RESUMO
The importance of the endocannabinoid system (ECS) in the modulation functions of the central nervous system has been extensively investigated during the last few years. In particular, accumulated evidence has implicated ECS in the pathophysiology of Alzheimers disease (AD), that is a progressive, degenerative, and irreversible disorder characterized by the accumulation in the brain of beta-amyloid fragments forming insoluble plaques, and of intracellular neurofibrillary tangles (NTFs) associated with synaptic and neuronal loss. In all the processes involved in the formation of both plaques and NFTs, the key-role played by the ECS has been documented. Here, we review current knowledge and future directions of ECS modulation both in animal models of AD and in human tissues, underlying the role of endocannabinoid signaling in the development of AD hallmarks. Overall, the available data suggest that next generation therapeutics might target distinct ECS elements, for instance CB2 receptor or fatty acid amide hydrolase, as a promising approach to halt or at least to slow down disease progression.
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Carvacrol is the major constituent of essential oils from aromatic plants. It showed antimicrobial, anticancer and antioxidant properties. Although it was approved for food use and included in the chemical flavorings list, no indication on its safety has been estimated. Since the use of plant extracts is relatively high among women, aim of this study was to evaluate carvacrol effects on female physiology and endocrine profiles by using female rats in proestrus and diestrus phases. Serotonin and metabolite tissue content in prefrontal cortex and nucleus accumbens, after carvacrol administration (0.15 and 0.45g/kg p.o.), was measured. Drug effects in behavioral tests for alterations in motor activity, depression, anxiety-related behaviors and endocrine alterations were also investigated. While in proestrus carvacrol reduced serotonin and metabolite levels in both brain areas, no effects were observed in diestrus phase. Only in proestrus phase, carvacrol induced a depressive-like behavior in forced swimming test, without accompanying changes in ambulation. The improvement of performance in FST after subchronic treatment with fluoxetine (20mg/kg) suggested a specific involvement of serotonergic system. No differences were found across the groups with regard to self-grooming behavior. Moreover, in proestrus phase, carvacrol reduced only estradiol levels without binding hypothalamic estradiol receptors. Our study showed an estrous-stage specific effect of carvacrol on depressive behaviors and endocrine parameters, involving serotonergic system. Given the wide carvacrol use not only as feed additive, but also as cosmetic essence and herbal remedy, our results suggest that an accurate investigation on the effects of its chronic exposure is warranted.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclo Estral/fisiologia , Ácido Hidroxi-Indolacético/metabolismo , Monoterpenos/farmacologia , Serotonina/metabolismo , Animais , Cimenos , Depressão/induzido quimicamente , Depressão/metabolismo , Estradiol/sangue , Feminino , Asseio Animal/efeitos dos fármacos , Ácido Hidroxi-Indolacético/análise , Atividade Motora/efeitos dos fármacos , Progesterona/sangue , Ratos , Ratos Wistar , Serotonina/análise , NataçãoRESUMO
An increased carotid intima-media thickness (IMT) is detectable in young subjects with parental history of premature myocardial infarction (PHPMI) or hypertension (PHH). In this study we evaluated if PHPMI and PHH exert a different influence on carotid IMT and if their conjunction produces additive effects. High-resolution B-mode ultrasonographic evaluation of common carotid artery IMT was acquired from 48 subjects without PHPMI and PHH (22 males, 26 females; mean age 22.1±4.9 years; controls), 24 age- (±1 year) and sex-matched subjects with PHH without PHPMI (PHH-positive/PHPMI-negative subjects), 24 age- and sex-matched subjects with PHPMI without PHH (PHH-negative/PHPMI-positive subjects) and 24 age- and sex-matched subjects with both PHPMI and PHH (PHH/PHPMI-positive subjects). Lipid profile, resting blood pressure, smoking behaviour and body mass index (BMI) were also assessed. Carotid IMT was smaller in controls (0.41±0.07mm) compared to PHH-positive/PHPMI-negative subjects (0.47±0.10, p=0.023), to PHH-negative/PHPMI-positive subjects (0.54±0.11, p<0.001) and to PHH/PHPMI-positive subjects (0.52±0.10mm, p<0.001). Carotid IMT was greater in PHH-negative/PHPMI-positive (p=0.006) and in PHH/PHPMI-positive (p=0.031) than in PHH-positive/PHPMI-negative subjects. No difference in carotid IMT was evident between PHH-negative/PHPMI-positive and PHH/PHPMI-positive subjects (p=0.549). In the comparison among subjects using multiple regression analysis, only PHPMI, age and BMI were independently associated with carotid IMT. In healthy young subjects with PHPMI and/or PHH, carotid IMT is increased. PHPMI is a stronger predictor of increased carotid IMT than PHH. PHH in conjunction with PHPMI does not add any further detrimental effect on carotid IMT.
