RESUMEN
This study establishes a fetal cannabinoid syndrome model to evaluate the effects of high doses of dronabinol (synthetic THC) during pregnancy and lactation on behavioral and brain changes in male and female progeny and their susceptibility to alcohol consumption. Female C57BL/6J mice received dronabinol (10 mg/kg/12 h, p.o.) from gestational day 5 to postnatal day 21. On the weaning day, the offspring were separated by sex, and on postnatal day 60, behavioral and neurobiological changes were analyzed. Mice exposed to dronabinol exhibited increased anxiogenic and depressive-like behaviors and cognitive impairment. These behaviors were associated with neurodevelopment-related gene and protein expression changes, establishing, for the first time, an association among behavioral changes, cognitive impairment, and neurobiological alterations. Exposure to dronabinol during pregnancy and lactation disrupted the reward system, leading to increased motivation to consume alcohol in the offspring. All these modifications exhibited sex-dependent patterns. These findings reveal the pronounced adverse effects on fetal neurodevelopment resulting from cannabis use during pregnancy and lactation and strongly suggest the need to prevent mothers who use cannabis in this period from the severe and permanent side effects on behavior and brain development that may occur in their children.
Asunto(s)
Conducta Animal , Encéfalo , Dronabinol , Lactancia , Ratones Endogámicos C57BL , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Embarazo , Ratones , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Dronabinol/efectos adversos , Conducta Animal/efectos de los fármacosRESUMEN
Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.
Asunto(s)
Cannabinoides , Manejo del Dolor , Dolor Postoperatorio , Humanos , Dolor Postoperatorio/tratamiento farmacológico , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Manejo del Dolor/métodos , Analgesia/métodos , Animales , Analgésicos/uso terapéutico , Analgésicos/farmacología , Endocannabinoides/metabolismo , Endocannabinoides/uso terapéuticoRESUMEN
Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.
Asunto(s)
Cannabidiol , Trastornos del Espectro Alcohólico Fetal , Humanos , Embarazo , Animales , Ratones , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Encéfalo/metabolismo , EtanolRESUMEN
The crosstalk between the opioidergic system and mitogen-activated protein kinases (MAPKs) has a critical role in mediating stress-induced behaviors related to the pathophysiology of anxiety. The present study evaluated the basal status and stress-induced alterations of cortico-thalamic MAPKs and other cell fate-related signaling pathways potentially underlying the anxiogenic endophenotype of PDYN gene-deficient mice. Compared to littermates, PDYN knockout (KO) mice had lower cortical and or thalamic amounts of the phospho-activated MAPKs c-Jun N-terminal kinase (JNK1/2) and extracellular signal-regulated kinase (ERK1/2). Similarly, PDYN-KO animals displayed reduced cortico-thalamic densities of total and phosphorylated (at Ser191) species of the cell fate regulator Fas-associated protein with death domain (FADD) without alterations in the Fas receptor. Exposure to acute restraint and chronic mild stress stimuli induced the robust stimulation of JNK1/2 and ERK1/2 MAPKs, FADD, and Akt-mTOR pathways, without apparent increases in apoptotic rates. Interestingly, PDYN deficiency prevented stress-induced JNK1/2 and FADD but not ERK1/2 or Akt-mTOR hyperactivations. These findings suggest that cortico-thalamic MAPK- and FADD-dependent neuroplasticity might be altered in PDYN-KO mice. In addition, the results also indicate that the PDYN gene (and hence dynorphin release) may be required to stimulate JNK1/2 and FADD (but not ERK1/2 or Akt/mTOR) pathways under environmental stress conditions.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Apoptosis/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Fosforilación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.
