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In vulnerable consumers, the first drug exposure induces various neurobehavioral adaptations that may represent the starting point toward addiction. Elucidating the neuroplastic mechanisms underlying that first rewarding experience would contribute to understanding the transition from recreational to compulsive drug use. In a preclinical model with juvenile rats, we analyzed the time-dependent fluctuations in the expression of neuroplasticity-related genes like the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and the neurotransmitters contents in the nucleus accumbens (NAc) and the dorsal striatum (DS) 45, 90, and 180 min after an amphetamine (AMPH) injection. As expected, AMPH altered the concentration of norepinephrine, dopamine, DOPAC, and serotonin in a region- and time-dependent manner. Regarding gene expression, AMPH at 45 min upregulated BDNF and primiR-132 expression in NAc and downregulated TrkB expression in DS. At 90 min, AMPH upregulated TrkB, CREB, p250GAP, and primiR-132 expression in NAc and BDNF, primiR-132, and CRF in DS. At 180 min, only BNDF in NAc continued to be upregulated by AMPH. Based on the levels of AMPH-induced hyperactivity, we classified the rats as low and high AMPH responders. High AMPH responders characterized by overexpressing BDNF, CREB, p250GAP, and CRF in NAc and by showing lower levels of dopamine and serotonin metabolites and turnovers in both regions. Our findings demonstrated that a single AMPH administration is enough to induce neuroplastic adaptations, especially in the NAc of prone rats.
Assuntos
Estimulantes do Sistema Nervoso Central , MicroRNAs , Ratos , Animais , Anfetamina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dopamina/metabolismo , Hormônio Liberador da Corticotropina , Serotonina/metabolismo , Ratos Sprague-Dawley , Núcleo Accumbens/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , MicroRNAs/metabolismoRESUMO
Resumen Introducción: se estima que entre un 80 % y un 90 % de la población mundial ha consumido sustancias psicoactivas (SPA), pero solo un 15 % llega a desarrollar una dependencia. El objetivo de este ensayo es describir los antecedentes epidemiológicos, los aspectos clínicos y los mecanismos neurobiológicos asociados a la dependencia de SPA. Luego, se reflexiona sobre algunas estrategias ambientales para su prevención y/o tratamiento. Proposición: la dependencia no es un simple vicio producto de la holgazanería o la falta de carácter, sino, un trastorno neuropsquiátrico que debe ser reconocido como tal. Para ello, es indispensable conocer sus factores etiológicos, así como los mecanismos neurobiológicos involucrados. Argumentos para la discusión: todas las SPA activan directa o indirectamente el sistema dopaminérgico mesolímbico, el cual, tras el abuso, produce la sensibilización del sistema motivacional y la desensibilización del sistema hedónico. Este fenómeno provoca el uso más frecuente y en mayor cantidad, a pesar de que los efectos placenteros sean cada vez menores. El malestar físico y emocional causado por el síndrome de abstinencia contribuye a dicha compulsión, la cual se sale de control producto de las alteraciones del funcionamiento ejecutivo y la corteza prefrontal. Conclusiones: la dependencia es una enfermedad del cerebro inducida por el consumo crónico de las SPA en conjunto con factores neurobiológicos y psicosociales de vulnerabilidad. El acceso a contacto social, ejercicio físico y estimulación sensorio-cognitiva podría representar una estrategia altamente eficaz para el manejo de la dependencia y el mejoramiento de la salud mental.
Abstract Introduction: It has been estimated that 80% to 90% of the population worldwide has ever consumed psychoactive substances (PAS), but only 15% will develop addiction. The goal of the current essay is to describe concisely the epidemiological background, the clinical foundations, and neurobiological mechanisms of addiction. Finally, it will briefly examine some environmental strategies aimed to prevent and/or treat addiction. Addiction is not a simple vice consequence of laziness or lack of character, but a neuropsychiatric disorder that must be recognized as such. Proposal: To attain this ultimate goal, the etiological factors and the neurobiological mechanisms of addiction must be revealed and disseminated. Arguments for discussion: All PAS directly or indirectly activate the mesolimbic dopaminergic system, which -after repeated intake- sensitizes and desensitizes the motivational and the hedonic system, respectively. This phenomenon causes PAS to be consumed more frequently and at higher doses despite their effects being progressively less rewarding. Consequently, the physical and emotional distress derived from the withdrawal syndrome exacerbates the compulsive PAS intake, while the completely loss of control results from impairments in the executive functions and the prefrontal cortex. Conclusions: Addiction is a brain disease induced by the chronic consumption of PAS combined with neurobiological and psychosocial risk factors. Exposure social contact, physical exercise, and sensory-cognitive stimulation may constitute a highly effective strategy for preventing and treating addiction and improving mental health as well.
