Impact of cannabidiol on brain glucose metabolism of C57Bl/6 male mice previously exposed to cocaine.

Despite evidence of the beneficial effects of cannabidiol (CBD) in animal models of cocaine use disorder (CUD), CBD neuronal mechanisms remain poorly understood. This study investigated the effects of CBD treatment on brain glucose metabolism, in a CUD animal model, using [18F]FDG positron emission tomography (PET). Male C57Bl/6 mice were injected with cocaine (20 mg/kg, i.p.) every other day for 9 days, followed by 8 days of CBD administration (30 mg/kg, i.p.). After 48 h, animals were challenged with cocaine. Control animals received saline/vehicle. [18F]FDG PET was performed at four time points: baseline, last day of sensitization, last day of withdrawal/CBD treatment, and challenge. Subsequently, the animals were euthanized and immunohistochemistry was performed on the hippocampus and amygdala to assess the CB1 receptors, neuronal nuclear protein, microglia (Iba1), and astrocytes (GFAP). Results showed that cocaine administration increased [18F]FDG uptake following sensitization. CBD treatment also increased [18F]FDG uptake in both saline and cocaine groups. However, animals that were sensitized and challenged with cocaine, and those receiving only an acute cocaine injection during the challenge phase, did not exhibit increased [18F]FDG uptake when treated with CBD. Furthermore, CBD induced modifications in the integrated density of NeuN, Iba, GFAP, and CB1R in the hippocampus and amygdala. This is the first study addressing the impact of CBD on brain glucose metabolism in a preclinical model of CUD using PET. Our findings suggest that CBD disrupts cocaine-induced changes in brain energy consumption and activity, which might be correlated with alterations in neuronal and glial function.

Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study.

Background: Preclinical studies show that clavulanic acid (CLAV) inhibits cocaine self-administration. This study investigates the effect of CLAV on regions of brain activation in response to cocaine cues during functional magnetic resonance imaging (fMRI) in participants with cocaine use disorder (CUD). Methods: A double-masked, placebo-controlled clinical trial with thirteen individuals with severe CUD who were randomized to treatment with CLAV (N = 10, 9 completers) 500 mg/day or matched placebo (PBO) (N = 3) for 3 days. fMRI was used to assess brain reactivity to 18 alternating six-second video clips of cocaine or neutral scenes. In this paradigm, participants were exposed to three different stimulus conditions: NEUTRAL, WATCH (passive watching), and DOWN (actively inhibiting craving while watching). Results: Participants who received CLAV demonstrated a significant reduction in brain activity in the anterior cingulate gyrus (p = 0.009) and the caudate (p = 0.018) in response to DOWN cocaine cues. There was a trend toward lessened cue reactivity in other regions implicated in CUD. Conclusion: CLAV reduced the response of the brain regions associated with motivation and emotional response during the DOWN condition compared to PBO, suggesting CLAV may strengthen voluntary efforts to avoid cocaine use. This pilot data supports the use of CLAV for CUD. (Trial registered in ClinicalTrials.gov NCT04411914).

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.

Estimated Number of Injection-Involved Overdose Deaths in US States From 2000 to 2020: Secondary Analysis of Surveillance Data.

