RESUMO

Childhood obesity increases the risk of health and cognitive disorders in adulthood. Consuming high-fat diets (HFD) during critical neurodevelopmental periods, like childhood, impairs cognition and memory in humans and animals, affecting the function and connectivity of brain structures related to emotional memory. However, the underlying mechanisms of such phenomena need to be better understood. This study aimed to investigate the neurochemical profile of the amygdala and hippocampus, brain structures involved in emotional memory, during the acquisition of conditioned odor aversion in male rats that consumed a HFD from weaning to adulthood. The rats gained weight, experienced metabolic changes, and reduced insulin sensitivity and glucose tolerance. Rats showed enhanced odor aversion memory, contrary to the expected cognitive impairments. This memory enhancement was accompanied by increased noradrenergic and glutamatergic neurotransmission in the amygdala and hippocampus. Importantly, this upregulation was specific to stimuli exposure, as basal neurotransmitter levels remained unaltered by the HFD. Our results suggest that HFD modifies cognitive function by altering neurochemical signaling, in this case, upregulating neurotransmitter levels rendering a stronger memory trace, demonstrating that metabolic dysfunctions do not only trigger exclusively detrimental plasticity processes but also render enhanced plastic effects depending on the type of information.

Assuntos

Tonsila do Cerebelo , Dieta Hiperlipídica , Ácido Glutâmico , Hipocampo , Transmissão Sináptica , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Tonsila do Cerebelo/metabolismo , Transmissão Sináptica/fisiologia , Ratos , Ácido Glutâmico/metabolismo , Norepinefrina/metabolismo , Ratos Wistar , Cognição/fisiologia , Aprendizagem da Esquiva/fisiologia

RESUMO

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

Assuntos

Fármacos Antiobesidade , Compostos Bicíclicos Heterocíclicos com Pontes , Neurônios GABAérgicos , Obesidade , Animais , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Ratos , Camundongos , Fármacos Antiobesidade/farmacologia , Masculino , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos Transgênicos , Redução de Peso/efeitos dos fármacos , Ratos Sprague-Dawley

RESUMO

D-norpseudoephedrine (NPE), also known as cathine, is found naturally in the shrub Catha edulis "Khat." NPE has been widely used as an appetite suppressant for the treatment of obesity. Although it is known that NPE acts on α1-adrenergic receptors, there is little information about the role of dopamine receptors on NPE's induced anorectic and weight loss effects. Equally untouched is the question of how NPE modulates neuronal activity in the nucleus accumbens shell (NAcSh), a brain reward center, and a pharmacological target for many appetite suppressants. To do this, in rats, we characterized the pharmacological effects induced by NPE on weight loss, food intake, and locomotion. We also determined the involvement of dopamine D1- and D2-like receptors using systemic and intra-NAcSh antagonists, and finally, we recorded single-unit activity in the NAcSh in freely moving rats. We found that NPE decreased 24-h food intake, induced weight loss, and as side effects increased locomotor activity and wakefulness. Also, intraperitoneal and intra-NAcSh administration of D1 and D2 dopamine antagonists partially reversed NPE's induced weight loss and food intake suppression. Furthermore, the D1 antagonist, SCH-23390, eliminated NPE-induced locomotion, whereas the D2 antagonist, raclopride, only delayed its onset. We also found that NPE evoked a net activation imbalance in NAcSh that propelled the population activity trajectories into a dynamic pharmacological brain state, which correlated with the onset of NPE-induced wakefulness. Together, our data demonstrate that NPE modulates NAcSh spiking activity and that both dopamine D1 and D2 receptors are necessary for NPE's induced food intake suppression and weight loss.