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1.
Int J Neuropsychopharmacol ; 24(1): 77-88, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-32951039

RESUMO

BACKGROUND: Prenatal alcohol exposure is a leading cause of neurobehavioral and neurocognitive deficits collectively known as fetal alcohol spectrum disorders, including eating disorders and increased risk for substance abuse as very common issues. In this context, the present study aimed to assess the interaction between prenatal and lactation alcohol exposure (PLAE) and a high-fat diet (HFD) during childhood and adolescence. METHODS: Pregnant C57BL/6 mice underwent a procedure for alcohol binge drinking during gestation and lactation periods. Subsequently, PLAE female offspring were fed with an HFD for 8 weeks, and thereafter, nutrition-related parameters as well as their response to cocaine were assessed. RESULTS: In our model, feeding young females with an HFD increased their triglyceride blood levels but did not induce overweight compared with those fed with a standard diet. Moreover, PLAE affected how females responded to the fatty diet as they consumed less food than water-exposed offspring, consistent with a lower gain of body weight. HFD increased the psychostimulant effects of cocaine. Surprisingly, PLAE reduced the locomotor responses to cocaine without modifying cocaine-induced reward. Moreover, PLAE prevented the striatal overexpression of cannabinoid 1 receptors induced by an HFD and induced an alteration of myelin damage biomarker in the prefrontal cortex, an effect that was mitigated by an HFD-based feeding. CONCLUSION: Therefore, in female offspring, some effects triggered by one of these factors, PLAE or an HFD, were blunted by the other, suggesting a close interaction between the involved mechanisms.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/complicações , Cocaína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Inibidores da Captação de Dopamina/farmacologia , Lactação , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores Etários , Animais , Animais Lactentes , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
2.
EMBO Rep ; 19(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30002119

RESUMO

Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self-administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.


Assuntos
Comportamento Aditivo/genética , Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína/farmacologia , Proteínas de Neoplasias/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Cocaína/administração & dosagem , Dependovirus , Dopamina/metabolismo , Deleção de Genes , Ácido Glutâmico/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Reforço Psicológico , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
3.
Addict Biol ; 25(4): e12778, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31162770

RESUMO

The administration of cannabidiol has shown promising evidence in the treatment of some neuropsychiatric disorders, including cocaine addiction. However, little information is available as to the mechanisms by which cannabidiol reduces drug use and compulsive seeking. We investigated the role of adult hippocampal neurogenesis in reducing cocaine voluntary intake produced by repeated cannabidiol treatment in mice. Cocaine intake was modelled using the intravenous cocaine self-administration procedure in CD1 male mice. Cannabidiol (20 mg/kg) reduced cocaine self-administration behaviour acquisition and total cocaine intake and enhanced adult hippocampal neurogenesis. Our results show that a 6-day repeated temozolomide treatment (25 mg/kg/day), a chemotherapy drug that blocks hippocampal neurogenesis, prevented cannabidiol-induced increment in the early stages of neuronal maturation and differentiation, without altering the basal levels of BrdU/NeuN and doublecortin immunostaining. The reduction of total cocaine intake and operant behaviour acquisition observed following cannabidiol exposure was attenuated by temozolomide treatment. Our results also show a similar effect of temozolamide on a cannabidiol-induced improvement of novel object recognition memory, a task influenced by the proneurogenic effects of cannabidiol (10 and 20 mg/kg). The anxiolytic effects of cannabidiol (10 and 20 mg/kg), however, remained unaffected after its proneurogenic effects decreased. The present study confirms that adult hippocampal neurogenesis is one of the mechanisms by which cannabidiol lowers cocaine reinforcement and demonstrates the functional implication of adult hippocampal neurogenesis in cocaine voluntary consumption in mice. Such findings highlight the possible use of cannabidiol for developing new pharmacotherapies to manage cocaine use disorders.


