RESUMEN
We have shown that CB1 receptor negative allosteric modulators (NAMs) attenuated the reinstatement of cocaine-seeking behaviors in rats. In an effort to further define the structure-activity relationships and assess the druglike properties of the 3-(4-chlorophenyl)-1-(phenethyl)urea-based CB1 NAMs that we recently reported, we introduced substituents of different electronic properties and sizes to the phenethyl group and evaluated their potency in CB1 calcium mobilization, cAMP, and GTPγS assays. We found that 3-position substitutions such as Cl, F, and Me afforded enhanced CB1 potency, whereas 4-position analogues were generally less potent. The 3-chloro analogue (31, RTICBM-189) showed no activity at >50 protein targets and excellent brain permeation but relatively low metabolic stability in rat liver microsomes. Pharmacokinetic studies in rats confirmed the excellent brain exposure of 31 with a brain/plasma ratio Kp of 2.0. Importantly, intraperitoneal administration of 31 significantly and selectively attenuated the reinstatement of the cocaine-seeking behavior in rats without affecting locomotion.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Cocaína/toxicidad , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Compuestos de Fenilurea/química , Receptor Cannabinoide CB1/metabolismo , Regulación Alostérica , Animales , Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/patología , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Vasoconstrictores/toxicidadRESUMEN
Ibudilast is a non-selective phosphodiesterase (PDE) inhibitor and glial cell modulator which has shown great promise for the treatment of drug and alcohol use disorders in recent clinical studies. However, it is unknown whether and how ibudilast affects cocaine seeking behavior. Here we show that systemic administration of ibudilast dose-dependently reduced cocaine self-administration under fixed- and progressive-ratio reinforcement schedules in rats and shifted cocaine dose-response curves downward. In addition, ibudilast decreased cocaine prime- and cue-induced reinstatement of cocaine seeking. These results indicate that ibudilast was effective in reducing the reinforcing effects of cocaine and relapse to cocaine seeking. Chronic cocaine exposure induces cAMP-related neuroadaptations in the reward circuitry of the brain. To investigate potential mechanisms for ibudilast-induced attenuation of cocaine self-administration, we recorded from ventral tegmental area (VTA) dopamine neurons in ex vivo midbrain slices prepared from rats that had undergone saline and cocaine self-administration. We found cocaine self-administration led to a decrease in inhibitory postsynaptic currents (IPSCs), an increase in the AMPAR/NMDAR ratio, and an increase in the excitation to inhibition (E/I) ratio. Ibudilast pretreatments enhanced GABAergic inhibition and did not further change cocaine-induced potentiation of excitation, leading to normalization of the E/I ratio. Restoration of the balance between excitation and inhibition in VTA dopamine neurons may contribute to the attenuation of cocaine self-administration by ibudilast.
Asunto(s)
Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/psicología , Cocaína/administración & dosificación , Cocaína/efectos adversos , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Esquema de Refuerzo , Animales , Trastornos Relacionados con Cocaína/etiología , Neuronas Dopaminérgicas/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Ratas Long-Evans , Autoadministración , Área Tegmental Ventral/fisiologíaRESUMEN
Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8-9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1+ cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1+ cells, as well as CD68+ and GFAP+ stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction.
