EXTRA-HYPOTHALAMIC CRF-1 RECEPTOR MECHANISMS IN A MODEL OF BINGE-LIKE PALATABLE FOOD CONSUMPTION IN FEMALE RATS

Purpose: The present study evaluated the effect of the corticotrophin releasing factor (CRF)1 receptor antagonist R121919 and the corticosterone synthesis inhibitor metyrapone in female rats, in which binge eating for highly palatable food was evoked by frustration stress and cycles of food restrictions. Methods: We used 4 groups of rats that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min, without allowing access to it (frustration stress) before assessing food consumption for 2 h. Results: We found that systemic injections of the CRF1 receptor antagonist R121919 but not of the metyrapone blocked binge-like eating behavior. Moreover, corticosterone injection did not induce binge eating in non-stressed rats. Restricted and stressed rats showed up regulation of CRH1 receptor mRNA signal in dorsal BNST and in CeA but not in PVN. Injection of CRF receptor antagonist D-Phe-CRF(12– 41) in CeA blocked binge-like eating behavior. Conclusions: These findings demonstrate that extra-hypothalamic CRF1 receptors, rather than those involved in endocrine functions, are involved in binge eating. Selective antagonism at CRF1 receptor may represent a novel pharmacological treatment for bingeing-related eating disorders

Modulation of pain sensitivity by chronic consumption of highly palatable food followed by abstinence: emerging role of fatty acid amide hydrolase

There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague–Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. Ex vivo analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients

Oleoylethanolamide decreases frustration stress-induced binge-like eating in female rats: a novel potential treatment for binge-eating disorder

Binge-eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell (“frustration stress”). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg–1) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior

The economic impact of moderate stage Alzheimer's disease in Italy: Evidence from the UP-TECH randomized trial

Background: There is consensus that dementia is the most burdensome disease for modern societies. Few cost-of-illness studies examined the complexity of Alzheimer's disease (AD) burden, considering at the same time health and social care, cash allowances, informal care, and out-of-pocket expenditure by families. Methods: This is a comprehensive cost-of-illness study based on the baseline data from a randomized controlled trial (UP-TECH) enrolling 438 patients with moderate AD and their primary caregiver living in the community. Results: The societal burden of AD, composed of public, patient, and informal care costs, was about �20,000/yr. Out of this, the cost borne by the public sector was �4,534/yr. The main driver of public cost was the national cash-for-care allowance (�2,324/yr), followed by drug prescriptions (�1,402/yr). Out-of-pocket expenditure predominantly concerned the cost of private care workers. The value of informal care peaked at �13,590/yr. Socioeconomic factors do not influence AD public cost, but do affect the level of out-of-pocket expenditure. Conclusion: The burden of AD reflects the structure of Italian welfare. The families predominantly manage AD patients. The public expenditure is mostly for drugs and cash-for-care benefits. From a State perspective in the short term, the advantage of these care arrangements is clear, compared to the cost of residential care. However, if caregivers are not adequately supported, savings may be soon offset by higher risk of caregiver morbidity and mortality produced by high burden and stress. The study has been registered on the website www.clinicaltrials.org (Trial Registration number: NCT01700556). Copyright � International Psychogeriatric Association 2015

Socioeconomic Predictors of the Employment of Migrant Care Workers by Italian Families Assisting Older Alzheimer's Disease Patients: Evidence from the Up-Tech Study

Background: The availability of family caregivers of older people is decreasing in Italy as the number of migrant care workers (MCWs) hired by families increases. There is little evidence on the influence of socioeconomic factors in the employment of MCWs. Method: We analyzed baseline data from 438 older people with moderate Alzheimer's disease (AD), and their family caregivers enrolled in the Up-Tech trial. We used bivariate analysis and multilevel regressions to investigate the association between independent variables - education, social class, and the availability of a care allowance - and three outcomes - employment of a MCW, hours of care provided by the primary family caregiver, and by the family network (primary and other family caregivers). Results: The availability of a care allowance and the educational level were independently associated with employing MCWs. A significant interaction between education and care allowance was found, suggesting that more educated families are more likely to spend the care allowance to hire a MCW. Discussion: Socioeconomic inequalities negatively influenced access both to private care and to care allowance, leading disadvantaged families to directly provide more assistance to AD patients. Care allowance entitlement needs to be reformed in Italy and in countries with similar long-term care and migration systems. � 2015 The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved

Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: Possible targets for obesity prediction?

Several factors play a role in obesity (i.e. behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexygenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opiomelanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism. ACKNOWLEDGMENTS: The work was supported by the Italian Ministry of University and Research under grant FIRB-RBFR12DELS to CC and CDA. The authors declare no competing financial interests