Assuntos
Canabidiol/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Temozolomida/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas do Domínio Duplacortina , Teste de Labirinto em Cruz Elevado , Hipocampo/metabolismo , Locomoção , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeos/metabolismo , Teste de Campo Aberto , Autoadministração
4.
Addict Biol ; 24(5): 1008-1018, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31237390

RESUMO

The co-occurrence of chronic pain and alcohol use disorders (AUDs) involves complex interactions between genetic and neurophysiological aspects, and the research has reported mixed findings when they both co-occur. There is also an indication of a gender-dependent effect; males are more likely to use alcohol to cope with chronic pain problems than females. Recently, a new conceptualization has emerged, proposing that the negative affective component of pain drives and maintains alcohol-related behaviors. We studied in a longitudinal fashion alterations in alcohol drinking patterns and pain thresholds in a mouse model of chronic neuropathic pain in a sex-dependent manner. Following partial denervation (spared nerve injury [SNI]), stimulus-evoked pain responses were measured before chronic alcohol consumption, during drinking, during a deprivation phase, and following an episode of excessive drinking. During the course of alcohol drinking, we observed pronounced sex differences in pain thresholds. Male mice showed a strong increase in pain thresholds, suggesting an analgesic effect induced by alcohol over time, an effect that was not observed in female mice. SNI mice did not differ from sham-operated controls in baseline alcohol consumption. However, following a deprivation phase and the reintroduction of ethanol, male SNI mice but not female mice showed more pronounced excessive drinking than controls. Finally, we observed decreased central ethanol sensitivity in male SNI mice but not in females. Together with our finding, that ethanol is able to decrease a pain-induced negative affective memory we come to following conclusion. We propose that a lower sensitivity to the intoxicating effects of alcohol together with the ability of alcohol to reduce the negative affective component of pain may explain the higher co-occurrence of AUD in male chronic pain patients.


Assuntos
Alcoolismo/fisiopatologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Neuralgia/fisiopatologia , Animais , Dor Crônica/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Recidiva , Reflexo Anormal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia
5.
Sci Rep ; 14(1): 20043, 2024 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-39209992

RESUMO

Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.


Assuntos
Proteína Relacionada com Agouti , Dieta Hiperlipídica , Núcleo Hipotalâmico Paraventricular , Animais , Proteína Relacionada com Agouti/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Masculino , Feminino , Camundongos , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/farmacologia , Gorduras na Dieta/metabolismo , Neurônios/metabolismo , Camundongos Endogâmicos C57BL , Sinaptofisina/metabolismo
6.
Life Sci Alliance ; 7(10)2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39107065

RESUMO

The brain controls energy homeostasis by regulating food intake through signaling within the melanocortin system. Whilst we understand the role of the hypothalamus within this system, how extra-hypothalamic brain regions are involved in controlling energy balance remains unclear. Here we show that the melanocortin 3 receptor (MC3R) is expressed in the paraventricular nucleus of the thalamus (PVT). We tested whether fasting would change the activity of MC3R neurons in this region by assessing the levels of c-Fos and pCREB as neuronal activity markers. We determined that overnight fasting causes a significant reduction in pCREB levels within PVT-MC3R neurons. We then questioned whether perturbation of MC3R signaling, during fasting, would result in altered refeeding. Using chemogenetic approaches, we show that modulation of MC3R activity, during the fasting period, does not impact body weight regain or total food intake in the refeeding period. However, we did observe significant differences in the pattern of feeding-related behavior. These findings suggest that the PVT is a region where MC3R neurons respond to energy deprivation and modulate refeeding behavior.


Assuntos
Jejum , Neurônios , Núcleo Hipotalâmico Paraventricular , Receptor Tipo 3 de Melanocortina , Animais , Jejum/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Receptor Tipo 3 de Melanocortina/metabolismo , Receptor Tipo 3 de Melanocortina/genética , Camundongos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Masculino , Comportamento Alimentar/fisiologia , Ingestão de Alimentos/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Núcleos da Linha Média do Tálamo/metabolismo , Metabolismo Energético , Camundongos Endogâmicos C57BL , Transdução de Sinais
7.
Mol Metab ; 79: 101860, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38142972