Asunto(s)
Aminopiridinas/farmacología , Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/prevención & control , Cocaína/toxicidad , Microglía/efectos de los fármacos , Pirroles/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/patología , Condicionamiento Clásico , Inhibidores de Captación de Dopamina/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Inhibición Psicológica , Masculino , Ratones , Microglía/metabolismo , Microglía/patologíaRESUMEN
Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 µl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 µl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/efectos adversos , Ácido Glutámico/metabolismo , Núcleo Accumbens/metabolismo , Receptor Cannabinoide CB1/agonistas , Estrés Fisiológico , Animales , Conducta Animal , Biomarcadores , Condicionamiento Clásico , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Extinción Psicológica , Espacio Extracelular/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Estrés Fisiológico/genéticaRESUMEN
Persons with co-occurring HIV infection and cocaine use disorder tend to engage in riskier decision-making. However, the neural correlates of sensitivity to risk are not well-characterized in this population. The purpose of this study was to examine the neural interaction effects of HIV infection and cocaine use disorder to sensitivity to risk. The sample included 79 adults who differed on HIV status and cocaine use disorder. During functional magnetic resonance imaging (fMRI), participants completed a Wheel of Fortune (WoF) task that assessed neural activation in response to variations of monetary risk (i.e., lower probability of winning a larger reward). Across groups, neural activation to increasing risk was in cortical and subcortical regions similar to previous investigations using the WoF in nondrug-using populations. Our analyses showed that there was a synergistic effect between HIV infection and cocaine use in the left precuneus/posterior cingulate cortex and hippocampus, and right postcentral gyrus, lateral occipital cortex, cerebellum, and posterior parietal cortex. HIV+ individuals with cocaine use disorder displayed neural hyperactivation to increasing risk that was not observed in the other groups. These results support a synergistic effect of co-occurring HIV infection and cocaine dependence in neural processing of risk probability that may reflect compensation. Future studies can further investigate and validate how neural activation to increasing risk is associated with risk-taking behavior.
Asunto(s)
Cerebelo/fisiopatología , Corteza Cerebral/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Disfunción Cognitiva/fisiopatología , Toma de Decisiones/fisiología , Infecciones por VIH/fisiopatología , Asunción de Riesgos , Adulto , Cerebelo/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Trastornos Relacionados con Cocaína/diagnóstico por imagen , Trastornos Relacionados con Cocaína/etiología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Hipocampo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Maternal diet significantly influences the proper development of offspring in utero. Modifications of diet composition may lead to metabolic and mental disorders that may predispose offspring to a substance use disorder. We assessed the impact of a maternal high-sugar diet (HSD, rich in sucrose) consumed during pregnancy and lactation on the offspring phenotype in the context of the rewarding and motivational effects of cocaine and changes within the central melanocortin (MC) system. Using an intravenous cocaine self-administration model, we showed that maternal HSD leads to increased relapse of cocaine-seeking behavior in male offspring. In addition, we demonstrated that cocaine induces changes in the level of MC-4 receptors in the offspring brain, and these changes depend on maternal diet. These studies also reveal that an MC-4 receptor antagonist reduces the reinstatement of cocaine-seeking behavior, and offspring exposed to maternal HSD are more sensitive to its effects than offspring exposed to the maternal control diet. Taken together, the results suggest that a maternal HSD and MC-4 receptors play an important role in cocaine relapse.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Cocaína/administración & dosificación , Dieta/efectos adversos , Comportamiento de Búsqueda de Drogas , Extinción Psicológica , Receptor de Melanocortina Tipo 4/metabolismo , Azúcares/toxicidad , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Trastornos Relacionados con Cocaína/patología , Femenino , Masculino , Exposición Materna/efectos adversos , Embarazo , Ratas Wistar , Receptor de Melanocortina Tipo 4/genética , AutoadministraciónRESUMEN
The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs' amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs' function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.
Asunto(s)
Cocaína/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ácido Glutámico/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Área Tegmental Ventral/citología , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Modelos Biológicos , Técnicas de Placa-Clamp , Terminales Presinápticos/metabolismo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Cocaine-induced vasoconstriction reduces blood flow, which can jeopardize neuronal function and in the prefrontal cortex (PFC) it may contribute to compulsive cocaine intake. Here, we used integrated optical imaging in a rat self-administration and a mouse noncontingent model, to investigate whether changes in the cerebrovascular system in the PFC contribute to cocaine self-administration, and whether they recover with detoxification. In both animal models, cocaine induced severe vasoconstriction and marked reductions in cerebral blood flow (CBF) in the PFC, which were exacerbated with chronic exposure and with escalation of cocaine intake. Though there was a significant proliferation of blood vessels in areas of vasoconstriction (angiogenesis), CBF remained reduced even after 1 month of detoxification. Treatment with Nifedipine (Ca2+ antagonist and vasodilator) prevented cocaine-induced CBF decreases and neuronal Ca2+ changes in the PFC, and decreased cocaine intake and blocked reinstatement of drug seeking. These findings provide support for the hypothesis that cocaine-induced CBF reductions lead to neuronal deficits that contribute to hypofrontality and to compulsive-like cocaine intake in addiction, and document that these deficits persist at least one month after detoxification. Our preliminary data showed that nifedipine might be beneficial in preventing cocaine-induced vascular toxicity and in reducing cocaine intake and preventing relapse.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Cocaína/administración & dosificación , Cocaína/farmacología , Isquemia/inducido químicamente , Animales , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Masculino , Ratones , Nifedipino/farmacología , Corteza Prefrontal/irrigación sanguínea , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , AutoadministraciónRESUMEN
Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increase the magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.
