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1.
Artigo em Inglês | MEDLINE | ID: mdl-31385259

RESUMO

This paper reports matrix-assisted laser desorption/ionization mass spectrometry imaging to investigate systematic effects of a lentil extract treatment to lower cholesterol levels. For this purpose, mass spectrometry imaging was used to spatially investigate modifications in the lipid composition and cholesterol levels in the brain, liver, and intestines as well as bile acids in the liver and intestine of rats treated with lentil extract. Neither the lipid composition nor cholesterol levels in the brain samples were found to be significantly different between the treated and not-treated animal groups. The hypercholesterolemic livers showed signs of steatosis (lipid marker PG 36:4), but no modifications in bile acid, cholesterol, and lipid composition. We found significant differences (AUC > 0.75) in the intestines regarding bile acid and lipid composition after treatment with the lentil extract. The treated rats showed a decreased reabsorption (increased excretion) of ursodeoxycholic acid, deoxycholic acid, and chenodeoxycholic acid and an increased deconjugation of taurine-conjugated bile acids (taurochenodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, and 3-keto-taurocholic acid). This indicates that the lentil extract lowers the total cholesterol level in two synergic ways: (i) it increases the excretion of bile acids; hence, new bile acids are produced in the liver from serum cholesterol and (ii) the prebiotic effect leads to free taurine which upregulates the de novo synthesis of bile acid from cholesterol while activating LDL receptors. We demonstrate here that mass spectrometry imaging is a valuable tool for a better understanding of the effects of treatments such as for the synergistic cholesterol-lowering effect of the lentil extract.

2.
ACS Chem Neurosci ; 10(8): 3391-3397, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31298830

RESUMO

The enantiomers of the potent σ1 receptor antagonist (±)-1 were synthesized and evaluated for their affinity at σ1, σ2 receptors and dopamine transporter (DAT). Analogously to (±)-1, both of the enantiomers showed very high affinity for the σ1 receptor and unprecedented selectivity over both the σ2 receptor and DAT. The lack of enantioselectivity between (+)-1 and (-)-1 indicated that the center of chirality in the 2-position of the benzothiochromane nucleus does not play a crucial role in the interaction with any of the studied targets. Docking studies confirmed that the configuration of the enantiomers has only marginal effects on the molecular interactions with the σ1 receptor. In in vivo studies in a female rat model of binge eating, (±)-1 dose-dependently decreased the binge eating episode elicited by a history of intermittent food restriction and stress, confirming and strengthening the important role played by the σ1 receptor in bingeing-related eating disorders.

3.
J Psychopharmacol ; : 269881119845798, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31161847

RESUMO

BACKGROUND: Pharmacological treatment approaches for eating disorders, such as binge eating disorder and bulimia nervosa, are currently limited. METHODS AND AIMS: Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the A2A Adenosine Receptor (A2AAR) and dopaminergic D2 receptor (D2R) genes. RESULTS: Gene expression analysis revealed a selective increase of both receptor mRNAs in the amygdaloid complex of stressed and restricted rats, which exhibited binge-like eating, when compared to non-stressed and non-restricted rats. Consistently, pyrosequencing analysis revealed a significant reduction of the percentage of DNA methylation but only at the A2AAR promoter region in rats showing binge-like behaviour compared to the control animals. Focusing thus on A2AAR agonist (VT 7) administration (which inhibited the episode of binge systemically at 0.1 mg/kg or intra-central amygdala (CeA) injection at 900 ng/side) induced a significant increase of A2AAR mRNA levels in restricted and stressed rats when compared to the control group. In addition, we observed a significant decrease in A2AAR mRNA levels in rats treated with the A2AAR antagonist (ANR 94) at 1 mg/kg. Consistent changes in the DNA methylation status of the A2AAR promoter were found in restricted and stressed rats after administration of VT 7 or ANR 94. CONCLUSION: We confirm the role of A2AAR in binge eating behaviours, and we underline the importance of epigenetic regulation of the A2AAR gene, possibly due to a compensatory mechanism to counteract the effect of binge eating. We suggest that A2AAR activation, inducing receptor gene up-regulation, could be relevant to reduction of food consumption.