RESUMO

OBJECTIVE: The incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood. As metformin promotes AMPK signaling, which plays a key role in axonal growth during development, we hypothesized that it may have an impact on hypothalamic signaling and the formation of neuronal projections in the hypothalamus, the key regulator of energy homeostasis. We further hypothesized that this is dependent on the metabolic and nutritional status of the mother at the time of metformin intervention. Using mouse models of maternal overnutrition, we aimed to assess the effects of metformin exposure on offspring physiology and hypothalamic neuronal circuits during key periods of development. METHODS: Female C57BL/6N mice received either a control diet or a high-fat diet (HFD) during pregnancy and lactation periods. A subset of dams was fed a HFD exclusively during the lactation. Anti-diabetic treatments were given during the first postnatal weeks. Body weights of male and female offspring were monitored daily until weaning. Circulating metabolic factors and molecular changes in the hypothalamus were assessed at postnatal day 16 using ELISA and Western Blot, respectively. Hypothalamic innervation was assessed by immunostaining at postnatal days 16 and 21. RESULTS: We identified alterations in weight gain and circulating hormones in male and female offspring induced by anti-diabetic treatment during the early postnatal period, which were critically dependent on the maternal metabolic state. Furthermore, hypothalamic agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neuronal innervation outcomes in response to anti-diabetic treatment were also modulated by maternal metabolic state. We also identified sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure. CONCLUSION: We demonstrate a unique interaction between anti-diabetic treatment and maternal metabolic state, resulting in sex-specific effects on offspring brain development and physiological outcomes. Overall, based on our findings, no positive effect of metformin intervention was observed in the offspring, despite ameliorating effects on maternal metabolic outcomes. In fact, the metabolic state of the mother drives the most dramatic differences in offspring physiology and metformin had no rescuing effect. Our results therefore highlight the need for a deeper understanding of how maternal metabolic state (excessive weight gain versus stable weight during GDM treatment) affects the developing offspring. Further, these results emphasize that the interventions to treat alterations in maternal metabolism during pregnancy need to be reassessed from the perspective of the offspring physiology.


Assuntos
Proteínas Quinases Ativadas por AMP , Diabetes Gestacional , Humanos , Camundongos , Feminino , Gravidez , Animais , Masculino , Placenta , Camundongos Endogâmicos C57BL , Aumento de Peso , Dieta Hiperlipídica/efeitos adversos , Diabetes Gestacional/tratamento farmacológico
8.
PLoS One ; 18(8): e0290043, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37590249

RESUMO

OBJECTIVE: In adult organisms, a number of receptors have been identified which modulate metabolic processes related to peptides derived from the intestinal tract. These receptors play significant roles in glucose homeostasis, food intake and energy balance. Here we assess these classical metabolic receptors and their expression as well as their potential role in early development of hypothalamic neuronal circuits. METHODS: Chow-fed C57BL6/N female mice were mated and hypothalamic tissue was collected from offspring across postnatal development (postnatal day 7-21). Subsequent qPCR and Western Blot analyses were used to determine mRNA and protein changes in gut-derived peptide hormone receptors. Correlations to body weight, blood glucose and circulating leptin levels were analyzed. RESULTS: We describe the gene expression and dynamic protein regulation of key gut-derived peptide hormone receptors in the early postnatal period of the mouse brain. Specifically, we show changes to Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide 1 receptor (GLP1R), and cholecystokinin receptor 2 (CCK2R) in the developing hypothalamus. The changes to GIPR and InsR seem to be strongly negatively correlated with body weight. CONCLUSIONS: This comprehensive analysis underscores the need to understand the roles of maternal-derived circulating gut hormones and their direct effect on offspring brain development.


Assuntos
Glicemia , Receptores de Peptídeos , Feminino , Animais , Camundongos , Western Blotting , Peso Corporal , Encéfalo
9.
Artigo em Inglês | MEDLINE | ID: mdl-34688811