BACKGROUND: In the United States, both drug overdose mortality and injection-involved drug overdose mortality have increased nationally over the past 25 years. Despite documented geographic differences in overdose mortality and substances implicated in overdose mortality trends, injection-involved overdose mortality has not been summarized at a subnational level. OBJECTIVE: We aimed to estimate the annual number of injection-involved overdose deaths in each US state from 2000 to 2020. METHODS: We conducted a stratified analysis that used data from drug treatment admissions (Treatment Episodes Data Set-Admissions; TEDS-A) and the National Vital Statistics System (NVSS) to estimate state-specific percentages of reported drug overdose deaths that were injection-involved from 2000 to 2020. TEDS-A collects data on the route of administration and the type of substance used upon treatment admission. We used these data to calculate the percentage of reported injections for each drug type by demographic group (race or ethnicity, sex, and age group), year, and state. Additionally, using NVSS mortality data, the annual number of overdose deaths involving selected drug types was identified by the following specific multiple-cause-of-death codes: heroin or synthetic opioids other than methadone (T40.1, T40.4), natural or semisynthetic opioids and methadone (T40.2, T40.3), cocaine (T40.5), psychostimulants with abuse potential (T43.6), sedatives (T42.3, T42.4), and others (T36-T59.0). We used the probabilities of injection with the annual number of overdose deaths, by year, primary substance, and demographic groups to estimate the number of overdose deaths that were injection-involved. RESULTS: In 2020, there were 91,071 overdose deaths among adults recorded in the United States, and 93.1% (84,753/91,071) occurred in the 46 jurisdictions that reported data to TEDS-A. Slightly less than half (38,253/84,753, 45.1%; 95% CI 41.1%-49.8%) of those overdose deaths were estimated to be injection-involved, translating to 38,253 (95% CI 34,839-42,181) injection-involved overdose deaths in 2020. There was large variation among states in the estimated injection-involved overdose death rate (median 14.72, range 5.45-31.77 per 100,000 people). The national injection-involved overdose death rate increased by 323% (95% CI 255%-391%) from 2010 (3.78, 95% CI 3.33-4.31) to 2020 (15.97, 95% CI 14.55-17.61). States in which the estimated injection-involved overdose death rate increased faster than the national average were disproportionately concentrated in the Northeast region. CONCLUSIONS: Although overdose mortality and injection-involved overdose mortality have increased dramatically across the country, these trends have been more pronounced in some regions. A better understanding of state-level trends in injection-involved mortality can inform the prioritization of public health strategies that aim to reduce overdose mortality and prevent downstream consequences of injection drug use.

Headache Attributed to a Substance or Its Withdrawal.

Identification of substances that may cause or trigger headache is important to start effective treatment early to prevent unnecessary suffering, deterioration in quality of life, and the development of chronic pain. Treatment in case of medication overuse and other chronic headache should be decisive and effective. Drug withdrawal and introduction of effective prophylactic medication for the underlying headache disorder should be the primary treatment strategy. Typical headache-inducing substances are nitric oxide, phosphodiesterase, cocaine, alcohol, histamine, carbon oxide, and calcitonin gene-related peptide. The withdrawal of caffeine, estrogen, and opioids is most often associated with the development of headache.

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.

Prehistoric or current primitive cranial operations.

Humankind demonstrates boundless curiosity, mostly expressed through the activities of a small number of individuals, whose achievements affect all members of society. The extent and distribution of pre-historic trepanation and trepanation in contemporary unsophisticated societies are reviewed. In the great majority of cases the intention of trepanation has been therapeutic, even if the understanding of underlying pathophysiology is not the same as that which scientific societies now accept. This review demonstrates variation in surgical technique. In the Atlas Mountains it was unacceptable to operate on the cranial sutures whereas in New Ireland it was not important. Pain relief was unnecessary in Melanesia because the patients were largely unconscious following injury. In South America, there was access to the coca leaf which could help with pain relief. In East Africa, one patient described the application of a powder to his wound which was thought to be for pain relief. The nature of the powder remains unknown. There were differences in the indications for trepanation. In New Britain, the operation was performed only for cases of fracture. In nearby New Ireland, epilepsy and certain forms of mental disturbance were also indications. In North and East Africa, the indication was most frequently headache following trauma. Most of these trepanations did not involve drilling, which is the main subject of this book.

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.

Indirect and direct cannabinoid agonists differentially affect mesolimbic dopamine release and related behaviors.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Drogas de abuso asociadas a las intoxicaciones agudas: descripción global y análisis de las diferencias en mujeres atendidas en el servicio de urgencias / Street drugs associated with acute poisoning: description and analysis of differences in women attended in a hospital emergency department