Assuntos
Artéria Carótida Primitiva/patologia , Infarto do Miocárdio/patologia , Túnica Íntima/patologia , Túnica Média/patologia , Adolescente , Adulto , Pressão Sanguínea , Índice de Massa Corporal , Artéria Carótida Primitiva/diagnóstico por imagem , Colesterol/sangue , Feminino , Humanos , Hipertensão/patologia , Masculino , Análise Multivariada , Pais , Análise de Regressão , Fatores de Risco , Triglicerídeos/sangue , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Ultrassonografia , Adulto JovemRESUMO
AIM: Healthy young subjects with parental history of premature myocardial infarction (PHPMI) might constitute a privileged population for the study of genetic risk markers (GRM) for atherosclerosis. Aim of this study was to evaluate which, if any, GRM atherosclerosis-associated in previous studies has increased prevalence in a selected population. METHODS: Twenty-four healthy young subjects (12 males and 12 females; mean age 18.0±8.0 years) with PHPMI and 24 age- (±1 year), sex-matched healthy subjects without PHPMI were enrolled in the study. They underwent: 1) fasting measurement of lipid profile, resting blood pressure and body mass index; 2) high resolution B-mode ultrasonographic evaluation of common carotid artery intima-media thickness (IMT); 3) evaluation of Single Nucleotide Polymorphisms (SNPs) for six candidate genes associated with preclinical atherosclerosis. RESULTS: Compared to controls, subjects with PHPMI had increased IMT of common carotid arteries (mean of combined sites: 0.535±0.171 mm versus 0.432± 0.133 mm in controls, P=0.017). Offspring of coronary patients showed an increased prevalence of the unfavourable chemochine (C-X-C motif) ligand 12 (CXCL12) SNP risk genotype (P=0.047). CONCLUSION: In healthy young subjects with PHPMI there is an increased prevalence of the unfavorable CXCL12 SNP risk genotype.
Assuntos
Aterosclerose/genética , Infarto do Miocárdio/genética , Adolescente , Fatores Etários , Feminino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Chronic use of levodopa, the most effective treatment for Parkinson's disease, causes abnormal involuntary movements named dyskinesias, which are linked to maladaptive changes in plasticity and disturbances of dopamine and glutamate neurotransmission in the basal ganglia. Dyskinesias can be modeled in rats with unilateral 6-hydroxydopamine lesions by repeated administration of low doses of levodopa (6 mg/kg, s.c.). Previous studies from our lab showed that sub-chronic treatment with the cannabinoid agonist WIN55,212-2 attenuates levodopa-induced dyskinesias at doses that do not interfere with physiological motor function. To investigate the neurochemical changes underlying WIN55,212-2 anti-dyskinetic effects, we used in vivo microdialysis to monitor extracellular dopamine and glutamate in the dorsal striatum of both the hemispheres of freely moving 6-hydroxydopamine-treated, SHAM-operated and intact rats receiving levodopa acutely or chronically (11 days), and studied how sub-chronic WIN55,212-2 (1 injection x 3 days, 20 min before levodopa) affected these neurochemical outputs. Our data indicate that: (1) the 6-hydroxydopamine lesion decreases dopamine turnover in the denervated striatum; (2) levodopa injection reduces extracellular glutamate in the side ipsilateral to the lesion of dyskinetic rats; (3) sub-chronic WIN55,212-2 prevents levodopa-induced glutamate volume transmission unbalances across the two hemispheres; and (4) levodopa-induced dyskinesias are inversely correlated with glutamate levels in the denervated striatum. These data indicate that the anti-dyskinetic properties of WIN55,212-2 are accompanied by changes of dopamine and glutamate outputs in the two brain hemispheres of 6-hydroxydopamine-treated rats.