RESUMO

No pharmacological treatments are yet approved for patients with cocaine use disorders. Cannabidiol, a constituent of the C. sativa plant has shown promising results in rodent models of drug addiction. However, the specific effects and mechanisms of action of cannabidiol in rodent operant models of extinction-based abstinence and drug-seeking relapse remain unclear. Cannabidiol (10 and 20 mg/kg, i.p.) was injected during extinction training to male CD-1 mice previously trained to self-administer cocaine (0.75 mg/kg/infusion). Then, we evaluated the reinstatement of cocaine seeking induced by cues and stressful stimuli (footshock). We found that cannabidiol (10 and 20 mg/kg) did not modulate extinction learning. After cannabidiol 20 mg/kg treatment, increased levels of CB1 receptor protein were found in the prelimbic and orbitofrontal regions of the prefrontal cortex, and in the ventral striatum; an effect paralleled by a reduction of striatal ∆FosB accumulation and an increment of GluR2 AMPA receptor subunits. Furthermore, cue-induced reinstatement of cocaine seeking was attenuated by cannabidiol. Unexpectedly, cannabidiol 20 mg/kg facilitated stress-induced restoration of cocaine-seeking behaviour. To ascertain the participation of CB1 receptors in these behavioural changes, we administered the CB1 antagonist AM4113 (5 mg/kg) before each reinstatement session. Both, the attenuation of cue-induced reinstatement and the facilitation of stress-induced reestablishment were abolished by AM4113 in cannabidiol 20 mg/kg-treated mice. Our results reveal a series of complex CB1-related changes induced by cannabidiol with a varying impact on the reinstatement of cocaine-seeking behaviour that could limit its therapeutic applications.


Assuntos
Canabidiol/farmacologia , Cocaína/administração & dosagem , Sinais (Psicologia) , Comportamento de Procura de Droga , Pirazóis/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Recidiva , Autoadministração , Estriado Ventral/efeitos dos fármacos
10.
Biomed Pharmacother ; 153: 113333, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35779420

RESUMO

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Its function has been recently associated with mood and reward processing alterations. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, and how this could affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice, including changes in locomotor activity with impaired habituation to environments, short-term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitisation and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum, as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterisation of Bmal1-KO animals. We suggest that reduced cocaine's rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.


Assuntos
Fatores de Transcrição ARNTL , Cocaína , Disfunção Cognitiva , Fatores de Transcrição ARNTL/genética , Animais , Ritmo Circadiano/genética , Cocaína/farmacologia , Dopamina , Camundongos , Camundongos Knockout
11.
Biomed Pharmacother ; 148: 112708, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35168076

RESUMO

Cocaine is a highly consumed drug worldwide which directly targets brain areas involved in reinforcement processing and motivation. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-induced addictive behavior, although many questions about the mechanisms of action and the specific affected processes remain unknown. Moreover, its effects on cue-induced cocaine-craving incubation have never been addressed. The present study aimed to assess the effects of cannabidiol (20 mg/kg, i.p.) administered during the acquisition of cocaine self-administration (0.75 mg/kg/infusion) and demand task or during cocaine abstinence and craving. Moreover, we measured the alterations in expression of AMPAR subunits and ERK1/2 phosphorylation due to cannabidiol treatment or cocaine withdrawal. Our results showed that cannabidiol reduced cocaine intake when administered during the acquisition phase of the self-administration paradigm, increased behavioral elasticity and reduced motivation for cocaine in a demand task. Cannabidiol also reduced GluA1/2 ratio and increased ERK1/2 phosphorylation in amygdala. No effects over cocaine-craving incubation were found when cannabidiol was administered during abstinence. Furthermore, cocaine withdrawal induced changes in GluA1 and GluA2 protein levels in the prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Taken together, our results show that cannabidiol exerts beneficial effects attenuating the acquisition of cocaine self-administration, in which an operant learning process is required. However, cannabidiol does not affect cocaine abstinence and craving.


Assuntos
Canabidiol , Cocaína , Animais , Canabidiol/farmacologia , Cocaína/metabolismo , Cocaína/farmacologia , Fissura , Economia Comportamental , Camundongos , Motivação , Núcleo Accumbens
12.
Artigo em Inglês | MEDLINE | ID: mdl-32758518

RESUMO

Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure. Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response. Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades. Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.