Asunto(s)
Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Trastornos de Estrés Traumático/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Cocaína/efectos adversos , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/psicología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Autoadministración , Trastornos de Estrés Traumático/complicaciones , Trastornos de Estrés Traumático/psicologíaAsunto(s)
Trastornos Relacionados con Cocaína/etiología , Cocaína/efectos adversos , Enfermedades de la Boca/inducido químicamente , Pénfigo/inducido químicamente , Adulto , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Masculino , Enfermedades de la Boca/tratamiento farmacológico , Pénfigo/tratamiento farmacológicoRESUMEN
O objetivo deste estudo foi investigar a motivaçaÌo para primeira experieÌncia no uso de drogas e recaiÌdas apoÌs abstineÌncia por pessoas com dependeÌncia quiÌmica induzida pelo crack. Estudo descritivo, de abordagem mista. Foram realizadas 600 entrevistas com a utilizaçaÌo de questionaÌrio estruturado, na etapa quantitativa, e oito grupos focais, na etapa qualitativa, com total de 39 participantes. Para anaÌlise de dados utilizou-se o software SPSS e o meÌtodo de interpretaçaÌo de sentidos. A curiosidade motivou a iniciaçaÌo do uso de drogas, assim como a pressaÌo dos amigos e problemas familiares. JaÌ a dificuldade de ficar sem a droga, vontade de sentir o efeito novamente, pressaÌo de amigos, problemas familiares, decepçaÌo pela desconfiança dos familiares e o uso de drogas na proÌpria instituiçaÌo de tratamento foram relatados como motivadores de recaiÌda. Os dados em ambas as metodologias foram convergentes e ratificaram os resultados obtidos.
The aim of this study was to investigate the motivation for first-time drug use and relapses after abstinence of people with chemical dependency to crack cocaine. A descriptive study, with a mixed approach. In the quantitative phase, six hundred interviews were conducted using a structured questionnaire. In the qualitative phase, eight focus groups were created, with 39 total participants. SPSS software and the sense interpretation method were used to analyze the data. Curiosity, as well as peer pressure and family problems, motivated the initiation of drug use. Difficulty to live without the drug, desire to feel its effect again, peer pressure, family problems, disappointment in lack of trust of family members, and drug use at the rehabilitation institution were reported as relapse motivators. The data in both methodologies were convergent and confirmed the obtained results.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Síndrome de Abstinencia a Sustancias , Cocaína Crack , Trastornos Relacionados con Cocaína/etiologíaRESUMEN
Addiction is a chronic disease that has serious consequences, both in terms of public health and economy. Clear characteristics distinguish recreational and controlled use from addiction. Thus, today, addiction includes the notions of compulsive drug use, associated with a loss of control over consumption, leading to craving. When consumption is stopped, withdrawal symptoms may emerge: a negative emotional state, cognitive problems and physical symptoms with some products (alcohol and opiates, for example). Relapse episodes may occur during this withdrawal period, countering the negative effects of withdrawal. Relapse episodes can also be observed after long periods of abstinence. They can be precipitated by re-exposure to the context in which the drugs were taken, or by stress. Regardless of the stage of addiction (e.g., development of the addictive behavior, or relapse) changes in brain function and structure can be observed. Some brain structures are therefore modified, such as the prefrontal cortex, where several neuroadaptations have been identified. Some of these changes are described in this paper.