Assuntos
Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canabinoides/farmacologia , Corpo Estriado/metabolismo , Discinesias/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Anfetamina/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Glutamina/metabolismo , Ácido Homovanílico/metabolismo , Levodopa/farmacologia , Masculino , Oxidopamina/farmacologia , Ratos , Ratos WistarRESUMO
The aim of the present review is to summarize integrated neurochemical, morphological and neurobehavioral evidence, in particular from our laboratory, which emphasize the short- and long-term consequences of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. The results obtained provide evidence that maternal exposure to WIN55,212-2 induces an impairment of cognitive capacities in the offspring. This impairment is associated with alterations of cortical and hippocampal glutamate outflow, cortical neuron morphology and hippocampal long-term potentiation. These findings are in line with clinical data showing that the consumption of marijuana by women during pregnancy has negative consequences on the cognitive functions of their children. Thus, although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of glutamate transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.
Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides , Cognição/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Transmissão Sináptica/efeitos dos fármacos , Envelhecimento , Animais , Canabinoides/farmacologia , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Cognição/fisiologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Ratos , Transmissão Sináptica/fisiologia , Fatores de TempoRESUMO
Studies dealing with the outcomes of developmental carbon monoxide (CO) exposure on myelination in rat offspring are reviewed. Prenatal CO exposure from gestational day 0 to gestational day 20 impairs myelin deposition around peripheral axons resulting in a significant hypomyelination in juvenile and adult rats. Myelin protein patterns analyzed by SDS-polyacrylamide gel electrophoresis and lipid patterns analyzed by the HPTLC method are not altered in both peripheral and central nervous systems of CO-exposed offspring. Interestingly, when sphingomyelin is extracted and purified, the derivatization by OPA reagent and analysis by reversed-phase HPLC reveal a significant increase in sphingosine levels in peripheral nervous system but not in central nervous system of CO-exposed rats. The above morphological and biochemical alterations are not accompanied by motor disabilities.
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Doenças do Sistema Nervoso Periférico/epidemiologia , Complicações na Gravidez/epidemiologia , Fumar/epidemiologia , Animais , Feminino , Humanos , Gravidez , Fatores de RiscoRESUMO
Fatty acids ethanolamides (FAEs) are a family of lipid mediators. A member of this family, anandamide, is an endogenous ligand for cannabinoid receptors targeted by the marijuana constituent Delta-9-tetrahydrocannabinol. Anandamide is now established as a brain endocannabinoid messenger and multiple roles for other FAEs have also been proposed. One emerging function of these lipid mediators is the regulation of feeding behavior and body weight. Anandamide causes overeating in rats because of its ability to activate cannabinoid receptors. This action is of therapeutic relevance: cannabinoid agonists are currently used to alleviate anorexia and nausea in AIDS patients, whereas the cannabinoid receptor CB1 antagonist rimonabant was recently found to be effective in the treatment of obesity. In contrast to anandamide, its monounsatured analogue, oleoylethanolamide (OEA), decreases food intake and body weight gain through a cannabinoid receptor-independent mechanism. In the rat proximal small intestine, endogenous OEA levels decrease during fasting and increase upon refeeding. These periprandial fluctuations may represent a previously undescribed signal that modulates between-meal satiety. Pharmacological studies have shown, indeed, that, as a drug, OEA produces profound anorexiant effects in rats and mice, due to selective prolongation of feeding latency and post-meal interval. The effects observed after chronic administration of OEA to different animal models of obesity, clearly indicate that inhibition of eating is not the only mechanism by which OEA can control energy metabolism. In fact, stimulation of lipolysis is responsible for the reduced fat mass and decrease of body weight gain observed in these models. Although OEA may bind to multiple receptors, several lines of evidence indicate that peripheral PPAR-alpha mediates the effects of this compound. The pathophysiological significance of OEA in the regulation of eating and body weight is further evidenced by preliminary clinical results, showing altered levels of this molecule in the cerebrospinal fluid and plasma of subjects recovered from eating disorders. These results complete previous observation on anandamide content, which resulted altered in plasma of women affected by anorexia nervosa or binge-eating disorder.