Assuntos
Encéfalo/efeitos dos fármacos , Encefalite/induzido quimicamente , Endocanabinoides/metabolismo , Etanol/farmacologia , Animais , Encéfalo/metabolismo , Encefalite/metabolismo , Etanol/efeitos adversos , Humanos , Transdução de Sinais/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-33002518

RESUMO

Using the social defeat (SD) model, numerous studies have shown that stressed mice display an enhanced response to the motivational effects of cocaine in the self-administration (SA) and conditioned-place preference (CPP) paradigms. However, not all subjects exposed to stress express its harmful effects. Some are particularly susceptible to the deleterious effects of repeated SD, while resilient mice successfully cope with stressful experiences and display adjusted psychological functioning after stress. Vulnerability to develop stress-related disorders, such as depression, has been linked to coping strategies and more recently to individual differences in the immune system. However, no studies have evaluated if coping strategies and immune system reactivity to social stress experiences can also predict susceptibility to stress-induced enhancement of the cocaine response. We evaluated cocaine response in socially defeated mice in the CPP and SA paradigms. To evaluate neuroimmune reactivity to stress the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 were measured in the striatum and hippocampus. Behavioral phenotype during and after SD episodes was also evaluated. Our results showed that susceptible mice to the depressive-like behaviors effects of stress showed increased conditioned rewarding effects of cocaine in the CPP. In addition, susceptible mice displayed passive-reactive coping behavior during social stress episodes and more pronounced changes in neuroinflammatory markers after the last SD episode, which lasted for one month. Although the complex mechanisms underlying susceptibility or resilience to social stress are still unclear, our results point to multiple adaptive stress responses expressed at different phenotypic levels.


Assuntos
Quimiocina CX3CL1/metabolismo , Cocaína/farmacologia , Corpo Estriado/metabolismo , Citocinas/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-32599136

RESUMO

Alcohol interferes with foetal development and prenatal alcohol exposure can lead to adverse effects known as foetal alcohol spectrum disorders. We aimed to assess the underlying neurobiological mechanisms involved in alcohol intake and withdrawal in adolescent mice exposed to alcohol during early life stages, in discrete brain areas. Pregnant C57BL/6 female mice were exposed to binge alcohol drinking from gestation to weaning. Subsequently, alcohol seeking and taking behaviour were evaluated in male adolescent offspring, as assessed in the two-bottle choice and oral self-administration paradigms. Brain area samples were analysed to quantify AMPAR subunits GluR1/2 and pCREB/CREB expression following alcohol self-administration. We measured the expression of mu and kappa opioid receptors both during acute alcohol withdrawal (assessing anxiety alterations by the EPM test) and following reinstatement in the two-bottle choice paradigm. In addition, alcohol metabolism was analysed by measuring blood alcohol concentrations under an acute dose of 3 g/kg alcohol. Our findings demonstrate that developmental alcohol exposure enhances alcohol intake during adolescence, which is associated with a decrease in the pCREB/CREB ratio in the hippocampus, prefrontal cortex and striatum, while the GluR1/GluR2 ratio showed a decrease in the hippocampus. Moreover, PLAE mice showed behavioural alterations, such as increased anxiety-like responses during acute alcohol withdrawal, and higher BAC levels. No significant changes were identified for mu and kappa opioid receptors mRNA expression. The current study highlights that early alcohol exposed mice increased alcohol consumption during late adolescence. Furthermore, a diminished CREB signalling and glutamatergic neuroplasticity are proposed as underpinning neurobiological mechanisms involved in the sensitivity to alcohol reinforcing properties.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Etanol/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Fatores Etários , Animais , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Encéfalo/efeitos dos fármacos , Etanol/administração & dosagem , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de AMPA/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-32109509

RESUMO

Alcohol exposure during development produces physical and mental abnormalities in the foetus that result in long-term molecular adjustments in the brain, which could underlie the neurobehavioural deficits observed in individuals suffering from foetal alcohol spectrum disorders. In this study, we assessed the effects of curcumin on cognitive impairments caused by prenatal and lactational alcohol exposure (PLAE). Furthermore, we examined whether curcumin could counteract the molecular alterations that may underlie these behavioural impairments. We focused on inflammatory and epigenetic mechanisms by analysing the expression of pro-inflammatory mediators, such as IL-6, TNF-α, and NF-κB, in the hippocampus and prefrontal cortex, as well as microglia and astrocyte activation in the dentate gyrus. We also assessed the activity of histone acetyltransferase in these brain areas. To model binge alcohol drinking, we exposed pregnant C57BL/6 mice to a 20% v/v alcohol solution during gestation and lactation, with limited access periods. We treated male offspring with curcumin during postnatal days (PD28-35) and then evaluated their behaviour in adulthood (PD60). Our results showed that curcumin treatment during the peri-adolescence period improved the anxiety and memory deficits observed in PLAE mice. At the molecular level, we found enhanced histone acetyltransferase activity in mice subjected to PLAE that curcumin treatment could not reverse to baseline levels. These mice also showed increased expression of pro-inflammatory mediators, which could be rescued by curcumin treatment. They also displayed astrogliosis and microglia activation. Our study provides further evidence to support the use of curcumin as a therapeutic agent for counteracting behavioural and molecular alterations induced by PLAE.