Objetivos. La prevalencia del uso de drogas de abuso es difícil de establecer en mujeres, debido a los estigmas asociados a ello. El objetivo principal fue analizar las posibles diferencias de las intoxicaciones agudas (IA) según el sexo en una muestra de pacientes atendidos en dos servicios de urgencias hospitalarios (SUH). El objetivo secundario fue identificar las variables asociadas a las intoxicaciones graves, definidas de forma arbitraria como las que requerían una atención intensiva médica de más de 12 horas y posterior ingreso hospitalario. Métodos. Estudio retrospectivo en dos SUH que incluyeron pacientes mayores de 18 años atendidos por IA por drogas de abuso, en el periodo comprendido entre el 1 de julio 2020 y el 31 de julio 2023. Se recogieron variables epidemiológicas, clínicas y de laboratorio. Resultados. Se incluyeron 1.032 pacientes, un 18,5% (191) mujeres. La edad media fue de 35 (DE 10) años, con elevada prevalencia de enfermedad mental aguda (32,2%) e infección por VIH (35,7%). El principal motivo de consumo fue lúdico (90,9%). Las principales drogas de abuso fueron cocaína, alcohol y metanfetaminas. El análisis multivariado mostró que únicamente la edad (OR: 1,03, IC 95%: 1,01-1,05, p = 0,003), el VIH (OR: 2,10, IC 95%: 1,29-3,41, p = 0,003), el consumo de benzodiacepinas (OR: 3,48, IC 95%: 2,14-5,66, p < 0,0001), y la ideación autolítica (OR: 1,82, IC 95%: 1,25-3,79, p = 0,004), se asociaron a gravedad de la intoxicación. Conclusiones. Las IA por drogas de abuso en mujeres presentan algunas diferencias en relación a las de los hombres, ya que son más jóvenes y asocian consumo de alcohol con mayor frecuencia. Las campañas de prevención y políticas sanitarias sobre el uso de sustancias deberían tener en cuenta las diferencias en el consumo según el sexo para adaptarlas a la población a las que vayan dirigidas. (AU)

Background. The prevalence of street drug abuse is difficult to establish in women because of stigma associated withthe practice. The main objective of this study was to analyze possible differences between men and women in a sample of patients attended for emergencies due to acute poisonings. The secondary aim was to identify variables associated with severe poisonings defined arbitrarily as requiring intensive care for more than 12 hours after hospital admission. Methods. Retrospective study in 2 hospital EDs. We included patients over the age of 18 years attended for street drug poisonings between July 1, 2020, and July 31, 2023. Epidemiologic, clinical, and laboratory variables were analyzed. Results. A total of 1032 patients were studied; 191 (18.5%) were women. The mean (SD) age was 35 years, and the prevalences of acute mental illness and HIV infection were high at 32.2% and 35.7%, respectively. Drug use was recreational in most cases (90.9%). Cocaine, alcohol, and methamphetamines were the substances most often used. Multivariate analysis showed that the factors associated with the seriousness of poisoning were age, with an odds ratio (OR) of 1.03 (95% CI, 1.01-1.05; P = .003); HIV (OR, 2.10; 95% CI, 1.29-3.41; P = .003); use of benzodiazepines (OR, 3.48; 95% CI, 2.14-5.66; P < .0001); and suicidal ideations (OR, 1.82; 95% CI, 1.25-3.79; P = .004). Conclusions. Differences in poisoning characteristics in women were found, probably related to the younger ages of men in the sample and their higher frequency of alcohol consumption. Public health policies and campaigns to prevent drug abuse should take gender differences into consideration in order to adapt messages to the target populations. (AU)

The Concordance of Electronic Health Record Diagnoses and Substance use Self-Reports Among Reproductive Aged Women Enrolled in a Community-Based Addiction Reduction Program.

Substance use disorders among reproductive aged women are a major public health issue. There is little work investigating the validity and reliability of electronic health record (EHR) data for measuring substance use in this population. This study examined the concordance of self-reported substance use with clinical diagnoses of substance use, substance abuse and substance use disorder in EHR data. Reproductive age women enrolled in the Community-Based Addiction Reduction (CARE) program were interviewed by peer recovery coaches (PRC) at enrollment. That survey data was linked with EHR data (n = 102). Concordance between self-reported substance use and clinical diagnoses in the EHR was examined for opioids, cannabis/THC, and cocaine. Cohen's kappa, sensitivity, and specificity were calculated. The survey captured a higher number of women who use substances compared to the EHR. The concordance of self-report with EHR diagnosis varied by substance and was higher for opioids (17.6%) relative to cannabis/THC (8.8%), and cocaine (3.0%). Additionally, opioids had higher sensitivity (46.2%) and lower specificity (76.2%) relative to cannabis/THC and cocaine. Survey data collected by PRCs captured more substance use than EHRs, suggesting that EHRs underestimate substance use prevalence. The higher sensitivity and lower specificity of opioids was due to a larger number of women who had a diagnosis of opioid use in the EHR who did not self-report opioid use in the self-report survey relative to cannabis/THC and cocaine. Opioid self-report and diagnosis may be influenced by research setting, question wording, or receipt of medication for opioid use disorder.