Asunto(s)
Trastornos Mentales , Suicidio , Adulto , Adolescente , Humanos , Intento de Suicidio/psicología , Suicidio/psicología , Ideación Suicida , Trastornos Mentales/psicología , Factores de RiesgoRESUMEN
The increasing prevalence of cognitive dysfunction and dementia in developed countries, associated with population aging, has generated great interest in characterizing and quantifying cognitive deficits in these patients. An essential tool for accurate diagnosis is cognitive assessment, a lengthy process that depends on the cognitive domains analyzed. Cognitive tests, functional capacity scales, and advanced neuroimaging studies explore the different mental functions in clinical practice. On the other hand, animal models of human diseases with cognitive impairment are essential for understanding disease pathophysiology. The study of cognitive function using animal models encompasses multiple dimensions, and deciding which ones to investigate is necessary to select the most appropriate and specific tests. Therefore, this review studies the main cognitive tests for assessing cognitive deficits in patients with neurodegenerative diseases. Cognitive tests, the most commonly used functional capacity scales, and those resulting from previous evidence are considered. In addition, the leading behavioral tests that assess cognitive functions in animal models of disorders with cognitive impairment are highlighted.
Asunto(s)
Trastornos del Conocimiento , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Animales , Humanos , Trastornos del Conocimiento/complicaciones , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/complicaciones , Cognición , Pruebas Neuropsicológicas , Enfermedades Neurodegenerativas/complicacionesRESUMEN
Cannabidiol (CBD) may represent a promising therapeutic tool for treating opioid use disorder (OUD). This study was aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous heroin withdrawal. Thirty hours after cessation of 8-day heroin treatment (5, 10, 20 and 40 mg·kg-1 /12 h; s.c.), spontaneous heroin withdrawal was evaluated in CD1 male mice. The effects of CBD (5, 10 and 20 mg·kg-1 ; i.p.) on withdrawal-related behaviour were evaluated by measuring anxiety-like behaviour, motor activity and somatic signs. Furthermore, gene expression changes of mu-opioid receptor (Oprm1), proopiomelanocortin (Pomc), cannabinoid CB1 (Cnr1) and CB2 (Cnr2) receptors in the nucleus accumbens (NAcc) and tyrosine hydroxylase (TH) and Pomc in the ventral tegmental area (VTA) were also evaluated by real-time PCR. Anxiety-like behaviour, motor activity and withdrawal-related somatic signs were significantly increased in heroin-treated mice compared to the control group. Interestingly, CBD treatment significantly reduced these behavioural impairments and normalized gene expression of Cnr1 and Pomc in the NAcc and TH in the VTA of mice exposed to spontaneous heroin withdrawal. Also, CBD induced an up-regulation of Cnr2, whereas it did not change the increased gene expression of Oprm1 in the NAcc of abstinent animals. The results suggest that CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for the treatment of heroin withdrawal.
Asunto(s)
Cannabidiol , Síndrome de Abstinencia a Sustancias , Animales , Cannabidiol/farmacología , Heroína/metabolismo , Heroína/farmacología , Masculino , Ratones , Núcleo Accumbens , Síndrome de Abstinencia a Sustancias/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: "Receptor, Cannabinoid, CB2" AND "Alcohol-Related Disorders" AND "human/or patients"; "Receptor, Cannabinoid, CB2" AND "Alcohol" OR "Ethanol" AND "rodents/or mice/or rats". Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.
Asunto(s)
Alcoholismo , Cannabinoides , Alcoholismo/genética , Animales , Cannabinoides/farmacología , Etanol , Humanos , Ratones , Ratones Endogámicos C57BL , Ratas , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2/genética , RecompensaRESUMEN
The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.