Assuntos
Depressores do Apetite/farmacologia , Moduladores de Receptores de Canabinoides/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides , Ácidos Oleicos/líquido cefalorraquidiano , Adulto , Análise de Variância , Peso Corporal/efeitos dos fármacos , Moduladores de Receptores de Canabinoides/farmacologia , Estudos de Casos e Controles , Ingestão de Alimentos/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Feminino , Humanos , Obesidade/fisiopatologia , PPAR alfaRESUMO
Several studies suggest a pivotal role of amyloid beta (Abeta)(1-42) and nitric oxide (NO) in the pathogenesis of Alzheimer's disease. NO also possess central neuromodulatory properties. To study the soluble Abeta(1-42) effects on dopamine concentrations in rat prefrontal cortex, microdialysis technique was used. We showed that i.c.v. injection or retrodialysis Abeta(1-42) administration reduced basal and K(+)-stimulated dopamine levels, measured 2 and 48 h after peptide administration. Immunofluorescent experiments revealed that after 48 h from i.c.v. injection Abeta(1-42) was no longer detectable in the ventricular space. We then evaluated the role of NO on Abeta(1-42)-induced reduction in dopamine concentrations. Subchronic L-arginine administration decreased basal dopamine levels, measured either 2 h after i.c.v. Abeta(1-42) or on day 2 post-injection, whereas subchronic 7-nitroindazole administration increased basal dopamine concentrations, measured 2 h after i.c.v. Abeta(1-42) injection, and decreased them when measured on day 2 post-Abeta(1-42)-injection. No dopaminergic response activity was observed after K(+) stimulation in all groups. These results suggest that the dopaminergic system seems to be acutely vulnerable to soluble Abeta(1-42) effects. Finally, the opposite role of NO occurring at different phases might be regarded as a possible link between Abeta(1-42)-induced effects and dopaminergic dysfunction.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Dopamina/metabolismo , Óxido Nítrico/fisiologia , Fragmentos de Peptídeos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Análise de Variância , Animais , Arginina/farmacologia , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Masculino , Microdiálise/métodos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Pharmacological inhibition of beta-amyloid (Abeta) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Abeta neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD. EXPERIMENTAL APPROACH: Mice were inoculated with human Abeta (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg(-1), i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1beta was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1beta level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Abeta inoculated mice, in the absence or presence of CBD. KEY RESULTS: In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Abeta injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release. CONCLUSION AND IMPLICATIONS: The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Canabidiol/farmacologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Fragmentos de Peptídeos/toxicidade , Animais , Canabidiol/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo , Inflamação/induzido quimicamente , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , RNA MensageiroRESUMO
UNLABELLED: While the effectiveness of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) is well established, its effectiveness in the most severe category of COPD, i.e. patients with chronic respiratory failure (CRF), is less well known. OBJECTIVE: To verify the effects of PR in patients with CRF, and compare the level of improvement with PR in these patients to that of COPDs not affected by CRF. METHODS: A multi-centre study was carried out on COPD patients with versus without CRF. The PR program included educational support, exercise training, and nutritional and psychological counselling. Lung function, arterial gases, walk test (6MWT), dyspnoea (MRC; BDI/TDI), and quality of life (MRF(28); SGRQ) were evaluated. RESULTS: Thousand forty seven consecutive COPD inpatients (327 with CRF) were evaluated. In patients with CRF all parameters improved after PR (0.001). Mean changes: FEV(1), 112 ml; PaO(2), 3.0 mmHg; PaCO(2), 3.3 mmHg; 6MWT, 48 m; MRC, 0.85 units; MRF(28) total score, 11.5 units. These changes were similar to those observed in patients without CRF. CONCLUSIONS: This study, featuring the largest cohort so far reported in the literature, shows that PR is equally effective in the more severe COPD patients, i.e. those with CRF, and supports the prescription of PR also in these patients.