Accidental substance-related acute toxicity deaths among youth in Canada: a descriptive analysis of a national chart review study of coroner and medical examiner data. / Décès accidentels attribuables à une intoxication aiguë due à une substance chez les jeunes au Canada : analyse descriptive d'une étude nationale portant sur l'examen des dossiers des données de coroners et de médecins légistes.

INTRODUCTION: Substance-related acute toxicity deaths (ATDs) are a public health crisis in Canada. Youth are often at higher risk for substance use due to social, environmental and structural factors. The objectives of this study were to understand the characteristics of youth (aged 12-24 years) dying of accidental acute toxicity in Canada and examine the substances contributing to and circumstances surrounding youth ATDs. METHODS: Data from a national chart review study of coroner and medical examiner data on ATDs that occurred in Canada between 2016 and 2017 were used to conduct descriptive analyses with proportions, mortality rates and proportionate mortality rates. Where possible, youth in the chart review study were compared with youth in the general population and youth who died of all causes, using census data. RESULTS: Of the 732 youth who died of accidental acute toxicity in 2016-2017, most (94%) were aged 18 to 24 years. Youth aged 20 to 24 who were unemployed, unhoused or living in collective housing were overrepresented among accidental ATDs. Many of the youth aged 12 to 24 who died of accidental acute toxicity had a documented history of substance use. Fentanyl, cocaine and methamphetamine were the most common substances contributing to death, and 38% of the deaths were witnessed or potentially witnessed. CONCLUSION: The findings of this study point to the need for early prevention and harm reduction strategies and programs that address mental health, exposure to trauma, unemployment and housing instability to reduce the harms of substance use on Canadian youth.

Accidental substance-related acute toxicity deaths in older adults in 2016 and 2017: a national chart review study. / Décès accidentels liés à une intoxication aiguë due à une substance chez les aînés en 2016 et en 2017 : une étude nationale d'examen des dossiers.

INTRODUCTION: Limited research exists on substance-related acute toxicity deaths (ATDs) in older adults (≥60 years) in Canada. This study aims to examine and describe the sociodemographic characteristics, health histories and circumstances of death for accidental ATDs among older adults. METHODS: Following a retrospective descriptive analysis of all coroner and medical examiner files on accidental substance-related ATDs in older adults in Canada from 2016 to 2017, proportions and mortality rates for coroner and medical examiner data were compared with general population data on older adults from the 2016 Census. Chisquare tests were conducted for categorical variables where possible. RESULTS: From 2016 to 2017, there were 705 documented accidental ATDs in older adults. Multiple substances contributed to 61% of these deaths. Fentanyl, cocaine and ethanol (alcohol) were the most common substances contributing to death. Heart disease (33%), chronic pain (27%) and depression (26%) were commonly documented. Approximately 84% of older adults had contact with health care services in the year preceding their death. Only 14% were confirmed as having their deaths witnessed. CONCLUSIONS: Findings provide insight into the demographic, contextual and medical history factors that may influence substance-related ATDs in older adults and suggest key areas for prevention.

Determination of fentanyl contamination on United States paper currency by LC-QQQ-MS.

Previous research has evaluated the extent to which cocaine and other drugs were detectable on currency in the USA. The literature was in agreement that the majority of bills exhibited some degree of contamination. With the increase of fentanyl in the illicit drug supply, this study was designed to evaluate the extent that fentanyl, cocaine, methamphetamine and other substances were present on circulating currency in 2022. A quantitative assay using liquid chromatography-triple quadrupole mass spectrometry was developed and validated to detect six analytes: fentanyl, 4-anilino-N-phenethylpiperidine, acetylfentanyl, benzylfentanyl, cocaine and methamphetamine. One-dollar bills were collected from 13 cities across the country. Sample preparation consisted of soaking the bills in methanol followed by liquid-liquid extraction. Chromatographic separation was achieved using a C18 analytical column and gradient elution with ammonium formate in water (5 mM, pH 3) and 0.1% formic acid in acetonitrile. The quantitative working range for this assay was 0.1 µg to 1.0 µg per bill (equivalent to 1 ng/mL to 100 ng/mL of extract). Fentanyl was detected on the majority (63%) of samples, with 61% of samples having ≥0.1 µg of fentanyl and 4% of samples having ≥1.0 µg. Cocaine and methamphetamine were detected on 100% and 98% of bills, respectively, typically in amounts >1.0 µg. The remaining fentanyl-related substances were detected in 15% of samples in amounts no >0.69 µg per bill and exclusively in the presence of fentanyl. Unsurprisingly, areas of the country with higher incidence of fentanyl use yielded higher frequency of contaminated bills and higher concentrations. Human exposure to drugs on currency is unlikely to have any significant impacts toxicologically or pharmacologically; however, our research findings suggest that paper currency could serve as a useful substrate for surveillance of drug trends regionally, nationally and/or internationally.