Assuntos
Humanos , Neurobiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Costa RicaRESUMO
Resumen Introducción: la depresión mayor es uno de los trastornos mentales más comunes y una de las principales causas de discapacidad en el mundo, con una prevalencia que ha aumentado en las últimas décadas. El objetivo de este ensayo es presentar datos epidemiológicos, así como revisar brevemente los mecanismos psicobiológicos de la depresión relacionados con el estrés crónico. Finalmente, discutiremos algunas estrategias para prevenirla y/o tratarla. Proposición: ciertos tratamientos alternativos complementarios a la medicación y psicoterapia podrían ser mucho más eficaces para evitar y mitigar los efectos del estrés crónico y el riesgo de padecer depresión. Argumentos para la discusión: el estrés crónico puede precipitar un episodio depresivo debido a la hiperactividad de la amígdala y del eje hipotalámico-hipofisario-suprarrenal (HHS), la falla en los mecanismos de retrocontrol negativo del HHS, la depleción de monoaminas, la disminución en los niveles de neurotrofinas, el aumento en la excitotoxicidad glutamatérgica, la reducción en la neurogénesis hipocampal, la disfunción de la corteza prefrontal y una respuesta inflamatoria excesiva. Conclusiones: la acumulación crónica de estresores psicosociales sobre los que se tiene poco control, más el sedentarismo, una mala alimentación y pocos espacios de esparcimiento le confieren a nuestro estilo de vida actual un alto potencial depresogénico. Actividades que incluyan ejercicio, interacciones sociales significativas, actividades recreativas, exposición a ambientes naturales, una dieta balanceada y rutinas saludables representarían una estrategia altamente eficaz para el manejo de la depresión y el mejoramiento de la salud integral.
Abstract Introduction: Major depression is one of the most common mental illnesses and one of the principal causes of disability worldwide, with an increasing prevalence in recent decades. The aim of this essay is to present epidemiological data, as well as to briefly review the psychobiological mechanisms of depression related to the exposure to chronic stress. Finally, we will also discuss some strategies for the prevention and/or treatment of the disease. Proposal: Alternative treatments complementing medication and psychotherapy could be much more effective in preventing and mitigating the effects of chronic stress and the risk of depression than these treatments alone. Arguments for discussion: Chronic stress can precipitate a depressive episode due to hyperactivity of the amygdala and hypothalamic-pituitary-adrenal (HPA) axis, failure of the HPA negative feedback, monoamine depletion, decreased levels of neurotrophins, increased glutamatergic excitotoxicity, reduced hippocampal neurogenesis, prefrontal cortex dysfunction, and excessive inflammatory response. Conclusions:The chronic accumulation of uncontrollable psychosocial stressors plus a sedentary lifestyle, a poor diet, and limited time or places for recreational activities underlie the high depresogenic potential of our current lifestyles. In contrast, activities that include exercise, meaningful social interactions, recreational activities, exposure to natural environments, a balanced diet, and healthy routines would represent a highly effective strategy for managing depression and improving overall health.
Assuntos
Humanos , Estresse Psicológico , Depressão , Exercício Físico , Costa RicaRESUMO
Modern westernized diet is a major risk factor associated with the current obesity epidemic. To study the effects of dietary choices of Western societies, the cafeteria diet has been validated as a preclinical model of obesity. We aimed to investigate the behavioral and metabolic alterations induced by a cafeteria diet on gene expression and neurotransmitter contents involved in neural plasticity and reward processing. Male Wistar rats were exposed to either standard or cafeteria diet for 9 weeks. Food intake and body weight were scored daily. Behavioral effects were assessed in the elevated plus-maze (EPM) and open field (OFT) tests. Serum biochemical parameters, brain monoamines, and BDNF, TrkB, CRF, CREB, and Dnmt3A mRNA levels were analyzed in reward-related brain regions. We found that cafeteria-diet rats consumed more energy and food than the control group, leading to increased body weight gain and adiposity. The cafeteria-diet rats showed an anxiolytic-like effect in the OFT, but not in the EPM. The cafeteria diet increased BDNF expression in the dorsal striatum (DS), and norepinephrine, 5-HT, TrkB, CREB, and Dnmt3A levels in the hippocampus. Additionally, multiple regression analysis showed that accumbal DOPAC and BDNF mRNA levels were robustly predicted by hyperphagia, fat mass accumulation, and body weight gain only in the cafeteria group. Overall, cafeteria diet-induced hyperphagia could lead to alterations in hedonic and motivational control of food intake through changes in dopamine metabolism and BDNF signaling in the nucleus accumbens and the DS.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Dopamina , Animais , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Dieta , Dopamina/metabolismo , Expressão Gênica , Hiperfagia/complicações , Masculino , Obesidade/metabolismo , RNA Mensageiro , Ratos , Ratos Wistar , Aumento de PesoRESUMO
