Glucose 6 phosphate dehydrogenase overexpression rescues the loss of cognition in the double transgenic APP/PS1 mouse model of Alzheimer's disease.

Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females. To further explore the potential benefits of modulating the G6PD activity in neurodegenerative diseases, triple transgenic mice (3xTg G6PD) were generated, overexpressing APP, PSEN1, and G6PD genes. The cognitive decline characteristic of APP/PS1 mice was prevented in 3xTg G6PD mice, despite similar amyloid-ß (Aß) levels in the hippocampus. This challenges the dominant hypothesis in Alzheimer's disease (AD) etiology and the majority of therapeutic efforts in the field, based on the notion that Aß is pivotal in cognitive preservation. Notably, the antioxidant properties of G6PD led to a decrease in oxidative stress parameters, such as improved GSH/GSSG and GSH/CysSSG ratios, without major changes in oxidative damage markers. Additionally, metabolic changes in 3xTg G6PD mice increased brain energy status, countering the hypometabolism observed in Alzheimer's models. Remarkably, a higher respiratory exchange ratio suggested increased carbohydrate utilization. The relative failures of Aß-targeted clinical trials have raised significant skepticism on the amyloid cascade hypothesis and whether the development of Alzheimer's drugs has followed the correct path. Our findings highlight the significance of targeting glucose-metabolizing enzymes rather than solely focusing on Aß in Alzheimer's research, advocating for a deeper exploration of glucose metabolism's role in cognitive preservation.

Stress inoculation during adolescence attenuates social stress-induced increase in ethanol intake in adult male mice.

Social stress exposure heightens the risk of substance abuse disorder development, especially when endured during adolescence, influencing long-term mental health. This study investigates early-life stress's potential to confer resilience against later-life stressors. To investigate this hypothesis, we examined the impact of a single social defeat (SD) incident during adolescent mice's lives on subsequent voluntary ethanol consumption following repeated adult social stress exposure. Half of the adolescent mice experienced SD at postnatal day 28. Three weeks later (postnatal day 49), defeated groups encountered four confrontations with aggressive residents every 72 h, while control groups were exposed to non-resident exploration. A day after the last SD, defeated mice were classified as resilient or susceptible based on their response to a social interaction test (SIT), a model for depressive behavior. To assess ethanol consumption during young adulthood, researchers used the 'drinking in the dark' and oral ethanol self-administration paradigms. Stress inoculation (IS) slightly increased resilient animals in the SIT. In mice without IS exposure during adolescence, susceptible defeated mice displayed higher ethanol consumption and motivation than control and resilient mice. IS in adolescence effectively counteracted this effect, as IS-SD groups, whether resilient or susceptible, showed no increase in ethanol intake. These groups also exhibited similar motivation to control, measured by the progressive ratio. Notably, elevated IL-6 levels seen in SD-S mice were absent in IS-exposed mice. Additionally, IS-exposed groups had lower prefrontal cortex IL-6 and CX3CL1 levels. These findings support the hypothesis that IS, induced by moderate-intensity stress during adolescence, can enhance resilience to more severe stressors in adulthood.

Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice.

RATIONALE: Exposure to social defeat (SD) induces a depressive phenotype, increased ethanol seeking and consumption, accompanied by activation of the neuroinflammatory response. However, a resilient response can be potentiated through physical exercise in the form of voluntary wheel running (VWR) during or after exposure to social stress. Therefore, the aim of this study was to test whether physical exercise during adolescence prior to being exposed to SD can enhance resilience to the increase in ethanol intake. METHODS: Male mice had access to VWR during adolescence and the effects of social defeat (4 sessions every 72 h) on oral ethanol self-administration (SA) was evaluated. Based on the social interaction test, mice were classified as resilient or susceptible to depressive-like behavior. Two weeks after the last encounter, mice were subjected to the drinking in the dark and oral ethanol SA paradigms. Mice were then sacrificed to measure brain-derived neurotrophic factor (BDNF) levels in the striatum and hippocampus. RESULTS: As expected, susceptible mice increased ethanol intake in the oral SA protocol. However, susceptible mice in the exercise condition did not increase ethanol intake, showing similar consumption and motivation for ethanol than the control and resilient groups. On the other hand, decreased BDNF levels were observed in susceptible mice in both experimental conditions compared to the control groups after ethanol SA. CONCLUSIONS: The pre-exposure of VWR prevented the increase in consumption and motivation for ethanol induced by SD in susceptible mice. On the other hand, it appears that VWR did not exhibit any significant long-term effects on BDNF signaling, which is mainly affected in susceptible mice after ethanol intake.