Asunto(s)
Trastornos Mentales , Esquizofrenia , Animales , Biomarcadores , Endocannabinoides/fisiología , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/genética , Trastornos del Humor , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
OBJECTIVE: The use of spinal cord stimulation for patients with failed back surgery syndrome (FBSS) is very common. In order to better understand the mechanisms of action of spinal cord stimulation (SCS), our aim was to determine potential changes in relative gene and protein expression in the peripheral blood mononuclear cells (PBMCs) of patients as potential biomarkers of disease outcomes and potential new targets for therapy. METHODS: Twenty-four patients with diagnosis of FBSS refractory to conservative therapy for at least six months were included in the study. Clinical evaluation in this study included validated questionnaires. Blood samples (10 mL) were collected five times from baseline until two months after implant of the leads. Proenkephalin (PENK), cannabinoid receptors CB1 and CB2, and interleukin 1ß (IL 1ß) were analyzed. Each patient served as his/her own control by comparing the samples collected at different time points against the baseline sample collected at T0. RESULTS: A total of 16 patients met all relevant criteria during the whole study and were assessed. Only PENK showed significant changes over time (Friedman p = 0.000). A positive correlation was observed between changes in visual analog scale (VAS) scores and PENK and a negative correlation between changes in PENK and Short Form-12 (SF-12) mental component score (MCS) scores, as well as between changes in IL 1ß and Pain Detect Questionnaire (PD-Q) scores. As PENK changes increased, so did pain (VAS). As changes in PENK increased, SF-12 MCS health worsened. As changes in IL 1ß increased, PD-Q values decreased. No severe adverse events occurred. CONCLUSIONS: Previously unknown effects of SCS on levels of PBMCs biomarkers are demonstrated. The findings of our research suggest a potential for useful integration of genome analysis and lymphocyte expression in the daily practice of neurostimulation for pain management and represent a novel road map in the light of the important questions that remain unanswered.
Asunto(s)
Cannabinoides , Síndrome de Fracaso de la Cirugía Espinal Lumbar , Estimulación de la Médula Espinal , Biomarcadores , Síndrome de Fracaso de la Cirugía Espinal Lumbar/genética , Síndrome de Fracaso de la Cirugía Espinal Lumbar/terapia , Femenino , Expresión Génica , Humanos , Interleucinas , Leucocitos Mononucleares , Masculino , Péptidos Opioides , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2 , Resultado del TratamientoRESUMEN
Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.
Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Factores de Edad , Consumo de Bebidas Alcohólicas/inmunología , Consumo de Bebidas Alcohólicas/prevención & control , Animales , Animales no Consanguíneos , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Quimiocina CXCL1/metabolismo , Dieta Alta en Grasa , Etanol/farmacología , Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Obesidad , Autoadministración/métodosRESUMEN
The purpose of this study was to explore the effects of cannabidiol (CBD) on binge drinking and evaluate potential gender-related differences. To this aim, male and female C57BL/6J mice (n = 60 per sex) were exposed to the drinking in the dark (DID) model for 4 weeks (DID-1 to DID-4). Dose-response effects of CBD on the ethanol intake were tested by acute (day-4 of DID-3) or repeated administration (day-1 to 4 of DID-4) (experiment 1: CBD 15, 30, and 60 mg/kg, i.p.; experiment 2: CBD 90 mg/kg, i.p.). Finally, we analyzed the relative gene expression of tyrosine hydroxylase (TH) and µ-opioid receptor (OPRM1) and cannabinoid CB1 receptor (CB1 r) in the ventral tegmental area (VTA) and in the nucleus accumbens (NAc), respectively, by real-time quantitative PCR. Females exhibited higher ethanol intake during each DID session. Interestingly, females also showed higher expression of TH and OPRM1, without any difference in CB1 r. Only the acute administration of CBD at the highest dose (90 mg/kg) reduced significantly ethanol consumption in both sexes. Chronic CBD administration (30, 60 and 90 mg/kg) reduced ethanol intake in males, whereas in females a significant reduction was only achieved with the highest dose (90 mg/kg). Repeated administration with CBD (60 mg/kg) significantly reduced TH and OPRM1 in males. In addition, CBD (30 and 60 mg/kg) significantly reduced CB1 r in males. No effect was observed in females. Taken together, these findings suggest that CBD may be of interest for treating binge-drinking patterns and that gender-related difference may affect the treatment outcome.