4.
Handb Exp Pharmacol ; 254: 279-295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073870

RESUMO

While lifestyle modifications should be the first-line actions in preventing and treating obesity and eating disorders, pharmacotherapy also provides a necessary tool for the management of these diseases.However, given the limitations of current anti-obesity drugs, innovative treatments that improve efficacy and safety are needed.Since the discovery that the activation of the Nociceptin/Orphanin (N/OFQ) FQ peptide (NOP) receptor by N/OFQ induces an increase of food intake in laboratory animals, and the finding that this effect can be blocked by NOP antagonists, many NOP agonists and antagonists have been synthesized and tested in vitro and in vivo for their potential regulation of feeding behavior. Promising results seem to suggest that the N/OFQergic system may be a potential therapeutic target for the neural control of feeding behavior and related pathologies, especially in binge-like eating behavior.


Assuntos
Obesidade/metabolismo , Peptídeos Opioides , Receptores Opioides , Animais , Comportamento Alimentar , Peptídeos Opioides/química , Peptídeos Opioides/metabolismo
5.
Int J Eat Disord ; 2018 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-30578649

RESUMO

OBJECTIVE: Binge-eating episodes are recurrent and are defining features of several eating disorders. Thus binge-eating episodes might influence eating disorder development of which exact underlying mechanisms are still largely unknown. METHODS: Here we focused on the transcriptional regulation of the endocannabinoid system, a potent regulator of feeding behavior, in relevant rat brain regions, using a rat model in which a history of intermittent food restriction and a frustration stress induce binge-like palatable food consumption. RESULTS: We observed a selective down-regulation of fatty acid amide hydrolase (faah) gene expression in the hypothalamus of rats showing the binge-eating behavior with a consistent reduction in histone 3 acetylation at lysine 4 of the gene promoter. No relevant changes were detected for any other endocannabinoid system components in any brain regions under study, as well as for the other epigenetic mechanisms investigated (DNA methylation and histone 3 lysine 27 methylation) at the faah gene promoter. DISCUSSION: Our findings suggest that faah transcriptional regulation is a potential biomarker of binge-eating episodes, with a relevant role in the homeostatic regulation of food intake.

6.
Biochem Biophys Res Commun ; 505(3): 801-806, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30297106

RESUMO

The aim of the study was to identify and functionally characterize novel candidate gene/s involved in the development of resistance to diet-induced obesity in rats. In a high-fat-diet (HFD) study of rats, we found subgroups which either developed resistance to HFD-induced obesity (DR) or showed an obesity-prone phenotype (DIO). Gene expression analysis in 10 samples (5 DIO vs 5 DR) was performed. The most promising gene, OR6C3 (orthologous with rat Olr984 and mouse Olfr788) was measured by qRT-PCR in paired samples of human visceral (Vis) and subcutaneous (SC) adipose tissue (AT) (n = 225) and in sub-fractions of adipocytes and cells of stromal vascular fraction. Gene expression analyses showed Olr984 with significantly reduced mRNA expression in DR rats. In the Vis AT of human samples we found an up-regulation of OR6C3 compared to SC AT, independent of gender, glucose tolerance or type 2 diabetes. We observed significantly lower levels of SC AT OR6C3 mRNA in subjects with obesity compared to those with normal-weight or overweight. OR6C3 is more expressed in SVF than in adipocytes. Olr984 could be a novel candidate gene related to diet-induced obesity in rats. Variation in human AT mRNA expression is related to obesity parameters and glucose homeostasis and linked to the regulatory role of insulin on the Olr984.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30017749

RESUMO

Alcohol exposure and stressful events in life can induce long-lasting changes in physiology, behavior and gene expression patterns, eventually facilitating the development of psychiatric diseases like alcohol use disorders (AUD). Epigenetic mechanisms have been recently proposed to play a role in the cellular actions of alcohol via chromatin remodeling. Here we discuss interactions between stress and the pharmacological effects of alcohol, including the possibility that early exposure to, or withdrawal of, alcohol might induce stressful effects of their own. A specific aim is to describe novel molecular mechanisms by which stress, alcohol or their combined presentation impact on the epigenome. A key question is why only a fraction of the population progresses from regular, non-problematic, alcohol use to AUD, despite suffering from similar alcohol exposure. It is important to analyze how environmental factors, most notably stress, interact with the epigenetic machinery to increase vulnerability for AUD. The knowledge derived from this endeavor will be critical for the development of preventive strategies and new, drug- or gene-based, therapies.