Oleoylethanolamide restores stress-induced prepulse inhibition deficits and modulates inflammatory signaling in a sex-dependent manner.

RATIONALE: Social stress contributes to the development of depressive and anxiety symptomatology and promotes pro-inflammatory signaling in the central nervous system. In this study, we explored the effects of a lipid messenger with anti-inflammatory properties - oleoylethanolamide (OEA) - on the behavioral deficits caused by social stress in both male and female mice. METHODS: Adult mice were assigned to an experimental group according to the stress condition (control or stress) and treatment (vehicle or OEA, 10 mg/kg, i.p.). Male mice in the stress condition underwent a protocol consisting of four social defeat (SD) encounters. In the case of female mice, we employed a procedure of vicarious SD. After the stress protocol resumed, anxiety, depressive-like behavior, social interaction, and prepulse inhibition (PPI) were assessed. In addition, we characterized the stress-induced inflammatory profile by measuring IL-6 and CX3CL1 levels in the striatum and hippocampus. RESULTS: Our results showed that both SD and VSD induced behavioral alterations. We found that OEA treatment restored PPI deficits in socially defeated mice. Also, OEA affected differently stress-induced anxiety and depressive-like behavior in male and female mice. Biochemical analyses showed that both male and female stressed mice showed increased levels of IL-6 in the striatum compared to control mice. Similarly, VSD female mice exhibited increased striatal CX3CL1 levels. These neuroinflammation-associated signals were not affected by OEA treatment. CONCLUSIONS: In summary, our results confirm that SD and VSD induced behavioral deficits together with inflammatory signaling in the striatum and hippocampus. We observed that OEA treatment reverses stress-induced PPI alterations in male and female mice. These data suggest that OEA can exert a buffering effect on stress-related sensorimotor gating behavioral processing.

Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge-like ethanol treatment in adolescent mice.

BACKGROUND: Extracellular vesicles (EVs) are heterogeneous membrane vesicles secreted by cells in extracellular spaces that play an important role in intercellular communication under both normal and pathological conditions. Mesenchymal stem cells (MSC) are anti-inflammatory and immunoregulatory cells capable of secreting EVs, which are considered promising molecules for treating immune, inflammatory, and degenerative diseases. Our previous studies demonstrate that, by activating innate immune receptors TLR4 (Toll-like receptor 4), binge-like ethanol exposure in adolescence causes neuroinflammation and neural damage. AIMS: To evaluate whether the intravenous administration of MSC-derived EVs is capable of reducing neuroinflammation, myelin and synaptic alterations, and the cognitive dysfunction induced by binge-like ethanol treatment in adolescent mice. MATERIALS & METHODS: MSC-derived EVs obtained from adipose tissue were administered in the tail vein (50 microg/dose, one weekly dose) to female WT adolescent mice treated intermittently with ethanol (3.0 g/kg) during two weeks. RESULTS: MSC-derived EVs from adipose tissue ameliorate ethanol-induced up-regulation of inflammatory genes (e.g., COX-2, iNOS, MIP-1α, NF-κB, CX3CL1, and MCP-1) in the prefrontal cortex of adolescent mice. Notably, MSC-derived EVs also restore the myelin and synaptic derangements, and the memory and learning impairments, induced by ethanol treatment. Using cortical astroglial cells in culture, our results further confirm that MSC-derived EVs decrease inflammatory genes in ethanol-treated astroglial cells. This, in turn, confirms in vivo findings. CONCLUSION: Taken together, these results provide the first evidence for the therapeutic potential of the MSC-derived EVs in the neuroimmune response and cognitive dysfunction induced by binge alcohol drinking in adolescence.

Oleoylethanolamide attenuates cocaine-primed reinstatement and alters dopaminergic gene expression in the striatum.