Asunto(s)
Consumo de Bebidas Alcohólicas , Conducta Animal/efectos de los fármacos , Consumo Excesivo de Bebidas Alcohólicas , Cannabidiol/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Animales , Femenino , Masculino , Ratones , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Distribución Aleatoria , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB1/genética , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/genética , Autoadministración , Factores Sexuales , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Previous studies have indicated the potential of cerebrospinal fluid (CSF) α-synuclein (α-syn) to be an additional biomarker for improving differential diagnosis of Alzheimer's disease (AD). We evaluated α-syn diagnostic performance across a well-characterized patient cohort with long-term follow-up. For this purpose, CSF α-syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI-AD; n = 32), 24 MCI cases due to Lewy body disease (MCI-LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α-syn levels discriminate between the four groups. There were higher α-syn levels in MCI-AD patients and lower levels in MCI-LBD patients. The combination of α-syn and P-tau resulted in a specificity of 99% and a sensitivity of 97% for MCI-AD. MCI-AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P-tau and α-syn compared to the MCI-AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α-syn to central core AD biomarkers improves an early differential diagnosis of MCI-AD from other forms of MCI. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Estudios Transversales , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Masculino , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeoRESUMEN
Recent evidence suggests that cannabidiol (CBD) may be useful for the treatment of different neuropsychiatric disorders. However, some controversy regarding its profile as a drug of abuse hampers the further development of basic and clinical studies. In this study, the behavioral profile of CBD as a potential drug of abuse was evaluated in C57BL/6J mice. Reinforcing properties of CBD (15, 30, and 60 mg/kg; i.p.) were assessed using the conditioned place preference (CPP) paradigm. Spontaneous withdrawal symptoms and motor activity in the open field were examined 12 h after the last CBD administration (30 mg/kg/12 h, i.p., 6 days). CBD plasma concentrations were measured at 2, 4, 8, 12, and 24 h after the administration of CBD (30 mg/kg, i.p.). Furthermore, an oral CBD self-administration paradigm (50 mg/kg; CBD water-soluble 1.2 mg/mL) was performed to evaluate whether this drug produced any effects on motivation compared with a non-reinforcing substance (water). We found that CBD failed to induce CPP, withdrawal symptoms, or altered motor behavior 12 h after its administration. At that time, only traces of CBD were detected, ensuring that the lack of alterations in somatic signs and locomotor activity was not due to residual drug in plasma. Interestingly, mice displayed similar motivation and consumption of CBD and water. Taken together, these results show that CBD lacks activity as a drug of abuse and should stimulate the development of the basic and clinical studies needed to elucidate its potential therapeutic use for the treatment of neuropsychiatric and drug use disorders.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cannabidiol/farmacología , Animales , Cannabidiol/administración & dosificación , Cannabidiol/sangre , Relación Dosis-Respuesta a Droga , Masculino , Ratones Endogámicos C57BL , AutoadministraciónRESUMEN
This study evaluated the effects of cannabidiol (CBD) on ethanol reinforcement, motivation and relapse in C57BL/6 J mice. The effects of CBD (60 mg/kg, i.p.) on blood ethanol concentration, hypothermia and handling-induced convulsions associated to acute ethanol administration were evaluated. The two-bottle choice paradigm was performed to assess the effects of CBD (30, 60 and 120 mg/kg/day, i.p.) on ethanol intake and preference. In addition, an oral ethanol self-administration experiment was carried out to evaluate the effects of CBD [a single s.c. administration of a microparticle formulation providing CBD continuous controlled release (30 mg/kg/day)] on the reinforcement and motivation for ethanol. The effects of CBD (60 and 120 mg/kg/day, i.p.) on ethanol-induced relapse were also evaluated. Gene expression analyses of tyrosine hydroxylase in ventral tegmental area and µ-opioid (Oprm1), cannabinoid (CB1 r and CB2 r) and GPR55 receptors in nucleus accumbens (NAcc) were carried out by real-time polymerase chain reaction. Cannabidiol reduced the ethanol-induced hypothermia and handling-induced convulsion but failed to modify blood ethanol concentration. CBD reduced ethanol consumption and preference in the two-bottle choice, significantly decreased ethanol intake and the number of effective responses in the oral ethanol self-administration, and reduced ethanol-induced relapse. Furthermore, the administration of CBD significantly reduced relative gene expression of tyrosine hydroxylase in the ventral tegmental area, Oprm1, CB1 r and GPR55 in the NAcc and significantly increased CB2 r in the NAcc. Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.
