Involvement of brain cell phenotypes in stress-vulnerability and resilience

Stress-related disorders’ prevalence is epidemically increasing in modern society, leading to a severe impact on individuals’ well-being and a great economic burden on public resources. Based on this, it is critical to understand the mechanisms by which stress induces these disorders. The study of stress made great progress in the past decades, from deeper into the hypothalamic–pituitary–adrenal axis to the understanding of the involvement of a single cell subtype on stress outcomes. In fact, many studies have used state-of-the-art tools such as chemogenetic, optogenetic, genetic manipulation, electrophysiology, pharmacology, and immunohistochemistry to investigate the role of specific cell subtypes in the stress response. In this review, we aim to gather studies addressing the involvement of specific brain cell subtypes in stress-related responses, exploring possible mechanisms associated with stress vulnerability versus resilience in preclinical models. We particularly focus on the involvement of the astrocytes, microglia, medium spiny neurons, parvalbumin neurons, pyramidal neurons, serotonergic neurons, and interneurons of different brain areas in stress-induced outcomes, resilience, and vulnerability to stress. We believe that this review can shed light on how diverse molecular mechanisms, involving specific receptors, neurotrophic factors, epigenetic enzymes, and miRNAs, among others, within these brain cell subtypes, are associated with the expression of a stress-susceptible or resilient phenotype, advancing the understanding/knowledge on the specific machinery implicate in those events

N-acetilcisteína bloqueia o desenvolvimento da sensibilização comportamental ao etanol e as alterações na proteína (Delta)FosB

Ethanol addiction is a serious public health problem that still needs more effective pharmacological treatment. A key factor in the development and maintenance of this disease is the development of neural plasticity that occurs in the mesocorticolimbic brain pathway upon chronic ethanol abuse. These plasticity events are, in general, maladaptive and affect numerous neurotransmitter systems and intracellular molecules. One of these molecules is ΔFosB, a transcriptional factor that is altered after chronic drug use. Behavioral sensitization is a phenomenon resulting from repeated administration of abuse drugs useful for the study of the neural alterations related to addiction. Recent works have shown a role for the imbalance of glutamatergic neurotransmission in the symptoms found in addicted people. In this line, the treatment with N-acetylcysteine, a L-cysteine prodrug that acts restoring extrasynaptic concentrations of glutamate through the activation of cystine-glutamate antiporter, has shown promising results in the treatment of psychostimulant addiction. Thus, we evaluated the effects of N-acetylcysteine treatment in behavioral and molecular alterations induced by chronic ethanol administration. Swiss mice were subject to thirteen days of daily ethanol administration to induce the development of behavioral sensitization. Two hours before each ethanol administration and locomotor activity assessment, animals received N-acetylcysteine injections i.p.. Right after the last test session, their brains were removed for ΔFosB and cystineglutamate antiporter quantification. We found that N-acetylcysteine treatment blocked ethanol-induced behavioral sensitization, the increase of ΔFosB content in the medial prefrontal cortex and its reduction in the nucleus accumbens. Our results suggest a possible use of N-acetylcysteine in the ethanol-related disorders.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)A dependência ao etanol é um grave problema de saúde pública que ainda necessita de tratamentos farmacológicos mais efetivos. Um fator chave no desenvolvimento e manutenção dessa doença são as plasticidades neurais que ocorrem na via mesocorticolímbica mediante o abuso crônico de etanol. Estas plasticidades são, em geral, maladaptativas e afetam inúmeros sistemas de neurotransmissores e moléculas intracelulares. Uma dessas moléculas é a ΔFosB, um fator de transcrição que é alterado após o uso crônico de drogas de abuso. A sensibilização comportamental é um fenômeno decorrente da administração repetida de drogas muito útil no estudo das alterações neurais relacionadas à dependência. Trabalhos recentes tem demonstrado um papel do desequilíbrio da neurotransmissão glutamatérgica nos sintomas encontrados em indivíduos dependentes. Neste sentido, o tratamento com a N-acetilcisteína, um pró-fármaco da L-cisteína que atua restaurando as concentrações extrasinápticas do glutamato através da ativação do trocador cistina-glutamato, tem mostrado resultados promissores no tratamento da dependência de psicostimulantes. Assim, avaliamos os efeitos do tratamento com a N-acetilcisteína nas alterações comportamentais e moleculares induzidas pela administração crônica de etanol. Camundongos suíços machos foram submetidos a administrações diárias de etanol por 13 dias a fim de induzir o desenvolvimento da sensibilização comportamental. Duas horas antes de cada administração, os animais receberam uma administração intraperitoneal de Nacetilcisteína. Imediatamente após a última sessão de teste, os cérebros dos animais foram removidos para quantificação de ΔFosB e do trocador cistinaglutamato. Nós encontramos que o tratamento com a N-acetilcisteína bloqueou o desenvolvimento da sensibilização comportamental ao etanol, o aumento de ΔFosB no córtex pré-frontal medial e a sua redução no núcleo acumbens. Nossos resultados sugerem um possível uso da N-acetilcisteína nas desordens relacionadas ao uso de etanol.FAPESP: 2015/01026-