TITLE: Circuits neuronaux et neuromédiateurs impliqués dans les effets des drogues psychoactives État de l'art avec un focus sur la cocaïne. ABSTRACT: L'addiction est une maladie chronique qui engendre de lourdes conséquences, à la fois en termes de santé publique et au niveau économique. Des caractéristiques claires distinguent bien l'usage récréatif et contrôlé, de l'addiction. Ainsi, aujourd'hui, l'addiction inclut les notions de recherche compulsive de la drogue, associées à une perte de contrôle sur sa prise, favorisant l'émergence d'un désir persistant et irrépressible pour la drogue (appelé craving). À l'arrêt de la consommation, des symptômes de sevrage peuvent émerger : un état émotionnel négatif, des troubles cognitifs et des symptômes physiques avec certains produits (alcool et opiacés, par exemple). Les épisodes de rechute peuvent survenir au cours de cette période de sevrage pour contrer les effets négatifs du sevrage. De tels épisodes peuvent aussi être observés après de longues périodes d'abstinence. Ils peuvent être précipités par une réexposition au contexte dans lequel les prises de drogues s'effectuaient, ou encore par un stress. Quel que soit le stade auquel on se place (e.g., mise en place de l'addiction, ou rechute), des changements dans les fonctions et la structure du cerveau peuvent être observés. Certaines structures cérébrales sont donc modifiées, comme le cortex préfrontal, où plusieurs neuroadaptations ont été mises en évidence. Certaines de ces modifications sont revisitées dans cet article.
Asunto(s)
Cocaína/farmacología , Red Nerviosa/efectos de los fármacos , Neurotransmisores/farmacología , Psicotrópicos/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Conducta Adictiva/inducido químicamente , Conducta Adictiva/fisiopatología , Conducta Adictiva/psicología , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Humanos , Red Nerviosa/fisiología , Transducción de Señal/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Background: Cocaine is a psychostimulant drug with high addictive proprieties. Evidence suggests that cocaine use leads to critical changes in the immune system, with significant effects on T, B, and natural killer (NK) cells and influencing peripheral levels of cytokines. The presence of abstinence-related symptoms during detoxification treatment is known to influence the prognosis. Here, our aim was to investigate immune profiles in women with cocaine use disorder (CUD) according to withdrawal symptoms severity. Methods: Blood samples and clinical data were collected at onset of detoxification treatment of 50 women with CUD. The patients were stratified according to Cocaine Selective Severity Assessment (CSSA) scores in low withdrawal (L-W) and high withdrawal (H-W) categories. In addition, we also included a control group with 19 healthy women as reference to immune parameters. Peripheral blood was collected and lymphocyte subsets were phenotyped by multi-color flow cytometry (B cells, CD4+ T, CD8+ T, NK cells, and different stages of T-cell differentiation). PBMCs from patients and healthy controls were stimulated in vitro with phytohemagglutinin (1%) for 72 h to assess the production of Th1/Th2/Th17 cytokines. Results: Following stimulation, lymphocytes from women with CUD produced increased levels of Th1/Th2/Th17 cytokines. However, higher levels of IL-2 and IL-17 were observed only in the L-W group, while higher levels of IL-6 were detected in the H-W group compared to controls. H-W group showed lower percentage of early-differentiated Th cells (CD4+CD27+CD28+), elevated percentage of Th cells (CD3+CD4+), intermediate-differentiated Th cells (CD4+CD27-CD28+), and B cells (CD3-CD19+). Both CUD groups showed decreased percentages of naïve T cells (CD3+CD4+CD45RA+ and CD3+CD8+CD45RA+). Conclusion: Our data demonstrated that CUD can lead to increased production of Th1/Th2/Th17 cytokines and lymphocyte changes.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/metabolismo , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Brasil , Trastornos Relacionados con Cocaína/diagnóstico , Femenino , Humanos , Inmunofenotipificación , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Alpha-synuclein (α-syn) is an abundant neuroprotein elevated in cocaine addicts, linked to drug craving, and recruited to axon terminals undergoing glutamatergic plasticity - a proposed mechanism for substance abuse. However, little is known about normal α-syn function or how it contributes to substance abuse. We show that α-syn is critical for preference of hedonic stimuli and the cognitive flexibility needed to change behavioral strategies, functions that are altered with substance abuse. Electron microscopic analysis reveals changes in α-syn targeting of ventral tegmental area axon terminals that is dependent upon the duration of cocaine exposure. The dynamic changes in presynaptic α-syn position it to control neurotransmission and fine-tune the complex afferent inputs to dopamine neurons, potentially altering functional dopamine output. Cocaine also increases postsynaptic α-syn where it is needed for normal ALIX function, multivesicular body formation, and cocaine-induced exosome release indicating potentially similar α-syn actions for vesicle release pre- and post-synaptically.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/metabolismo , Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/metabolismo , Mesencéfalo/fisiopatología , alfa-Sinucleína/metabolismo , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Neuronas Dopaminérgicas/ultraestructura , Espacio Extracelular/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Motivación , Actividad Motora , Recompensa , Transducción de Señal , alfa-Sinucleína/genéticaRESUMEN
Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the 'hunger' hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.