The lipid oleoylethanolamide (OEA) has been shown to affect reward-related behavior. However, there is limited experimental evidence about the specific neurotransmission systems OEA may be affecting to exert this modulatory effect. The aim of this study was to evaluate the effects of OEA on the rewarding properties of cocaine and relapse-related gene expression in the striatum and hippocampus. For this purpose, we evaluated male OF1 mice on a cocaine-induced CPP procedure (10 mg/kg) and after the corresponding extinction sessions, we tested drug-induced reinstatement. The effects of OEA (10 mg/kg, i.p.) were evaluated at three different timepoints: (1) Before each cocaine conditioning session (OEA-C), (2) Before extinction sessions (OEA-EXT) and (3) Before the reinstatement test (OEA-REINST). Furthermore, gene expression changes in dopamine receptor D1 gene, dopamine receptor D2 gene, opioid receptor µ, cannabinoid receptor 1, in the striatum and hippocampus were analyzed by qRT-PCR. The results obtained in the study showed that OEA administration did not affect cocaine CPP acquisition. However, mice receiving different OEA treatment schedules (OEA-C, OEA-EXT and OEA-REINST) failed to display drug-induced reinstatement. Interestingly, the administration of OEA blocked the increase of dopamine receptor gene D1 in the striatum and hippocampus caused by cocaine exposure. In addition, OEA-treated mice exhibited reduced striatal dopamine receptor gene D2 and cannabinoid receptor 1. Together, these findings suggest that OEA may be a promising pharmacological agent in the treatment of cocaine use disorder.

Food addiction and its relationship with other eating behaviours among Spanish university students.

BACKGROUND: Food addiction (FA) is characterised by symptoms such as loss of control over food consumption, inability to reduce consumption despite the desire to do so, and continued consumption despite negative consequences. The modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a widely used instrument to assess FA. OBJECTIVES: To validate the Spanish mYFAS 2.0; to analyse the relationships between FA with other eating behaviours, sociodemographic variables, and Body Mass Index (BMI); and to test the eating-related variables that account for the variance in FA. METHODS: The sample consisted of 400 university students (Mage = 24.16, SDage = 6.12; 51% female), who completed the mYFAS 2.0 and measures of eating-related constructs. RESULTS: A confirmatory factor analysis (CFA) supported the one-factor structure of the mYFAS 2.0. The scale showed good internal consistency (α = .78), and good convergent validity with the mYFAS. FA was related to eating styles, binge eating, and bulimia. No differences in FA were observed between males and females, and there was no association between FA and BMI. In addition, younger participants scored higher on FA than older participants. The eating-related variables explain 54.7% of the variance in FA. CONCLUSIONS: The mYFAS 2.0 is a valid and reliable scale to assess FA in the Spanish population. The positive and significant relationship of variables related to eating (eating styles, binge eating and bulimia) with FA was demonstrated. These variables were indicated by those at high risk of FA.

Vicarious Social Defeat Increases Conditioned Rewarding Effects of Cocaine and Ethanol Intake in Female Mice.

Stress is a critical factor in the development of mood and drug use disorders. The social defeat model is not appropriate for female rodents due to their low level of aggression. Therefore, a robust female model of social stress needs to be developed and validated. The aim of the present study was to unravel the long-lasting effects of vicarious social defeat (VSD) on the conditioned rewarding effects of cocaine and ethanol intake in female mice. Although VSD seems to be a good model for inducing behavioral and physiologic endophenotypes induced by stress, there are no studies to date that characterize the effect of VSD on cocaine or alcohol use. The results confirm that VSD females showed an increase in corticosterone levels after a vicarious experience while also displaying an increase in anxiety- and anhedonic-like behaviors. Three weeks after the last VSD, vicariously defeated female mice showed an increased developed preference for a non-effective dose of cocaine in the conditioned place preference (CPP) paradigm and showed an increase in ethanol intake. Our results suggest that female mice vicariously experience a state of distress through the social observation of others suffering from adverse events, confirming the use of VSD as a valid model to study the response to social stress in females. The fact that VSD in females induced a comparable behavioral phenotype to that observed in physically defeated males could indicate a relationship with the higher rate of psychopathologies observed in women. Notwithstanding, more studies are needed to dissect the neurobiological and behavioral peculiarities of the female response to social stress.

Oleoylethanolamide attenuates the stress-mediated potentiation of rewarding properties of cocaine associated with an increased TLR4 proinflammatory response.