Stress Abolishes the Effect of Previous Chronic Ethanol Consumption on Drug Place Preference and on the Mesocorticolimbic Brain Pathway

BackgroundConditioned place preference (CPP) to ethanol (EtOH) is an important addiction-related alteration thought to be mediated by changed neurotransmission in the mesocorticolimbic brain pathway. Stress is a factor of major importance for the initiation, maintenance, and reinstatement of drug abuse and modulates the neurochemical outcomes of drugs. Thus, the aim of this study was to investigate the effects of concomitant exposure to chronic EtOH and stress on CPP to this drug and alterations of dopaminergic and serotonergic neurotransmission in mice.MethodsMale Swiss mice were chronically treated with EtOH via a liquid diet and were exposed to forced swimming stress. After treatment, animals were evaluated for conditioning, extinction, and reinstatement of CPP to EtOH. Also, mice exposed to the same treatment protocol had their prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala dissected for the quantitation of dopamine, serotonin, and their metabolites content.ResultsData showed that previous chronic exposure to EtOH potentiated EtOH conditioning and increased dopaminergic turnover in PFC. Exposure to stress potentiated EtOH conditioning and decreased dopaminergic turnover in the NAc. However, animals exposed to both chronic EtOH and stress did not display alterations of CPP and showed an elevated content of dopamine in amygdala. No treatment yielded serotonergic changes.ConclusionsThe present study indicates that previous EtOH consumption as well as stress exposure induces increased EtOH conditioning, which can be related to dopaminergic alterations in the PFC or NAc. Interestingly, concomitant exposure to both stimuli abolished each other's effect on conditioning and PFC or NAc alterations. This protective outcome can be related to the dopaminergic increase in the amygdala

Alcohol Deprivation Differentially Changes Alcohol Intake in Female and Male Rats Depending on Early-Life Stressful Experience

Experiencing early-life adverse events has enduring effects on individual vulnerability to alcohol abuse and the development of addiction-related behaviors. In rodents, it can be studied using maternal separation (MS) stress. Studies have shown that, depending on the protocol used, MS can affect the mother and pups’ behavior and are associated with behavioral alterations later in adulthood, associated with both positive or negative outcomes. However, it is not fully elucidated how MS affects relapse-like behaviors when experienced by female or male individuals. Therefore, the aim of our study was to evaluate the effects of brief and prolonged MS on the alcohol deprivation effect (ADE) in female and male rats. Female and male Wistar rats were exposed to brief (15 min/day) or prolonged (180 min/day) MS from postnatal day (PND) 2 to 10. Later, during adulthood (PND 70), animals were submitted to an ADE protocol. Brief MS exposure prevented the ADE in both females and males, while prolonged MS exposure also prevented the ADE in female rats. Moreover, the ADE was more robust in females when compared to males. In conclusion, we showed that male and female rats are differentially affected by alcohol deprivation periods depending on their early-life experiences

Alcohol Deprivation Differentially Changes Alcohol Intake in Female and Male Rats Depending on Early-Life Stressful Experience

Experiencing early-life adverse events has enduring effects on individual vulnerability to alcohol abuse and the development of addiction-related behaviors. In rodents, it can be studied using maternal separation (MS) stress. Studies have shown that, depending on the protocol used, MS can affect the mother and pups’ behavior and are associated with behavioral alterations later in adulthood, associated with both positive or negative outcomes. However, it is not fully elucidated how MS affects relapse-like behaviors when experienced by female or male individuals. Therefore, the aim of our study was to evaluate the effects of brief and prolonged MS on the alcohol deprivation effect (ADE) in female and male rats. Female and male Wistar rats were exposed to brief (15 min/day) or prolonged (180 min/day) MS from postnatal day (PND) 2 to 10. Later, during adulthood (PND 70), animals were submitted to an ADE protocol. Brief MS exposure prevented the ADE in both females and males, while prolonged MS exposure also prevented the ADE in female rats. Moreover, the ADE was more robust in females when compared to males. In conclusion, we showed that male and female rats are differentially affected by alcohol deprivation periods depending on their early-life experiences