Assuntos
Curcumina/uso terapêutico , Modelos Animais de Doenças , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/farmacologia , Etanol/administração & dosagem , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Transtornos do Espectro Alcoólico Fetal/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Resultado do Tratamento
16.
Br J Pharmacol ; 177(5): 1090-1105, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31705540

RESUMO

BACKGROUND AND PURPOSE: Alcohol exposure in utero may lead to a wide range of long-lasting morphological and behavioural deficiencies known as fetal alcohol spectrum disorders (FASD), associated with a higher risk of later developing neuropsychiatric disorders. However, little is known about the long-term consequences of cocaine use and abuse in individuals with FASD. This study aimed to investigate the effects of maternal binge alcohol drinking during prenatal and postnatal periods on cocaine reward-related behaviours in adult offspring. EXPERIMENTAL APPROACH: Pregnant C57BL/6 female mice were exposed to an experimental protocol of binge alcohol consumption (drinking-in-the-dark test) from gestation to weaning. Male offspring were subsequently left undisturbed until reaching adulthood and were tested for cocaine-induced motivational responses (conditioned place preference, behavioural sensitization and operant self-administration). Protein expression of dopamine- and glutamate-related molecules was assessed following cocaine-induced reinstatement. KEY RESULTS: The results show that prenatal and postnatal alcohol exposure enhanced the preference for the cocaine-paired chamber in the conditioned place preference test. Furthermore, early alcohol-exposed mice displayed attenuated cocaine-induced behavioural sensitization but also higher cocaine self-administration. Furthermore, alterations in glutamatergic excitability (GluA1/GluA2 ratio) and ΔFosB expression were found in the prefrontal cortex and the striatum of alcohol-exposed mice after cocaine-primed reinstatement. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that maternal binge-like alcohol consumption during gestation and lactation alters sensitivity to the reinforcing effects of cocaine in adult offspring mice. Together, such data suggest that prenatal and postnatal alcohol exposure may underlie an enhanced susceptibility of alcohol-exposed offspring to develop drug addiction later in adulthood.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Animais , Etanol , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Recompensa
17.
J Psychopharmacol ; 33(12): 1573-1587, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31294671

RESUMO

BACKGROUND: Alcohol exposure during development has detrimental effects, including a wide range of physical, cognitive and neurobehavioural anomalies known as foetal alcohol spectrum disorders. However, alcohol consumption among pregnant woman is an ongoing latent health problem. AIM: In the present study, the effects of trichostatin A (TSA) on emotional and cognitive impairments caused by prenatal and lactational alcohol exposure were assessed. TSA is an inhibitor of class I and II histone deacetylases enzymes (HDAC), and for that, HDAC4 activity was determined. We also evaluated mechanisms underlying the behavioural effects observed, including the expression of brain-derived neurotrophic factor (BDNF) in discrete brain regions and newly differentiated neurons in the dentate gyrus (DG). METHODS: C57BL/6 female pregnant mice were used, with limited access to a 20% v/v alcohol solution as a procedure to model binge alcohol drinking during gestation and lactation. Male offspring were treated with TSA during the postnatal days (PD28-35) and behaviourally evaluated (PD36-55). RESULTS: Early alcohol exposure mice presented increased anxiogenic-like responses and memory deterioration - effects that were partially reversed with TSA. Early alcohol exposure produces a decrease in BDNF levels in the hippocampus (HPC) and prefrontal cortex, a reduction of neurogenesis in the DG and increased activity levels of the HDAC4 in the HPC. CONCLUSIONS: Such findings support the participation of HDAC enzymes in cognitive and emotional alterations induced by binge alcohol consumption during gestation and lactation and would indicate potential benefits of HDAC inhibitors for some aspects of foetal alcohol spectrum disorders.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/complicações , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Gravidez
18.
J Psychopharmacol ; 33(12): 1562-1572, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31210079