The lipid-derived messenger oleoylethanolamide (OEA) has been involved in multiple physiological functions including metabolism and the immune response. More recently, OEA has been observed to affect reward-related behavior. Stress is a major risk factor for drug use and a predictor of drug relapse. In the laboratory, social stress has been largely studied using the social defeat (SD) model. Here, we explored the effects of different OEA administration schedules on the increased rewarding properties of cocaine induced by SD. In addition, we evaluated the anti-inflammatory action of OEA pretreatment in TLR4 expression caused by SD in the cerebellum, a novel brain structure that has been involved in the development of cocaine addiction. Adult OF1 mice were assigned to an experimental group according to the stress condition (exploration or SD) and treatment (OEA before SD, OEA before conditioning or subchronic OEA treatment). Mice were administered with OEA i.p (10 mg/kg) 10 min previously to the corresponding event. Three weeks after the last SD encounter, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg). As expected, socially defeated mice presented greater vulnerability to the cocaine reinforcing effects and expressed CPP. Conversely, this effect was not observed under a non-stressed condition. Most importantly, we observed that OEA pretreatment before SD or before conditioning prevented cocaine CPP in defeated mice. Biochemical analysis showed that OEA administration before SD decreased proinflammatory TLR4 upregulation in the cerebellum caused by social stress. In summary, our results suggest that OEA may have a protective effect on stress-induced increased cocaine sensitivity by exerting an anti-inflammatory action.

Effect of Voluntary Wheel-Running Exercise on the Endocrine and Inflammatory Response to Social Stress: Conditioned Rewarding Effects of Cocaine.

The present paper evaluates the effect of physical activity on the increase of the conditioned rewarding effects of cocaine induced by intermittent social stress and on the neuroinflammatory response that contributes to the enhancement of drug response. For that purpose, three studies were designed in which social stress was induced in different samples of mice through a social-defeat protocol; the mice underwent an increase of physical activity by different modalities of voluntary wheel running (continuous and intermittent access). The results showed that continuous access to running wheels prior to stress enhanced the establishment of cocaine place preference, whereas an intermittent access exerted a protective effect. Wheel running contingent to cocaine administration prevented the development of conditioned preference, and if applied during the extinction of drug memories, it exerted a dual effect depending on the stress background of the animal. Our biological analysis revealed that increased sensitivity to cocaine may be related to the fact that wheel running promotes inflammation though the increase of IL-6 and BDNF levels. Together, these results highlight that physical exercise deeply impacts the organism's response to stress and cocaine, and these effects should be taken into consideration in the design of a physical intervention.

Eating behaviors, eating styles and body mass index during COVID-19 confinement in a college sample: a predictive model.

BACKGROUND: COVID-19 confinement affected lifestyles. There is inconclusive evidence about changes in eating patterns, and there are few studies on the impact on body mass index (BMI), the occurrence of dysfunctional behaviors (binge eating, fat intake), and the predictive role of maladaptive eating styles (emotional, external, and restrained eating). OBJECTIVES: (1) To analyze the differences in binge eating, fat intake, BMI, and maladaptive eating styles before and during COVID-19 confinement, and (2) to analyze whether maladaptive eating styles (before confinement) predicted binge eating, fat intake, and BMI during confinement. METHODS: The sample consisted of 146 Spanish college students, divided into 104 females (71.2%; age: M = 22.20, SD = 2.97) and 42 males (28.8%; age: M = 24.74; SD = 3.53). All completed several dietary measures and BMI twice: before COVID-19 confinement (T1, November 2019) and during COVID-19 confinement (T2, April 2020). RESULTS: BMI and maladaptive eating styles did not change in T2 (vs. T1). However, binge eating and fat intake decreased in T2. Emotional eating at T1 positively predicted BMI and binge eating at T2. External eating at T1 positively (and marginally) predicted fat intake at T2. Restrained eating at T1 positively predicted binge eating at T2, and negatively (and marginally) predicted BMI and fat intake at T2. The model explained 80.5% of the variance in BMI, 41.5% of the variance in binge eating, and 25.8% of the variance in fat intake during COVID-19 confinement. CONCLUSIONS: The COVID-19 confinement had a positive impact on some eating behaviors. Future policies should focus part of their prevention on maladaptive eating styles to curb dysfunctional eating behaviors and BMI problems in times of stress.

The COVID-19 confinement affected the lifestyles of the young population, especially eating behaviors. It is not yet known whether eating problems, such as binge eating and high fat intake, changed during this period in the young people. It is also not known whether the young population perceived changes in their BMI during COVID-19 confinement. In addition, eating styles (emotional eating, restrictive eating, and external eating) may be predictors of this change. The present study found that binge eating and fat intake decreased in COVID-19 confinement, and BMI and eating styles remained stable. Eating styles predicted change in these eating problems (binge eating and fat intake) and change in BMI during this period of elevated stress. Therefore, eating styles may help to understand dietary changes during times of high stress.

Hormonal Profile in Response to an Empathic Induction Task in Perpetrators of Intimate Partner Violence: Oxytocin/Testosterone Ratio and Social Cognition.