Assuntos
Terapia por Exercício/métodos , Doença Pulmonar Obstrutiva Crônica/reabilitação , Insuficiência Respiratória/reabilitação , Idoso , Análise de Variância , Exercícios Respiratórios , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Educação Física e Treinamento , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Músculos Respiratórios/fisiopatologia , Resultado do TratamentoRESUMO
The ability of CB(1) receptors to regulate the release of glutamate in the striatum, together with the finding that, in experimental models of Huntington disease (HD), both endocannabinoid levels and CB(1) receptor densities are reduced, has prompted the investigation on the neuroprotective role of the cannabinoids in HD. Quinolinic acid (QA) is an excitotoxin that, when injected in the rat striatum reproduces many features of HD and that acts by stimulating glutamate outflow. The aim of the present study was to test the ability of the cannabinoid receptor agonist WIN 55,212-2 to prevent the effects induced by QA in the rat striatum. In microdialysis experiments, probe perfusion with WIN 55,212-2 significantly and dose-dependently prevented the increase in extracellular glutamate induced by QA. In electrophysiological recordings in corticostriatal slices, the application of WIN 55,212-2 prevented QA-induced reduction of the field potential amplitude. Both effects of WIN 55,212-2 were prevented by the CB(1) receptor antagonist AM 251. In in vivo experiments, intrastriatal WIN 55,212-2 significantly attenuated the striatal damage induced by QA, although no significant effects were observed on a behavioural ground. These data demonstrate that the stimulation of CB(1) receptors might lead to neuroprotective effects against excitotoxic striatal toxicity.
Assuntos
Corpo Estriado/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/farmacologia , Ácido Quinolínico/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzoxazinas , Córtex Cerebral/citologia , Ventrículos Cerebrais/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Técnicas In Vitro , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Ratos , Ratos WistarRESUMO
The neurobehavioral and neurochemical effects produced by prenatal methylmercury exposure (8 mg/kg, gestational-days 8 or 15), were investigated in rats. On postnatal day 40, animals exposed to methylmercury and tested in the open field arena, showed a reduction in the number of rearings, whereas the number of crossings and resting time was not altered with respect to the age-matched control rats. The methylmercury-exposed groups showed a lower level of exploratory behavior as well as an impairment in habituation and working memory when subjected to the novel object exploration task. The neophobia displayed by methylmercury-exposed rats is unlikely to be attributed to a higher degree of anxiety. Prenatal methylmercury exposure did not affect motor coordination or motor learning in 40-day-old rats subjected to the balance task on a rotating rod, and it did not impair the onset of reflexive behavior in pups screened for righting reflex, cliff aversion and negative geotaxis. In cortical cell cultures from pups exposed to methylmercury during gestation, basal extracellular glutamate levels were higher, whereas the KCl-evoked extracellular glutamate levels were lower than that measured in cultures from rats born to control mothers. In addition, a higher responsiveness of glutamate release to N-methyl-D-aspartic acid receptor activation was evident in cortical cell cultures from pups born from methylmercury-treated dams than in cultures obtained from control rats. The present results suggest that acute maternal methylmercury exposure induces, in rat offspring, subtle changes in short-term memory as well as in exploratory behavior. These impairments seem to be associated to alterations of cortical glutamatergic signaling.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Reflexo de Sobressalto/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Feminino , Ácido Glutâmico/metabolismo , Inibição Psicológica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod/métodos , Fatores de TempoRESUMO
The effects of prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 (0.5 mg/kg s.c.), alone or in combination with carbon monoxide, on extracellular glutamate levels in primary rat cerebral cortical neuronal cultures, were investigated. Dam weight gain, pregnancy length and litter size at birth were not affected by prenatal treatment with WIN 55,212-2 and carbon monoxide alone or in combination. Basal and K(+)-evoked extracellular glutamate levels were reduced in cortical cultures from pups born to mothers exposed to WIN 55,212-2 and carbon monoxide alone or in combination compared to cultures from rats born to vehicle-treated mothers. In cultures obtained from rats exposed to vehicle or carbon monoxide alone during gestation, WIN 55,212-2 (0.01-100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. In cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide the WIN 55,212-2 ( 1 nM)-induced increase in extracellular glutamate levels was lower than that observed in cultures from rats born to vehicle-treated mothers and similar at those observed at 10 and 100 nM concentrations. The selective CB1 receptor antagonist SR141716A (10 nM) counteracted the WIN 55,212-2-induced increase in extracellular glutamate levels in cultures exposed to vehicle or carbon monoxide during gestation, but failed to antagonise it in cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide. These findings provide evidence that prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide, alone or in combination, is associated with an impairment in cortical glutamatergic transmission. It could be speculated that such detrimental effects might be involved in the reported deficit in learning and memory associated with prenatal marijuana exposure.