8.
J Med Chem ; 61(8): 3712-3725, 2018 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-29589445

RESUMO

In the present article, the M1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D4R selectivity over D2R and D3R and to behave as a D4R antagonist. To better understand the structural features required for the selective interaction with the D4R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D4R affinity and selectivity not only over the other D2-like subtypes, but also over M1-M5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating Gi protein and inhibiting ß-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D4R in disorders in which this subtype is involved.

9.
Addict Biol ; 23(2): 699-712, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28661034

RESUMO

We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock-induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions.

10.
Neuron ; 96(2): 414-427.e8, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29024664

RESUMO

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist. Here we used a novel rat model, in which the availability of a mutually exclusive palatable food maintains prolonged voluntary abstinence from intravenous methamphetamine self-administration, to demonstrate that the activation of monosynaptic glutamatergic projections from anterior insular cortex to central amygdala is critical to relapse after the cessation of contingency management. We identified the anterior insular cortex-to-central amygdala projection as a new addiction- and motivation-related projection and a potential target for relapse prevention.


Assuntos
Comportamento Aditivo/psicologia , Núcleo Central da Amígdala/fisiologia , Córtex Cerebral/fisiologia , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Metanfetamina/administração & dosagem , Animais , Núcleo Central da Amígdala/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Injeções Intravenosas , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Recidiva , Autoadministração
12.
Int J Eat Disord ; 50(10): 1194-1204, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28833350

RESUMO

OBJECTIVE: The present study evaluated the effect of systemic injection of the CRF1 receptor antagonist R121919, the corticosterone synthesis inhibitor metyrapone and central amygdala (CeA) injections of the nonselective CRF antagonist D-Phe-CRF(12-41) in rats in which binge eating was evoked by stress and cycles of food restriction. METHOD: Female rats were subjected or not to repeated cycles of regular chow food restriction/ad libitum feeding during which they were also given limited access (2 h) to palatable food. On the test day, rats were either exposed or not to the sight of the palatable food for 15 min without allowing access, before assessing food consumption. RESULTS: Systemic injections of R121919, but not of the metyrapone, blocked binge-like eating behavior. Restricted and stressed rats showed up-regulation of crh1 receptor mRNA signal in the bed nucleus of the stria terminalis and CeA but not in basolateral amygdala (BLA) or in the paraventricular nucleus. Injection D-Phe-CRF(12-41) in CeA but not in the BLA-blocked binge-like eating behavior. DISCUSSION: These findings demonstrate that extra-hypothalamic CRF1 receptors, rather than those involved in endocrine functions, are involved in binge eating and the crucial role of CRF receptors in CeA. CRF1 receptor antagonism may represent a novel pharmacological treatment for binge-related eating disorders.


Assuntos
Transtorno da Compulsão Alimentar/genética , Comportamento Alimentar/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/imunologia , Animais , Feminino , Humanos , Ratos , Ratos Sprague-Dawley
13.
Mol Nutr Food Res ; 61(11)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28730708

RESUMO

SCOPE: The aim of our work was to produce a hydroalcoholic extract of lentils and to examine (a) the hypocholesterolemic action in an animal model, by studying the plasma cholesterol level and the concentration of bile acids in the feces; (b) the potential prebiotic effect, by conducting an in vitro culture fermentation experiment and assessing the level of SCFAs in the feces of rats. METHODS AND RESULTS: Lentil extract (LE) was obtained by extracting lentils with a solution of H2 0/EtOH (70/30 v/v) for 3 h, and the content of main nutrients was determined. After 71 days of diet-induced hypercholesterolemia in rats, LE reduced the cholesterol level of rats of 16.8% (p < 0.05) and increased the level of bile acids in the feces of rats (p < 0.01). LE revealed the same prebiotic activity of inulin and good bifidogenic activity, inasmuch as it enhanced the growth of Bifidobacterium spp. by 3 log (p < 0.05). The concentration of SCFAs in the feces of rats fed with LE increased during the time of the study. CONCLUSION: This new hydroalcoholic extract obtained from lentils was shown to possess hypocholesterolemic and prebiotic properties, and could have interesting applications in the field of nutraceuticals.