Asunto(s)
Consumo de Bebidas Alcohólicas , Conducta Animal/efectos de los fármacos , Cannabidiol/farmacología , Motivación/efectos de los fármacos , Refuerzo en Psicología , Animales , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/efectos de los fármacos , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Receptores de Cannabinoides/efectos de los fármacos , Receptores de Cannabinoides/genética , Receptores de Cannabinoides/metabolismo , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Recurrencia , Autoadministración , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
BACKGROUND: Previous studies demonstrated that patients with alcohol use disorders (AUDs) show altered startle reflex responses to alcohol-related stimuli. However, there is little information about the role of these altered responses in the development of AUDs. This study examined the startle reflex response to different visual stimuli and the role of these patterns in the development of AUDs in a 4-year follow-up. METHODS: Two hundred and thirty-nine (nondependent) heavy-drinking participants were selected. In the baseline period, the startle reflex responses to alcohol-related, aversive, appetitive, and neutral pictures were assessed. Startle reflex responses to these pictures were used as predictive variables. Status drinking (alcohol dependence and nondependence) assessed at 4-year follow-up was used as outcome measure. RESULTS: At the 4-year follow-up assessment, 46% of participants fulfilled DSM-IV alcohol abuse or dependence criteria. Alcohol dependence status was predicted by an attenuated startle reflex response to alcohol-related and aversive pictures. CONCLUSIONS: This study revealed that an attenuated modulation of startle reflex response to alcohol-related and aversive stimuli could be used as a clinical marker to predict the development of AUDs in participants with previous alcohol consumption.
Asunto(s)
Alcoholismo/diagnóstico , Alcoholismo/psicología , Estimulación Luminosa/métodos , Reflejo de Sobresalto , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/psicología , Intoxicación Alcohólica/diagnóstico , Intoxicación Alcohólica/epidemiología , Intoxicación Alcohólica/psicología , Alcoholismo/epidemiología , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reflejo de Sobresalto/fisiologíaRESUMEN
Inflammatory cytokines and reactive oxygen species are reported to be involved in blood-brain barrier (BBB) disruption. Because there is evidence that ethanol (EtOH) induces release of free radicals, cytokines and inflammatory mediators we examined BBB integrity and matrix metalloproteinase (MMP) activity in postmortem human alcoholic brain and investigated the role of TLR4 signaling in BBB permeability in TLR4-knockout mice under a binge-like EtOH drinking protocol. Immunohistochemical studies showed reduced immunoreactivity of the basal lamina protein, collagen-IV and of the tight junction protein, claudin-5 in dorsolateral prefrontal cortex of alcoholics. There was also increased MMP-9 activity and expression of phosphorylated ERK1/2 and p-38. Greater number of CD45+ IR cells were observed associated with an enhanced neuroinflammatory response reflected by increased GFAP and Iba-1 immunostaining. To further explore effects of high EtOH consumption on BBB integrity we studied TLR4-knockout mice exposed to the drinking in the dark paradigm. Repetitive EtOH exposure in wild-type mice decreased hippocampal expression of laminin and collagen-IV and increased IgG immunoreactivity, indicating IgG extravasation. Western blot analysis also revealed increased MyD88 and p-ERK1/2 levels. None of these changes was observed in TLR4-knockout mice. Collectively, these findings indicate that chronic EtOH increases degradation of tight junctions and extracellular matrix in postmortem human brain and induces a neuroinflammatory response associated with activation of ERK1/2 and p-38 and greater MMP-9 activity. The EtOH-induced effects on BBB impairment are not evident in the hippocampus of TLR4-knockout mice, suggesting the involvement of TLR4 signaling in the underlying mechanism leading to BBB disruption in mice.