Assuntos
Agonistas de Receptores de Canabinoides , Monóxido de Carbono/farmacologia , Córtex Cerebral/metabolismo , Espaço Extracelular/metabolismo , Glutamatos/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Animais , Benzoxazinas , Antagonistas de Receptores de Canabinoides , Carboxihemoglobina/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Feminino , Piperidinas/farmacologia , Potássio/farmacologia , Gravidez , Pirazóis/farmacologia , Ratos , Ratos Wistar , Reprodução/fisiologia , RimonabantoRESUMO
Recent evidence points towards a role of oxidative stress in suicidality. However, few studies were carried out on the sources of reactive oxygen species (ROS) in subjects with suicidal behaviour. We have previously demonstrated that the NADPH oxidase NOX2-derived oxidative stress has a major role in the development of neuropathological alterations observed in an animal model of psychosis. Here, we investigated the possible increase in NOX2 in post mortem brain samples of subjects who died by asphyctic suicide (AS) compared with controls (CTRL) and subjects who died by non-suicidal asphyxia (NSA). We found that NOX2 expression was significantly higher in the cortex of AS subjects than in the other two experimental groups. NOX2 immunostaining was mainly detected in GABAergic neurons, with a minor presence of NOX2-positive-stained cells in glutamatergic and dopaminergic neurons, as well as astrocytes and microglia. A sustained increase in the expression of 8-hydroxy-2'-deoxyguanosine, an indirect marker of oxidative stress, was also detected in the cortex of AS subjects, compared with CTRL and NSA subjects. A significant elevation in cortical interleukin-6 immunoreactivity in AS subjects suggested an involvement of cytokine-associated molecular pathways in NOX2 elevations. Our results suggest that the increase in NOX2-derived oxidative stress in the brain might be involved in the neuropathological pathways leading to suicidal behaviour. These results may open innovative insights in the identification of new pathogenetic and necroscopic biomarkers, predictive for suicidality and potentially useful for suicide prevention.
Assuntos
Asfixia/metabolismo , Encéfalo/metabolismo , NADPH Oxidase 2/metabolismo , Estresse Oxidativo , Suicídio , Adolescente , Adulto , Idoso , Astrócitos/metabolismo , Autopsia , Estudos de Casos e Controles , Neurônios Dopaminérgicos/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Neurônios/metabolismo , Adulto JovemRESUMO
The neurofunctional effects of developmental alcohol exposure (3% v/v solution from day 15 of gestation to day 7 after parturition) have been investigated in Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rat lines, selectively bred for opposite alcohol preference and consumption. Alcohol exposure significantly decreased the rate of ultrasonic emission in sP male pups; whereas, it did not affect this indicator of emotional reactivity in sNP animals. Perinatal alcohol intake did not influence either learning of an active avoidance task or hippocampal long-term potentiation in both offspring lines. Significant differences in time spent exploring novel objects were observed between control sP and sNP rats subjected to the novel exploration object test. Alcohol exposed sP rats, but not alcohol exposed sNP rats, apparently lost the capacity to discriminate between the novel and the familiar object, even though this difference is difficult to interpret because of the large differences in the respective responses to the novel objects. Neurochemical experiments have shown that basal levels of dopamine (DA) and homovanillic acid (HVA) were significantly higher in the nucleus accumbens (NAC) of sP rats with respect to sNP animals. Perinatal alcohol did not affect basal DA and HVA concentrations or amphetamine-induced DA increase and HVA decrease in the NAC of either sP or sNP offspring. These results suggest that subtle behavioral alterations induced by developmental exposure to low doses of alcohol, which do not cause malformations and/or overt neurotoxicity, may be associated with genetic factors, although not necessarily those responsible for differences in alcohol preference.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/congênito , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Alcoolismo/fisiopatologia , Encéfalo/efeitos dos fármacos , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Preferências Alimentares/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Anfetamina/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Dopamina/metabolismo , Etanol/sangue , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Gravidez , Ratos , Ratos Wistar , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologiaRESUMO
Chronic administration of haloperidol (0.5 mg/kg, s.c.) during early postnatal life did not modify the effects produced by a small dose of apomorphine (0.02 mg/kg, s.c.) on the locomotor activity of adult rats; conversely, the reduction of locomotion induced by a large dose of apomorphine (1 mg/kg, s.c.) was much more kared in haloperidol-pretreated rat than in saline-pretreated ones. The differential ontogeny of dopamine auto- and postsynaptic receptors could be partly responsible for the different influence of postnatal treatment with haloperidol on the responsiveness of the adult to small and large doses of apomorphine.