Mounting evidence shows that physical activity, social interaction and sensorimotor stimulation provided by environmental enrichment (EE) exert several neurobehavioural effects traditionally interpreted as enhancements relative to standard housing (SH) conditions. However, this evidence rather indicates that SH induces many deficits, which could be ameliorated by exposing animals to an environment vaguely mimicking some features of their wild habitat. Rearing rodents in social isolation (SI) can aggravate such deficits, which can be restored by SH or EE. It is not surprising, therefore, that most preclinical stress models have included severe and unnatural stressors to produce a stress response prominent enough to be distinguishable from SH or SI-frequently used as control groups. Although current stress models induce a stress-related phenotype, they may fail to represent the stress of our urban lifestyle characterized by SI, poor housing and working environments, sedentarism, obesity and limited access to recreational activities and exercise. In the following review, we discuss the stress of living in urban areas and how exposures to and performing activities in green environments are stress relievers. Based on the commonalities between human and animal EE, we discuss how models of housing conditions (e.g., SI-SH-EE) could be adapted to study the stress of our modern lifestyle. The housing conditions model might be easy to implement and replicate leading to more translational results. It may also contribute to accomplishing some ethical commitments by promoting the refinement of procedures to model stress, diminishing animal suffering, enhancing animal welfare and eventually reducing the number of experimental animals needed.
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Ansiedade , Meio Ambiente , Animais , Abrigo para AnimaisRESUMO
We assessed the antidepressant-like effects of environmental enrichment (EE) and physical exercise (PE) compared with the selective serotonin reuptake inhibitor fluoxetine against the depression-related neurobehavioral alterations induced by postweaning social isolation (SI) in rats. After 1 month of SI, rats were submitted to PE (treadmill), EE, or fluoxetine (10 mg/kg), which were compared with naïve SI and group-housed rats. After 1 month, behavior was analyzed in the open field (OFT), the sucrose preference (SPT), and the forced swimming (FST) tests. Afterward, the hippocampal serotonin contents, its metabolite, and turnover were measured. SI induced a depression-related phenotype characterized by a marginal bodyweight gain, anxiety, anhedonia, behavioral despair, and alterations of serotonin metabolism. EE produced the widest and largest antidepressive-like effect, followed by PE and fluoxetine, which were almost equivalent. The treatments, however, affected differentially the neurobehavioral domains investigated. EE exerted its largest effect on anhedonia and was the only treatment inducing anxiolytic-like effects. Fluoxetine, in contrast, produced its largest effect on serotonin metabolism, followed by its anti-behavioral despair action. PE was a middle-ground treatment with broader behavioral outcomes than fluoxetine, but ineffective to reverse the serotonergic alterations induced by SI. The most responsive test to the treatments was the FST, followed closely by the SPT. Although OFT locomotion and body weight varied considerably between groups, they were barely responsive to PE and fluoxetine. From a translational standpoint, our data suggest that exercise and recreational activities may have broader health benefits than antidepressants to overcome confinement and the consequences of chronic stress.
RESUMO
To study how motivational factors modulate experience-dependent neurobehavioral plasticity, we modify a protocol of environmental enrichment (EE) in rats. We assumed that the benefits derived from EE might vary according to the level of incentive salience attributed to it. To enhance the rewarding properties of EE, access to the EE cage varied randomly from 2 to 48 h for 30 days (REE). The REE group was enriched only 50% of the time and was compared to standard housing and continuous EE (CEE) groups. As behavioral readout, we analyzed the spontaneous activity and the ultrasonic vocalizations (USVs) within the EE cage weekly, and in the open field test at the end of the experiment. In the cage, REE increased the utilization of materials, physical activity, and the rate of appetitive USVs. In the OF, the CEE-induced enhancements in novelty habituation and social signaling were equaled by the REE. At the neural level, we measured the expression of genes related to neural plasticity and epigenetic regulations in different brain regions. In the dorsal striatum and hippocampus, REE upregulated the expression of the brain-derived neurotrophic factor, its tropomyosin kinase B receptor, and the DNA methyltransferase 3A. Altogether, our results suggest that the higher activity within the cage and the augmented incentive motivation provoked by the REE boosted its neurobehavioral effects equaling or surpassing those observed in the CEE condition. As constant exposures to treatments or stimulating environments are virtually impossible for humans, restricted EE protocols would have greater translational value than traditional ones.