Asunto(s)
Apetito/genética , Trastornos Relacionados con Cocaína/etiología , Receptores sigma/genética , Animales , Calcio/metabolismo , Cocaína/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dopamina/metabolismo , Conducta Alimentaria , Humanos , Ligandos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Ghrelina/metabolismo , Receptores sigma/metabolismo , Recompensa , Transducción de Señal , Receptor Sigma-1Asunto(s)
Antipsicóticos/farmacología , Aripiprazol/farmacología , Trastornos Relacionados con Cocaína/prevención & control , Cocaína/toxicidad , Modelos Animales de Enfermedad , Fumarato de Quetiapina/farmacología , Convulsiones/prevención & control , Anestésicos Locales/toxicidad , Animales , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/mortalidad , Ratones , Ratones Endogámicos BALB C , Convulsiones/inducido químicamente , Convulsiones/mortalidad , Tasa de SupervivenciaRESUMEN
There is strong support for the role of the endocannabinoid system and the noncannabinoid lipid signaling molecules, N-acylethanolamines (NAEs), in cocaine reward and withdrawal. In the latest study, we investigated the changes in the levels of the above molecules and expression of cannabinoid receptors (CB1 and CB2) in several brain regions during cocaine-induced reinstatement in rats. By using intravenous cocaine self-administration and extinction procedures linked with yoked triad controls, we found that a priming dose of cocaine (10 mg/kg, i.p.) evoked an increase of the anadamide (AEA) level in the hippocampus and prefrontal cortex only in animals that had previously self-administered cocaine. In the same animals, the level of 2-arachidonoylglycerol (2-AG) increased in the hippocampus and nucleus accumbens. Moreover, the drug-induced relapse resulted in a potent increase in NAEs levels in the cortical areas and striatum and, at the same time, a decrease in the tissue levels of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) was noted in the nucleus accumbens, cerebellum, and/or hippocampus. At the level of cannabinoid receptors, a priming dose of cocaine evoked either upregulation of the CB1 and CB2 receptors in the prefrontal cortex and lateral septal nuclei or downregulation of the CB1 receptors in the ventral tegmental area. In the medial globus pallidus we observed the upregulation of the CB2 receptor only after yoked chronic cocaine treatment. Our findings support that in the rat brain, the endocannabinoid system and NAEs are involved in cocaine induced-reinstatement where these molecules changed in a region-specific manner and may represent brain molecular signatures for the development of new treatments for cocaine addiction.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/farmacología , Endocannabinoides/metabolismo , Etanolaminas/metabolismo , Animales , Biomarcadores , Cromatografía Liquida , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/fisiopatología , Expresión Génica , Inmunohistoquímica , Masculino , Ratas , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Receptores de Cannabinoides , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Cocaine use disorder is a significant public health problem and currently no medications are FDA-approved to reduce cocaine relapse. Drug-associated cues are reported to elicit craving and cocaine-seeking in humans. Repeated, non-reinforced presentations of drug-associated cues (cue extinction) have been proposed to reduce the ability of such cues to prompt drug-seeking. In rodent models of cocaine relapse, cue extinction reduces cocaine relapse when such extinction occurs in the same context as cocaine self-administration, which is not akin to the manner in which treatment would occur in humans. Here we sought to determine whether cue extinction outside of the cocaine self-administration context would reduce relapse in the drug context. We also hypothesized that ceftriaxone, an antibiotic consistently shown to attenuate cocaine relapse in rats, would enhance the relapse-preventing effects of cue extinction. METHODS: Rats self-administered