Adolescent chronic sleep restriction promotes alcohol drinking in adulthood: evidence from epidemiological and preclinical data.

Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.

A Role for Neuropeptide S in Alcohol and Cocaine Seeking.

The neuropeptide S (NPS) is the endogenous ligand of the NPS receptor (NPSR). The NPSR is widely expressed in brain regions that process emotional and affective behavior. NPS possesses a unique physio-pharmacological profile, being anxiolytic and promoting arousal at the same time. Intracerebroventricular NPS decreased alcohol consumption in alcohol-preferring rats with no effect in non-preferring control animals. This outcome is most probably linked to the anxiolytic properties of NPS, since alcohol preference is often associated with high levels of basal anxiety and intense stress-reactivity. In addition, NPSR mRNA was overexpressed during ethanol withdrawal and the anxiolytic-like effects of NPS were increased in rodents with a history of alcohol dependence. In line with these preclinical findings, a polymorphism of the NPSR gene was associated with anxiety traits contributing to alcohol use disorders in humans. NPS also potentiated the reinstatement of cocaine and ethanol seeking induced by drug-paired environmental stimuli and the blockade of NPSR reduced reinstatement of cocaine-seeking. Altogether, the work conducted so far indicates the NPS/NPSR system as a potential target to develop new treatments for alcohol and cocaine abuse. An NPSR agonist would be indicated to help individuals to quit alcohol consumption and to alleviate withdrawal syndrome, while NPSR antagonists would be indicated to prevent relapse to alcohol- and cocaine-seeking behavior.

Modulation of Gut Microbiota and Neuroprotective Effect of a Yeast-Enriched Beer.

Beer is the most consumed alcoholic beverage worldwide. It is rich in nutrients, and with its microbial component it could play a role in gut microbiota modulation. Conflicting data are currently available regarding the consequences of alcohol and alcohol-containing beverages on dementia and age-associated disorders including Alzheimer's disease (AD), a neurodegeneration characterized by protein aggregation, inflammatory processes and alterations of components of the gut-brain axis. The effects of an unfiltered and unpasteurized craft beer on AD molecular hallmarks, levels of gut hormones and composition of micro/mycobiota were dissected using 3xTg-AD mice. In addition, to better assess the role of yeasts, beer was enriched with the same Saccharomyces cerevisiae strain used for brewing. The treatment with the yeast-enriched beer ameliorated cognition and favored the reduction of Aß(1-42) and pro-inflammatory molecules, also contributing to an increase in the concentration of anti-inflammatory cytokines. A significant improvement in the richness and presence of beneficial taxa in the gut bacterial population of the 3xTg-AD animals was observed. In addition, the fungal order, Sordariomycetes, associated with gut inflammatory conditions, noticeably decreased with beer treatments. These data demonstrate, for the first time, the beneficial effects of a yeast-enriched beer on AD signs, suggesting gut microbiota modulation as a mechanism of action.

NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats.

In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 µg/µl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

Cognitive, Olfactory, and Affective Determinants of Body Weight in Aging Individuals.

OBJECTIVE: A complex interplay of factors including cognitive, sensory and affective aspects has been associated in a controversial way with anthropometric measures related to body weight. METHODS: Here we propose two studies to investigate whether and how cognitive, olfactory and affective variables resulted associated with body weight during healthy aging. In Study 1, we investigated the cognitive status, the odor identification skills, and the BMI of 209 individuals (50-96 yo). In Study 2 an extensive evaluation of cognitive functions (in particular executive functions and memory), odor threshold, discrimination and identification and affective skills (i.e., depression and anxiety) was performed in a group of 35 healthy, free-living aging individuals (58-85 yo). RESULTS: In Study 1, greater BMI was not associated with performance on the odor identification task but was significantly associated with better cognitive skills. In Study 2, we observed that executive functions seemed to favor a successful managing of body weight, and individuals with greater BMI and waist circumference showed significantly better odor discrimination skills. Finally, lower waist circumference (but not BMI) was found significantly associated with greater levels of anxiety. CONCLUSIONS: These results confirm that cognitive, olfactory and affective factors may influence body weight during healthy aging.