RESUMO

BACKGROUND: Alcohol exposure impairs brain development and leads to a range of behavioural and cognitive dysfunctions, termed as foetal alcohol spectrum disorders. Although different mechanisms have been proposed to participate in foetal alcohol spectrum disorders, the molecular insights of such effects are still uncertain. Using a mouse model of foetal alcohol spectrum disorder, we have previously shown that maternal binge-like alcohol drinking causes persistent effects on motor, cognitive and emotional-related behaviours associated with neuroimmune dysfunctions. AIMS: In this study, we sought to evaluate whether the long-term behavioural alterations found in offspring with early exposure to alcohol are associated with epigenetic changes in the hippocampus and prefrontal cortex. METHODS: Pregnant C57BL/6 female mice underwent a model procedure for binge alcohol drinking throughout both the gestation and lactation periods. Subsequently, adult offspring were assessed for their cognitive function in a reversal learning task and brain areas were extracted for epigenetic analyses. RESULTS: The results demonstrated that early binge alcohol exposure induces long-term behavioural effects along with alterations in histone acetylation (histone H4 lysine 5 and histone H4 lysine 12) in the hippocampus and prefrontal cortex. The epigenetic effects were linked with an imbalance in histone acetyltransferase activity that was found to be increased in the prefrontal cortex of mice exposed to alcohol. CONCLUSIONS: In conclusion, our results reveal that maternal binge-like alcohol consumption induces persistent epigenetic modifications, effects that might be associated with the long-term cognitive and behavioural impairments observed in foetal alcohol spectrum disorder models.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Disfunção Cognitiva/etiologia , Epigênese Genética , Transtornos do Espectro Alcoólico Fetal/genética , Animais , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Histona Acetiltransferases/metabolismo , Lactação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/patologia , Gravidez , Fatores de Tempo
19.
Prog Neuropsychopharmacol Biol Psychiatry ; 84(Pt A): 237-249, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29526773

RESUMO

Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional-related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/complicações , Encéfalo/fisiopatologia , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Animais , Ansiedade/etiologia , Ansiedade/patologia , Ansiedade/fisiopatologia , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Distribuição Aleatória
20.
Eur Neuropsychopharmacol ; 28(4): 499-512, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29478745

RESUMO

Childhood adversity is associated with an increased risk of mood, anxiety and substance use disorders. Maternal separation is a reliable rodent model of early life adversity that leads to depression-like symptoms, which may increase the vulnerability to alcohol consumption during adolescence. However, the specific alterations in the pattern of alcohol consumption induced by maternal separation and the underlying molecular mechanisms are still unclear. The purpose of this study is to evaluate the long-term effects of maternal separation with early weaning (MSEW) on emotional and social behaviour, alcohol rewarding properties, and alcohol consumption, abstinence and relapse in adolescent male C57BL/6 mice. In addition, endocannabinoid and monoamine levels were analysed in discrete brain areas. Results showed that MSEW mice presented emotional alterations related to depressive-like behaviour and modified endocannabinoid levels in the striatum and the prefrontal cortex. MSEW mice also showed impairments in alcohol-induced conditioned place preference and higher alcohol intake in a model of binge drinking. Moreover, MSEW animals displayed a higher propensity to relapse in the two-bottle choice paradigm following a period of alcohol abstinence associated with reduced monoamine levels in the striatum. Such results indicate that exposure to early life stress increased the vulnerability to alcohol binge-drinking during adolescence, which may be partially explained by decreased sensitivity to alcohol rewarding properties and the ability to potentiate alcohol intake following a period of abstinence.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Corpo Estriado/metabolismo , Endocanabinoides/metabolismo , Privação Materna , Córtex Pré-Frontal/metabolismo , Animais , Consumo Excessivo de Bebidas Alcoólicas/etiologia , Monoaminas Biogênicas/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Corpo Estriado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Recompensa , Comportamento Social , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Estresse Psicológico/metabolismo
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