Empathy deficits have been proposed to be an important factor for intimate partner violence (IPV). IPV perpetrators have shown a differential change in salivary oxytocin (sOXT), testosterone (sT), and cortisol (sC), following empathic and stress tasks, compared to non-violent men. However, the influence of empathic deficits in those hormones after an emotion-induction task in IPV perpetrators remains unclear. We analyzed the effects of an empathic induction task on endogenous sOXT, sT and sC levels, as well as their hormonal ratios, in IPV perpetrators (n = 12), and compared them to controls (n = 12). Additionally, we explored the predictive capacity of empathy-related functions (measured with the interpersonal reactivity index) in the hormonal responses to the task. IPV perpetrators presented lower sOXT changes and higher total sT levels than controls after the task, lower sOXT/T change and total sOXT/T levels, as well as higher total sT/C levels. Notably, for all participants, the lower the perspective taking score, the lower the total sOXT levels and sOXT changes and the higher the sT changes were. Low perspective taking also predicted smaller sOXT/T and sOXT/C changes in the empathic induction task, and higher total sT/C levels for all participants. Therefore, our results could contribute to furthering our ability to focus on new therapeutic targets, increasing the effectiveness of intervention programs and helping to reduce IPV recidivism in the medium term.

Resilience to social defeat stress in adolescent male mice.

Adverse social experiences during adolescence are associated with the appearance of mental illness in adulthood. Social defeat (SD) is an ethologically valid murine model to study the consequences of social stress. In adolescent mice, SD induces depressive-like behaviors, increased anxiety and potentiates the reinforcing effects of cocaine and alcohol. However, not all mice exposed to SD will be susceptible to these effects. Adult mice resilient to the effects of SD show a consistent phenotype being resilient to depressive-like behaviors and to the increase in cocaine and alcohol consumption. The aim of the present study was to characterize the resilient phenotype to depressive-like behaviors and increase cocaine and ethanol rewarding effects of mice socially defeated during adolescence. To that end, adolescent mice were exposed to repeated SD, and 24 h after the last encounter, they underwent a social interaction test (SIT) in order to evaluate depressive-like behaviors. Cocaine-induced reward conditioning and ethanol intake was evaluated in two different sets of mice 3 weeks after the last SD using cocaine-induced conditioned place preference (CPP) and oral ethanol self-administration (SA). The neuroinflammation response was measured at the end of the experimental procedure by measuring striatal and cortical levels of IL-6 and CX3CL1. The results confirmed that a comparable percentage of adolescent mice develop resilience to depressive-like behaviors to that observed in adult mice. However, increased anxiety was more severe in resilient mice. Likewise, an increased preference for an ineffective dose of cocaine and an increased ethanol consumption was observed in resilient mice compared to controls. The increase in IL-6 and CX3CL1 was mainly observed in the striatum of susceptible mice compared to that of control mice. Our results confirm that, contrary to prior assumptions in adults, responses to SD stress are more complex and singular in adolescents, and caution should be taken for the correct interpretation and translation of those phenotypes.

Cognitive profile of male mice exposed to a Ketogenic Diet.

In recent years, nutritional interventions for different psychiatric diseases have gained increasing attention, such as the ketogenic diet (KD). This has led to positive effects in neurological disorders such as Parkinson's disease, addiction, autism or epilepsy. The neurobiological mechanisms through which these effects are induced and the effects in cognition still warrant investigation, and considering that other high-fat diets (HFD) can lead to cognitive disturbances that may affect the results achieved, the main aim of the present work was to evaluate the effects of a KD to determine whether it can induce such cognitive effects. A total of 30 OF1 male mice were employed to establish the behavioral profile of mice fed a KD by testing anxiety behavior (Elevated Plus Maze), locomotor activity (Open Field), learning (Hebb Williams Maze), and memory (Passive Avoidance Test). The results revealed that the KD did not affect locomotor activity, memory or hippocampal-dependent learning, as similar results were obtained with mice on a standard diet, albeit with increased anxiety behavior. We conclude that a KD is a promising nutritional approach to apply in research studies, given that it does not cause cognitive alterations.

Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice.

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.

Effects of ketosis on cocaine-induced reinstatement in male mice.