Asunto(s)
Alcoholismo/complicaciones , Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Etanol/farmacología , Receptor Toll-Like 4/metabolismo , Adulto , Anciano , Alcoholismo/genética , Alcoholismo/metabolismo , Animales , Autopsia , Consumo Excesivo de Bebidas Alcohólicas/genética , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Western Blotting , Encéfalo/metabolismo , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Modelos Animales de Enfermedad , Etanol/metabolismo , Femenino , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/genética , Uniones Estrechas/metabolismo , Receptor Toll-Like 4/genéticaRESUMEN
The purpose of this study was to evaluate the effects of early life stress on the vulnerability to ethanol consumption in adolescence. To this aim, mice were separated from their mothers for 12 hours/day on postnatal days 8 and 12. Emotional behavior (light-dark box, elevated plus maze and tail suspension tests) and pre-attentional deficit (pre-pulse inhibition) were evaluated in adolescent maternal separated (MS) mice. Alterations of the corticotropin-releasing factor (CRF), glucocorticoid receptor (NR3C1), tyrosine hydroxylase (TH), mu-opioid receptor (MOr), brain-derived neurotrophic factor (BDNF), neuronal nuclei (NeuN), microtubule-associated protein 2 (MAP2) and neurofilament heavy (NF200)-immunoreactive fibers were studied in the paraventricular nucleus of the hypothalamus (PVN), ventral tegmental area (VTA), nucleus accumbens (NAc) or hippocampus (HIP). The effects of maternal separation (alone or in combination with additional stressful stimuli) on ethanol consumption during adolescence were evaluated using the oral ethanol self-administration paradigm. MS mice presented mood-related alterations and pre-attentional deficit. Increased CRF, MOr and TH, and reduced BDNF, NR3C1, NeuN, MAP2 and NF200-immunoreactive fibers were observed in the PVN, NAc and HIP of adolescent MS mice. In the oral ethanol self-administration test, adolescent MS mice presented higher ethanol consumption and motivation. Exposure to additional new stressful stimuli during adolescence significantly increased the vulnerability to ethanol consumption induced by maternal separation. These results clearly demonstrated that exposure to early life stress increased the vulnerability to ethanol consumption, potentiated the effects of stressful stimuli exposure during adolescence on ethanol consumption and modified the expression of key targets involved in the response to stress, ethanol reinforcing properties and cognitive processes.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Conducta Animal/fisiología , Etanol/administración & dosificación , Privación Materna , Estrés Psicológico/fisiopatología , Consumo de Bebidas Alcohólicas/psicología , Animales , Depresores del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Estrés Psicológico/psicologíaRESUMEN
This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Conducta Animal , Encéfalo/metabolismo , Condicionamiento Operante , Perfilación de la Expresión Génica , Conducta Social , Estrés Psicológico/genética , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/psicología , Animales , Ansiedad/genética , Ansiedad/metabolismo , Ansiedad/psicología , Reacción de Prevención , Depresores del Sistema Nervioso Central/administración & dosificación , Hormona Liberadora de Corticotropina/genética , Depresión/genética , Depresión/metabolismo , Depresión/psicología , Etanol/administración & dosificación , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Opioides mu/genética , Autoadministración , Estrés Psicológico/psicología , Tirosina 3-Monooxigenasa/genética , Área Tegmental Ventral/metabolismoRESUMEN
This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption. The time-related and dose-response effects of ethanol on rectal temperature, handling-induced convulsions (HIC) and blood ethanol concentrations were evaluated in CB2 KO and wild-type (WT) mice. The reinforcing properties of ethanol were evaluated in conditioned place preference (CPP), preference and voluntary ethanol consumption and oral ethanol self-administration. Water-maintained behavior schedule was performed to evaluate the degree of motivation induced by a natural stimulus. Preference for non-alcohol tastants assay was performed to evaluate the differences in taste sensitivity. Tyrosine hydroxylase (TH) and µ-opioid receptor gene expressions were also measured in the ventral tegmental area and nucleus accumbens (NAcc), respectively. CB2 KO mice presented increased HIC score, ethanol-CPP, voluntary ethanol consumption and preference, acquisition of ethanol self-administration, and increased motivation to drink ethanol compared with WT mice. No differences were found between genotypes in the water-maintained behavior schedule or preference for non-alcohol tastants. Naïve CB2 KO mice presented increased µ-opioid receptor gene expression in NAcc. Acute ethanol administration (1-2 g/kg) increased TH and µ-opioid receptor gene expressions in CB2 KO mice, whereas the lower dose of ethanol decreased TH gene expression in WT mice. These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption, at least in part, by increased ethanol-induced sensitivity of the TH and µ-opioid receptor gene expressions in mesolimbic neurons. Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.