RESUMO
Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet-induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon-like peptide-1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long-term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in vivo FSCV to detect rapid fluctuations in dopamine concentration, we showed that intra-VTA insulin via action at insulin receptors reduced pedunculopontine nucleus-evoked dopamine release in the NAc. Furthermore, intra-VTA insulin reduced cocaine-potentiated NAc dopamine. Finally, intra-VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra-VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin.
Assuntos
Dopamina/metabolismo , Insulina/farmacologia , Receptor de Insulina/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Animais , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Insulina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Receptor de Insulina/metabolismo , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.
Assuntos
Comportamento Alimentar , Sinapses , Área Tegmentar Ventral/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents.
Assuntos
Bulimia/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Obesidade/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , HumanosRESUMO
Perturbations in the perinatal environment have been shown to significantly alter mesolimbic dopamine (DA) and hypothalamic-pituitary-adrenal (HPA) responses to stressors in adulthood. We have previously demonstrated that adult offspring exposed to high fat during the last week of gestation and throughout lactation display permanent alterations in mesolimbic DA function and behavior. The goal of the present study was to investigate nucleus accumbens (NAc) DA and HPA responses to acute and repeated stress in high fat exposed (HFD, 30% fat) and control (CD, 5% fat) offspring. Using microdialysis to monitor extracellular DA, we report that adult HFD offspring show an enhanced NAc DA response to acute tail-pinch compared to CD offspring. With repeated tail-pinch, the response of the HFD animals remains unchanged while CD offspring exhibit a sensitized DA response. The pattern of the DA response to both acute and repeated stress is also significantly altered by early diet exposure with an earlier peak and faster return to baseline levels in CD compared with HFD offspring. Similarly, neuroendocrine adaptations to repeated tail-pinch are observed in CD animals, but not in HFD animals. While controls display a habituated adrenocorticotropic hormone (ACTH) response to repeated tail-pinch, and an exacerbated ACTH response to a novel stressor, this effect was not observed in the HFD offspring. Together, our data demonstrate that exposure to high fat during early development impairs adaptations in NAc DA and HPA responses usually observed with repeated stress.
Assuntos
Gorduras na Dieta/administração & dosagem , Dopamina/sangue , Núcleo Accumbens/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Feminino , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Restrição Física , CaudaRESUMO
The lateral orbitofrontal cortex (lOFC) receives sensory information about food and integrates these signals with expected outcomes to guide future actions, and thus may play a key role in a distributed network of neural circuits that regulate feeding behavior. Here, we reveal a new role for the lOFC in the cognitive control of behavior in obesity. Food-seeking behavior is biased in obesity such that in male obese mice, behaviors are less flexible to changes in the perceived value of the outcome. Obesity is associated with reduced lOFC inhibitory drive and chemogenetic reduction in GABAergic neurotransmission in the lOFC induces obesity-like impairments in goal-directed behavior. Conversely, pharmacological or optogenetic restoration of inhibitory neurotransmission in the lOFC of obese mice reinstates flexible behavior. Our results indicate that obesity-induced disinhibition of the lOFC leads to a failure to update changes in the value of food with satiety, which in turn may influence how individuals make decisions in an obesogenic environment.