In recent years, the benefits of the ketogenic diet (KD) on different psychiatric disorders have been gaining attention, but the substance abuse field is still unexplored. Some studies have reported that palatable food can modulate the rewarding effects of cocaine, but the negative metabolic consequences rule out the recommendation of using it as a complementary treatment. Thus, the main aim of this study was to evaluate the effects of the KD on cocaine conditioned place preference (CPP) during acquisition, extinction, and reinstatement. 41 OF1 male mice were employed to assess the effects of the KD on a 10 mg/kg cocaine-induced CPP. Animals were divided into three groups: SD, KD, and KD after the Post-Conditioning test. The results revealed that, while access to the KD did not block CPP acquisition, it did significantly reduce the number of sessions required to extinguish the drug-associated memories and it blocked the priming-induced reinstatement.

Impact of adolescent methamphetamine use on social cognition: A human-mice reverse translation study.

BACKGROUND: Methamphetamine dependence is associated with social cognition deficits that may underpin negative social outcomes. However, there are considerable inter-individual differences in social cognition within people with methamphetamine dependence, with age of onset of methamphetamine use being a potential contributing factor. MATERIALS AND METHODS: We conducted two sequential studies examining the link between age of onset of methamphetamine use (adolescence versus young adulthood) and performance in social cognition tests: (1) a human cross-sectional study in 95 participants with methamphetamine dependence varying in age of onset (38 with adolescent onset and 57 with adult onset) and 49 drug-naïve controls; (2) a mice study in which we tested the effects of methamphetamine exposure during adolescence versus young adulthood on social interaction and aggression, and their potential neurochemical substrates in the striatal dopaminergic system. RESULTS: We initially showed that people with methamphetamine dependence who started use in adolescence had higher antisocial beliefs (p = 0.046, Cohen's d=0.42) and worse emotion recognition (p = 0.031, Cohen's d=0.44) than those who started use during adulthood. We reasoned that this could be due to either social cognition deficits leading to earlier onset of methamphetamine use, or methamphetamine-induced neuroadaptive effects specific to adolescence. Mice experiments showed that methamphetamine exposure during adolescence specifically decreased social investigation during social interaction and upregulated striatal tyrosine hydroxylase (p < 0.05, Bonferroni corrected). There was no evidence of adolescent-specific methamphetamine effects on aggression or other measures of dopaminergic function. CONCLUSION: Together, translational findings demonstrate heightened sensitivity to methamphetamine effects on social cognition during adolescence.

Behavioural and neurochemical effects after repeated administration of N-ethylpentylone (ephylone) in mice.

N-ethyl-pentylone (NEP), also known as 'ephylone' and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease in serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer's Disease.

Neurogenesis in the adult brain takes place in two neurogenic niches: the ventricular-subventricular zone (V-SVZ) and the subgranular zone. After differentiation, neural precursor cells (neuroblasts) have to move to an adequate position, a process known as neuronal migration. Some studies show that in Alzheimer's disease, the adult neurogenesis is impaired. Our main aim was to investigate some proteins involved both in the physiopathology of Alzheimer's disease and in the neuronal migration process using the APP/PS1 Alzheimer's mouse model. Progenitor migrating cells are accumulated in the V-SVZ of the APP/PS1 mice. Furthermore, we find an increase of Cdh1 levels and a decrease of Cdk5/p35 and cyclin B1, indicating that these cells have an alteration of the cell cycle, which triggers a senescence state. We find less cells in the rostral migratory stream and less mature neurons in the olfactory bulbs from APP/PS1 mice, leading to an impaired odour discriminatory ability compared with WT mice. Alzheimer's disease mice present a deficit in cell migration from V-SVZ due to a senescent phenotype. Therefore, these results can contribute to a new approach of Alzheimer's based on senolytic compounds or pro-neurogenic factors.

Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience.

Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuroinflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end of the oral ethanol self-administration (SA) procedure, measuring levels of the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 or fractalkine in the striatum and prefrontal cortex. Previous studies have shown that environmental enrichment (EE) is an effective mechanism to dimish the detrimental effects of social stress. In a second study, we aimed to evaluate if EE housing before exposure to SD could potentiate resilience. Our results showed that mice with a phenotype susceptible to SD-induced depressive-like behaviors showed increased ethanol consumption and increased neuroinflammatory signaling. In contrast, despite the lack of effect on depressive-like behaviors, defeated mice previously housed under EE conditions did not show an increase in ethanol SA or an increase in immune response. To sum up, the resilient phenotype to SD develops at different levels, such as depressive-like behaviors, ethanol consumption and the neuroinflammatory response. Our results also point to the protective role of EE in potentiating resilience to SD effects.