Assuntos
Anticolesterolemiantes/uso terapêutico , Microbioma Gastrointestinal , Hipercolesterolemia/dietoterapia , Lens (Planta)/química , Extratos Vegetais/uso terapêutico , Prebióticos , Sementes/química , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/isolamento & purificação , Anticolesterolemiantes/metabolismo , Bifidobacterium/crescimento & desenvolvimento , Bifidobacterium/isolamento & purificação , Bifidobacterium/metabolismo , Ácidos e Sais Biliares/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Contagem de Colônia Microbiana , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Fezes/microbiologia , Fermentação , Liofilização , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/microbiologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Prebióticos/efeitos adversos , Prebióticos/análise , Ratos Sprague-Dawley , Saponinas/análise , Saponinas/isolamento & purificação , Saponinas/metabolismo , Saponinas/uso terapêutico , Triglicerídeos/sangue
14.
Pharmacol Res ; 122: 20-34, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28535974

RESUMO

The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg-1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA's behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA's central effects that sustain its pro-satiety action.


Assuntos
Área Postrema/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides/farmacologia , Hipotálamo/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Animais , Área Postrema/fisiologia , Tronco Encefálico/fisiologia , Dopamina beta-Hidroxilase/análise , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/fisiologia , Masculino , Ocitocina/análise , Ocitocina/metabolismo , PPAR alfa/análise , PPAR alfa/metabolismo , Proteínas Proto-Oncogênicas c-fos/análise , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar
15.
J Psychopharmacol ; 31(6): 691-703, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28417659

RESUMO

The present study investigated the effect of [Nphe1] Arg14, Lys15-N/OFQ-NH2 (UFP-101), a selective NOP receptor antagonist, in chronic mild stress (CMS) in male Wistar rats. NOP receptor antagonists were reported to elicit antidepressant-like effects in rodents. Our aim was to investigate UFP-101 effects on CMS-induced anhedonia and impairment of hippocampal neurogenesis. UFP-101 (10 nmol/rat intracerebroventricularly) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals from the second week of treatment. UFP-101 also reversed stress effects in forced swimming test and in open field. Fluoxetine (10 mg/kg intraperitoneally) produced similar effects. Moreover, we investigated whether UFP-101 could affect CMS-induced impairment in hippocampal cell proliferation and neurogenesis, and in fibroblast growth factor (FGF-2) expression. Our data confirm that CMS reduced neural stem cell proliferation and neurogenesis in adult rat hippocampus. Chronic UFP-101 treatment did not affect the reduced proliferation (bromodeoxyuridine-positive cells) observed in stressed animals. However, UFP-101 increased the number of doublecortin-positive cells, restoring neurogenesis. Finally, UFP-101 significantly increased FGF-2 expression, reduced by CMS. These findings support the view that blockade of NOP receptors produces antidepressant-like effects in CMS associated with positive effects on neurogenesis and FGF-2 expression. Therefore, NOP receptors may represent a target for innovative antidepressant drugs.


Assuntos
Antidepressivos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/farmacologia , Receptores Opioides/metabolismo , Anedonia/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neurogênese/efeitos dos fármacos , Ratos , Ratos Wistar , Natação/fisiologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-28336495

RESUMO

Dynorphins are critically involved in the development, maintenance and relapse of alcoholism. Alcohol-induced changes in the prodynorphin gene expression may be influenced by both gene polymorphisms and epigenetic modifications. The present study of human alcoholics aims to evaluate DNA methylation patterns in the prodynorphin gene (PDYN) promoter and to identify single nucleotide polymorphisms (SNPs) associated with alcohol dependence and with altered DNA methylation. Genomic DNA was isolated from peripheral blood cells of alcoholics and healthy controls, and DNA methylation was studied in the PDYN promoter by bisulfite pyrosequencing. In alcoholics, DNA methylation increased in three of the seven CpG sites investigated, as well as in the average of the seven CpG sites. Data stratification showed lower increase in DNA methylation levels in individuals reporting craving and with higher levels of alcohol consumption. Association with alcoholism was observed for rs2235751 and the presence of the minor allele G was associated with reduced DNA methylation at PDYN promoter in females and younger subjects. Genetic and epigenetic factors within PDYN are related to risk for alcoholism, providing further evidence of its involvement on ethanol effects. These results might be of relevance for developing new biomarkers to predict disease trajectories and therapeutic outcome.