The HMGB1-RAGE axis in nucleus accumbens facilitates cocaine-induced conditioned place preference via modulating microglial activation.

INTRODUCTION: Repeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box-1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown. METHODS: Rats were trained by intraperitoneal cocaine administration and cocaine-induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide. RESULTS: Cocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine-induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1-RAGE interaction suppressed cocaine-induced microglial activation, as well as the consolidation of cocaine-induced memory. CONCLUSION: All above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1-RAGE axis as a new target for the treatment of drug addiction.

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.

ß2* nAChR sensitivity modulates acquisition of cocaine self-administration in male rats.

Signaling through nicotinic acetylcholine receptors (nAChRs) plays a role in cocaine reward and reinforcement, suggesting that the cholinergic system could be manipulated with therapeutics to modulate aspects of cocaine use disorder (CUD). We examined the interaction between nAChRs and cocaine reinforcement by expressing a hypersensitive ß2 nAChR subunit (ß2Leu9'Ser) in the ventral tegmental area of male Sprague Dawley rats. Compared to control rats, ß2Leu9'Ser rats acquired (fixed ratio) intravenous cocaine self-administration faster and with greater likelihood. By contrast, ß2Leu9'Ser rats were approximately equivalent to controls in their intake of cocaine on a progressive ratio schedule of reinforcement, suggesting differential effects of cholinergic signaling depending on experimental parameters. Like progressive ratio cocaine SA, ß2Leu9'Ser rats and controls did not differ significantly in food SA assays, including acquisition on a fixed ratio schedule or in progressive ratio sessions. These results highlight the specific role of high-affinity, heteropentameric ß2* (ß2-containing) nAChRs in acquisition of cocaine SA, suggesting that mesolimbic acetylcholine signaling is active during this process.

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats.

BACKGROUND: Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic receptors' type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. METHODS: In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-L-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. RESULTS: Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5-5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. CONCLUSIONS: Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions.

Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.

Modeling the Therapeutic Process of Patients with Cocaine Use Disorders: A Guide for Predicting Readmission.

INTRODUCTION: Patients with cocaine use disorders have very high readmission rates. Our aim was to model the relationships between attributes of patients with cocaine use disorder at the beginning of treatment, therapeutic process indicators of time in treatment or proportion of appointments attended, and treatment outcomes, including outcomes at discharge and non-readmissions posttreatment as indicators of therapeutic success. METHOD: A retrospective observational design was used with 10,298 cocaine use disorder patients. Electronic health records were used for statistical analysis of the data. Randomized subsample 1 (n = 5,150) was used for exploratory analysis and subsample 2 (n = 5,148) for modeling relationships between the variables. RESULTS: Patients attributes at intake (e.g., legal services as the source of referral) were of limited significance in explaining time in treatment, proportion of appointments attended, and treatment outcomes. Time in treatment and proportion of appointments attended emerged as significant factors in explaining outcomes at discharge. However, readmissions were primarily explained by time in treatment and outcomes at discharge, although referrals to addiction centers by health services also appeared to be relevant for explaining readmission. DISCUSSION/CONCLUSION: Our study has shown that maintaining a sufficient appointment attendance rate and remaining in treatment for a longer duration are critical therapeutic process indicators for explaining outcomes at the point of discharge and therapeutic success, as indicated by a reduced likelihood of readmissions. Patients who remained in treatment for an extended period were found to have a reduced risk of future readmissions. In addition, our study highlights the importance of maintaining a satisfactory appointment attendance rate to attain successful short- and medium-term therapeutic discharge outcomes. These guidelines could help to increase the efficiency of patient treatment and alleviate the suffering of both patients and their families.