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The study of individual differences provides an important methodological approach to analyze the neurobehavioral spectrum of a given cohort in order to understand brain function and disease. Based on immobility time in the forced swimming test (FST) juvenile and adult rats were classified as subgroups with low and high immobility. Afterwards, we compared behavior, neurochemical parameters, and gene expression profiles in some brain areas of rats with low and high immobility only. No differences in the open field test (OFT) were observed between subgroups. Regarding neurochemistry, juvenile animals with low immobility showed higher accumbal dopamine turnover and lower hippocampal norepinephrine concentrations, whereas adult rats only differed for accumbal dopamine, although in an opposite direction from that observed in juveniles. Moreover, the expression of accumbal corticotrophin-releasing factor receptor 1 (CRFR1) was significantly different in animals with low and high immobility at both ages, with animals less immobile showing higher levels of CRFR1 mRNA levels. Taken together, our findings suggest that differences in monoaminergic neurotransmission and CRFR1 expression are associated with the coping strategy adopted by the animal and with the tendency to develop depression-related behaviors. Concerning monoaminergic neurotransmission such association is modulated by age, and such modulation could be related to the differential behavioral results observed between juvenile and adult rats.
Assuntos
Envelhecimento , Monoaminas Biogênicas/metabolismo , Regulação da Expressão Gênica/fisiologia , Resposta de Imobilidade Tônica/fisiologia , Individualidade , Núcleo Accumbens/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Cromatografia Líquida de Alta Pressão , Eletroquímica , Asseio Animal , Masculino , Atividade Motora/fisiologia , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/genética , Natação/psicologia , Fatores de TempoRESUMO
Maternal care represents a major constituent of early life environment and has the potential to modulate critical neurobehavioral responses to stress. The aim of the present study was to determine the effects of naturally occurring variations in maternal care on behavioral and neurochemical responses of juvenile Sprague-Dawley rats. A group of dams were classified based on their licking behavior in high and low licking-grooming mothers. Afterwards, the male offspring was tested in a series of behavioral tests: open field test (OFT), elevated plus maze (EPM) and forced swimming test (FST). Additionally, monoamine concentrations were determined post-mortem in three brain regions: hippocampus, ventral striatum and prefrontal cortex. Our findings suggest that maternal care variations have an effect on several anxiety-related behaviors in OFT and EPM but not in depression-like behaviors in FST. Such behavioral differences could be related to an increased DOPAC concentration and 5-HT turnover in prefrontal cortex. These evidences suggest that natural variations in maternal care modified some behavioral and neurochemical parameters related with anxiety and stress in this strain.
Assuntos
Comportamento Animal/fisiologia , Química Encefálica/fisiologia , Comportamento Materno/fisiologia , Animais , Ansiedade/fisiopatologia , Ansiedade/psicologia , Monoaminas Biogênicas/metabolismo , Cromatografia Líquida de Alta Pressão , Interpretação Estatística de Dados , Dopamina/metabolismo , Eletroquímica , Eletrodos Implantados , Feminino , Asseio Animal , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Atividade Motora/fisiologia , Neostriado/metabolismo , Neurotransmissores/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Restrição Física/fisiologia , Restrição Física/psicologia , Serotonina/metabolismo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Natação/psicologiaRESUMO
Maternal care plays an important role as an early modeler of neurodevelopment and brain function, and its effects remain until adulthood. Such modeling or programming has shown to influence the stress response and represents a key susceptibility factor in the development of mood disorders. In order to characterize such process which is still not clear, male offspring were classified in animals with low, medium and high licking/grooming (LG) according to the maternal behavior. Juvenile animals were subjected to the open field test (OFT) and the forced swimming test (FST), and offspring of low and high LG mothers were compared. Seven days after the FST, neurochemical and gene expression analyses were carried out in order to identify possible changes on relevant targets. Maternal care did determine locomotor behaviors in the OFT, supporting an anxiogenic effect of low maternal investment. This effect seems to be associated with the serotonergic systems in both nucleus accumbens (NAc) and hippocampus (HPC), since offspring of low LG mothers showed decreased 5-HT neurotransmission in those brain regions compared with animals of high LG mothers. Furthermore, TrkB expression was higher in offspring of high LG compared to the group of low LG mothers, supporting its influence as a mechanistic intermediate of such effect, at least in the NAc. Taken together, these findings strongly support the influence of differential maternal care on the neurodevelopment and responsivity of juvenile rats.