Assuntos
Alcoolismo/sangue , Alcoolismo/genética , Metilação de DNA/genética , Encefalinas/genética , Epigênese Genética/genética , Precursores de Proteínas/genética , Adulto , Fatores Etários , Ilhas de CpG , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
17.
Int J Eat Disord ; 50(6): 624-635, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28230907

RESUMO

Because binge eating and emotional eating vary through the menstrual cycle in human females, we investigated cyclic changes in binge-like eating in female rats and their control by estrogens. Binge-like eating was elicited by three cycles of 4 days of food restriction and 4 days of free feeding followed by a single frustrative nonreward-stress episode (15 min visual and olfactory exposure to a familiar palatable food) immediately before presentation of the palatable food. Intact rats showed binge-like eating during the diestrous and proestrous phases of the ovarian cycle, but not during the estrous (periovulatory) phase. Ovariectomized (OVX) rats not treated with estradiol (E2) displayed binge-like eating, whereas E2-treated OVX rats did not. The procedure did not increase signs of anxiety in an open-field test. OVX rats not treated with E2 that were subjected to food restriction and sacrificed immediately after frustrative nonreward had increased numbers of cells expressing phosphorylated extracellular signal-regulated kinases (ERK) in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), and dorsal and ventral bed nuclei of the stria terminalis (BNST) compared with nonrestricted or E2-treated rats. These data suggest that this female rat model is appropriate for mechanistic studies of some aspects of menstrual-cycle effects on emotional and binge eating in human females, that anxiety is not a sufficient cause of binge-like eating, and that the PVN, CeA, and BNST may contribute to information processing underlying binge-like eating.


Assuntos
Transtorno da Compulsão Alimentar/complicações , Estrogênios/metabolismo , Privação de Alimentos/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico
18.
Eur J Med Chem ; 125: 233-244, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27662034

RESUMO

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A receptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved.


Assuntos
Aminas/metabolismo , Dioxanos/metabolismo , Etilaminas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ligantes , Camundongos , Simulação de Acoplamento Molecular , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Estudos Retrospectivos , Relação Estrutura-Atividade
19.
Behav Brain Res ; 320: 420-430, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27984048

RESUMO

Binge eating episodes are characterized by uncontrollable, distressing eating of a large amount of highly palatable food and represent a central feature of bingeing related eating disorders. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behavior. Markers of inflammation can be selectively altered in discrete brain regions where they can directly or indirectly regulate food intake. In the present study, we measured expression levels of different components of cytokine systems (IL-1, IL-6, IL-18, TNF-α and IFN-É£) and related molecules (iNOS and COX2) in the preoptic and anterior-tuberal parts of the hypothalamus of a validated animal model of binge eating. In this animal model, based on the exposure to both food restriction and frustration stress, binge-like eating behavior for highly palatable food is not shown when animals are exposed to the frustration stress during the estrus phase. We found a characteristic down-regulation of the IL-18/IL-18 receptor system (with increased expression of the inhibitor of the pro-inflammatory cytokine IL-18, IL-18BP, together with a decreased expression of the binding chain of the IL-18 receptor) and a three-fold increase in the expression of iNOS specifically in the anterior-tuberal region of the hypothalamus of animals that develop a binge-like eating behavior. Differently, when food restricted animals were stressed during the estrus phase, IL-18 expression increased, while iNOS expression was not significantly affected. Considering the role of this region of the hypothalamus in controlling feeding related behavior, this can be relevant in eating disorders and obesity. Our data suggest that by targeting centrally selected inflammatory markers, we may prevent that disordered eating turns into a full blown eating disorder.


Assuntos
Bulimia/patologia , Citocinas/metabolismo , Regulação para Baixo/fisiologia , Hipotálamo/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Análise de Variância , Animais , Peso Corporal/fisiologia , Bulimia/fisiopatologia , Citocinas/genética , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Ciclo Estral/fisiologia , Feminino , Privação de Alimentos , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
20.
ACS Med Chem Lett ; 7(10): 956-961, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774136

RESUMO

Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/α2-ARs. The compounds showing the highest affinities for I1-/I2-IBS or I1-/I2-IBS/α2-ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9, displaying I1-/I2-IBS/α2-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction.

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