Assuntos
Fenômenos Fisiológicos do Sistema Nervoso , Córtex Pré-Frontal , Camundongos , Animais , Masculino , Camundongos Obesos , Córtex Pré-Frontal/fisiologia , Comportamento Animal , Transmissão SinápticaRESUMO
RATIONALE: Early environment can shape the development and function of the mesocorticolimbic dopamine (DA) system and represents a possible risk factor for adult pathologies. One critical variable in the early environment is nutrition, and exposure to high fat (HF) in adulthood is known to change this DA system. OBJECTIVES: We tested whether perinatal HF intake in rats could have long-term effects on DA function and behavior in adult offspring. MATERIALS AND METHODS: Rat dams were fed either a control (5% fat, CD) or high fat (30% fat, HF) diet during the last week of gestation and lactation, and adult offspring were tested (PND 56-90) after weaning on CD. Locomotor responses to acute and repeated doses of D: -amphetamine (AMP, 0.75 mg/kg bw) were determined as were indices of DA function in the ventral tegmental area (VTA), nucleus accumbens (NAc), and the prefrontal cortex (PFC). RESULTS: Adult HF offspring displayed increased tyrosine hydroxylase expression in the VTA and NAc and significant increases in DA and DOPAC content in the NAc, suggesting an elevated DA tone in this target field. In the NAc, there were no significant changes in D1, D2 receptors, or DA transporter (DAT) levels between diet groups. Perinatal HF feeding reduced AMP-induced locomotion and behavioral sensitization to AMP, suggesting that early diet might have caused long-lasting desensitization of postsynaptic receptor mechanisms in the NAc. CONCLUSIONS: Our results demonstrate that both synthetic activity in VTA neurons and the responsiveness of accumbens DA neurons is altered by maternal nutrition. These effects subside long after termination of exposure to the HF diet.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Gorduras na Dieta/administração & dosagem , Dopamina/metabolismo , Sistema Límbico/fisiopatologia , Mesencéfalo/fisiopatologia , Atividade Motora/fisiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Animais Recém-Nascidos , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Idade Gestacional , Lactação/fisiologia , Leptina/sangue , Sistema Límbico/efeitos dos fármacos , Masculino , Mesencéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiopatologiaRESUMO
Recent evidence suggests that the peptide hormone prolactin (PRL) modulates energy balance through a number of mechanisms, including acting in the brain to increase food intake. In the current studies, we first demonstrated that chronic infusions of PRL into the lateral ventricles increased food intake in cycling rats without disrupting estrous cyclicity. In subsequent experiments the hypothesis that at least part of PRL's ability to increase food intake resulted from PRL-induced leptin resistance was tested. Female rats given chronic infusions of PRL (5 microg/h) into the cerebral ventricles for 10 d did not show a reduction in food intake or body weight after a central injection of 4 microg murine leptin, whereas the expected reduction in both of these parameters was seen in vehicle-infused rats. Leptin injections were without effect on these parameters, whether they were administered to free feeding PRL-infused rats or after 24-h food deprivation. This lack of a behavioral response to leptin was accompanied by an attenuation in Fos induction and phosphorylation of signal transducer and activator of transcription 3 after leptin administration in PRL-infused rats in both the ventromedial hypothalamus and paraventricular hypothalamic nucleus.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Leptina/farmacologia , Prolactina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Imuno-Histoquímica , Leptina/administração & dosagem , Leptina/sangue , Prolactina/administração & dosagem , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismoRESUMO
Both undernutrition and overnutrition of the mother during pregnancy and lactation produce a syndrome of altered energy balance in the offspring and has long-lasting consequences on CNS systems regulating food intake, metabolism, and food reward. Homeostatic circulating factors like insulin, glucocorticoids, and leptin that are generally increased by exposure to high fat/high caloric diets constitute important signals in these processes. They trigger functional activation of specific intracellular cascades mediating cellular sensitivity, survival, and synaptic plasticity. Using a model whereby the late fetal and neonatal rat is exposed to increased high fat (HF) via HF feeding of the mother, we investigated the proximal (neonatal) and distal (adult) consequences on metabolism and hippocampal function in the offspring. Adult offspring of HF-fed mothers displayed several of the physiological and behavioral changes susceptible to leading to metabolic complications. These include elevated circulating concentrations of leptin and corticosterone, increased body weight gain and food intake, modest preference for fat-containing food types, as well as the onset of hypothalamic leptin resistance. In the hippocampus, HF-fed offspring or neonates treated with leptin show similar increases in neurogenesis and survival of newborn neurons. We identified some of the direct effects of leptin to increase synaptic proteins, N-methyl-d-aspartate (NMDA), and glucocorticoid receptors, and to reduce long-term potentiation (LTP) prior to weaning. While these studies have documented effects in animal models, concepts can easily be translated to human nutrition in order to help design better perinatal diets and nutritional preventive measures for mothers in a coordinated effort to curb the obesity trend.