intravenous cocaine for 12 days followed by 20-21 days of abstinence. Immediately preceding the relapse test, rats either underwent 6 single daily cue extinction sessions (1 h/day) outside the self-administration context or no extinction with daily handling. Rats also received vehicle or ceftriaxone (200 mg/kg IP) on those six days. RESULTS: Ceftriaxone attenuated cued relapse relative to vehicle-treated rats, but there was no additive effect of cue extinction on cocaine-seeking. Cue extinction alone did not attenuate relapse. CONCLUSIONS: Thus, in agreement with work in humans, when cue extinction is conducted outside the drug-associated context it does not reduce the risk of relapse alone. Ceftriaxone remains a strong possibility for medication to reduce cocaine relapse in humans.
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Ceftriaxona/farmacología , Trastornos Relacionados con Cocaína/psicología , Trastornos Relacionados con Cocaína/terapia , Señales (Psicología) , Extinción Psicológica/efectos de los fármacos , Animales , Antibacterianos/farmacología , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/etiología , Ansia/efectos de los fármacos , Modelos Animales de Enfermedad , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Recurrencia , AutoadministraciónRESUMEN
INTRODUCTION: The addictive disorder is a multifactorial pathology variable in its manifestations, environmental, developmental, inheritable, neurobiological, and behavioral. METHODS: Synthesis of recent data from the literature. RESULTS/DISCUSSION: Addiction is a pathology affecting decision-making, the emotional balance, the voluntary control of behaviour, not only in cases of psychoactive products use but also in behavioural dependencies. The social environment, developmental stages, and genetic factors are closely related to the vulnerability to addiction. In this article, after reviewing risk factors and neurobiology data, we will use cannabis, synthetic cannabinoids and cocaine as an example of substance use disorder.
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Conducta Adictiva , Trastornos Relacionados con Sustancias , Conducta Adictiva/epidemiología , Conducta Adictiva/etiología , Conducta Adictiva/psicología , Cannabinoides/síntesis química , Cannabinoides/clasificación , Trastornos Relacionados con Cocaína/epidemiología , Trastornos Relacionados con Cocaína/etiología , Susceptibilidad a Enfermedades/epidemiología , Susceptibilidad a Enfermedades/psicología , Humanos , Abuso de Marihuana/epidemiología , Abuso de Marihuana/etiología , Red Nerviosa/fisiología , Recompensa , Factores de Riesgo , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/etiología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
Despite the initiative by WHO and other international organizations to eliminate HCV in the medium term, hepatitis C infection is still a major public health problem. Even non-injecting drugs users who engage in harmful or addictive drug use are at greater risk of acquiring the infection, when compared to the general population. This study evaluate risk factors for HCV infection in users of crack/cocaine in Brazil, using multilevel models that incorporate variations in the sensitivity and specificity of the respective diagnostic tests. The sample included all the participants of a national survey on street crack cocaine users with serologically reactive result in the rapid test for the HCV as well as 4 non-reactive controls, matched by sex, age category, and major geographic region of residence. Multilevel logistic regression models were used, with and without incorporation of the diagnostic test's sensitivity and specificity values. The odds of HCV infection were 85% higher among polydrug users, 7.81 times higher among injecting drug users, and 3.69 times higher in those reporting to have genital ulcers. Statistical modeling strategies that incorporate the sensitivity and specificity of diagnostic tests in challenging settings are useful for studying the association between risk factors and infection status.