Assuntos
Apomorfina/farmacologia , Haloperidol/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Interações Medicamentosas , Ratos , Ratos EndogâmicosRESUMO
SCH 23390 (SCH), a DA1-receptor antagonist, did not influence the decrease in locomotor activity elicited by a dose of apomorphine (20 micrograms/kg) believed to stimulate DA autoreceptors in rats. Conversely, SCH antagonized the effects on locomotion and the stereotyped behaviour elicited by a dose of apomorphine (1 mg/kg) which stimulates postsynaptic DA receptors. These results showing that the behavioural effects produced by small and large doses of apomorphine are differently affected by SCH, further confirm that DA autoreceptors can be pharmacologically distinguished from postsynaptic DA receptors.
Assuntos
Apomorfina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Benzazepinas/administração & dosagem , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Interações Medicamentosas , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de Dopamina D1 , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Early postnatal administration of SCH 23390 and sulpiride induced marked changes in the ultrasonic vocalization elicited by the removal of rat pups from their nest. In particular, SCH 23390 produced a significant increase in the length, as well as in the sound pressure level, of ultrasonic calls; moreover, a significant decrease in minimum and maximum frequency values was found in pups treated with this DA1-receptor antagonist. Sulpiride significantly reduced the rate of calling, as well as the pressure level of sounds, whereas it did not influence other parameters of the ultrasonic emission. These behavioural alterations seemed to be the consequence of an impaired functional maturation of the dopamine (DA) system; however, the different changes caused by SCH 23390 and sulpiride, respectively, suggest that DA1- and DA2-receptor populations could play a distinct role in the ultrasonic calling during early postnatal life.
Assuntos
Benzazepinas/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Sulpirida/farmacologia , Vocalização Animal/efeitos dos fármacos , Animais , Ratos , Ratos Endogâmicos , UltrassomRESUMO
The aim of the present in vivo microdialysis study was to investigate whether prenatal exposure to the CB(1) receptor agonist WIN55,212-2 mesylate (WIN; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone), at a dose of 0.5 mg/kg (s.c. from the fifth to the 20th day of gestation), that causes neither malformations nor overt signs of toxicity, influences cortical glutamate extracellular levels in adult (90-day old) rats. Dam weight gain, pregnancy length and litter size at birth were not significantly affected by prenatal treatment with WIN. Basal and K(+)-evoked dialysate glutamate levels were lower in the cerebral cortex of adult rats exposed to WIN during gestation than in those born from vehicle-treated mothers. In both group of animals WIN (0.1 mg/kg, i.p.) increased dialysate glutamate levels. However, while the blockade of the CB1 receptors with the selective receptor antagonist SR141716A completely counteracted the WIN-induced increase in those rats exposed to vehicle during gestation, it failed to antagonise the increase in those born from WIN-treated dams. These findings suggest that prenatal exposure to the CB1 receptor agonist WIN, at a concentration which is not associated with gross malformations and/or overt signs of toxicity, induces permanent alterations in cortical glutamatergic function. The possibility that these effects might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users is discussed.