Transcending the amyloid-beta dominance paradigm in Alzheimer's disease: An exploration of behavioural, metabolic, and gut microbiota phenotypes in 5xFAD mice.

The amyloid cascade hypothesis is widely accepted as an explanation for the neuropathological changes in Alzheimer's disease (AD). However, the role of amyloid-beta (Aß) as the sole cause of these changes is being questioned. Using the 5xFAD mouse model of AD, we investigated various factors contributing to neuropathology, including genetic load (heterozygous (HTZ) versus homozygous (HZ) condition), behavioural phenotype, neuropathology markers, metabolic physiology, and gut microbiota composition at early (5 months of age) and late (12 months of age) stages of disease onset, and considering both sexes. At 5 months of age, both HTZ and HZ mice exhibited hippocampal alterations associated with Aß accumulation, leading to increased neuroinflammation and disrupted PI3K-Akt pathway. However, only HZ mice showed cognitive impairment in the Y-maze and Morris water maze tests, worsening with age. Dysregulation of both insulin and insulin secretion-regulating GIP peptide were observed at 5 months of age, disappearing later. Circulating levels of metabolic-regulating hormones, such as Ghrelin and resisting helped to differentiates HTZ mice from HZ mice. Differences between HTZ and HZ mice were also observed in gut microbiota composition, disrupted intestinal barrier proteins, and increased proinflammatory products in the intestine. These findings suggest that cognitive impairment in 5xFAD mice may not solely result from Aß aggregation. Other factors, including altered PI3K-Akt signalling, disrupted insulin-linked metabolic pathways, and changes in gut microbiota, contribute to disease progression. Targeting Aß deposition alone may not suffice. Understanding AD pathogenesis and its multiple contributing factors is vital for effective therapies.

COVID-19 Mortality in Patients Aged 80 and over Residing in Nursing Homes-Six Pandemic Waves: OCTA-COVID Study.

During the first COVID-19 pandemic wave in Spain, 50% of deaths occurred in nursing homes, making it necessary for some hospitals to support these facilities with the care of infected patients. This study compares origin, characteristics, and mortality of patients admitted with COVID-19 during six pandemic waves in the Hospital Central de la Cruz Roja in Madrid. It is a retrospective observational study of patients ≥80 years old, admitted with an acute SARS-CoV-2 infection, with a total of 546 patients included, whose final outcome was death or discharge. During the first wave, those from nursing homes had a higher risk of death than those from home; during the two successive waves, the risk was higher for those from home; and in the last two waves, the risk equalized and decreased exponentially in both groups. Men had 72% higher risk of death than women. For each year of age, the risk increased by 4% (p = 0.036). For each Charlson index point, the risk increased by 14% (p = 0.019). Individuals in nursing homes, despite being older with higher comorbidity, did not show a higher overall lethality. The mortality decreased progressively in each successive wave due to high vaccination rates and COVID-19 control measures in this population.

Elderly Population with COVID-19 and the Accuracy of Clinical Scales and D-Dimer for Pulmonary Embolism: The OCTA-COVID Study.

BACKGROUND: Elderly COVID-19 patients have a high risk of pulmonary embolism (PE), but factors that predict PE are unknown in this population. This study assessed the Wells and revised Geneva scoring systems as predictors of PE and their relationships with D-dimer (DD) in this population. METHODS: This was a longitudinal, observational study that included patients ≥75 years old with COVID-19 and suspected PE. The performances of the Wells score, revised Geneva score and DD levels were assessed. The combinations of the DD level and the clinical scales were evaluated using positive rules for higher specificity. RESULTS: Among 305 patients included in the OCTA-COVID study cohort, 50 had suspected PE based on computed tomography pulmonary arteriography (CTPA), and the prevalence was 5.6%. The frequencies of PE in the low-, intermediate- and high-probability categories were 5.9%, 88.2% and 5.9% for the Geneva model and 35.3%, 58.8% and 5.9% for the Wells model, respectively. The DD median was higher in the PE group (4.33 mg/L; interquartile range (IQR) 2.40-7.17) than in the no PE group (1.39 mg/L; IQR 1.01-2.75) (p < 0.001). The area under the curve (AUC) for DD was 0.789 (0.652-0.927). After changing the cutoff point for DD to 4.33 mg/L, the specificity increased from 42.5% to 93.9%. CONCLUSIONS: The cutoff point DD > 4.33 mg/L has an increased specificity, which can discriminate false positives. The addition of the DD and the clinical probability scales increases the specificity and negative predictive value, which helps to avoid unnecessary invasive tests in this population.

Mortality risk factors in a Spanish cohort of oldest-old patients hospitalized with COVID-19 in an acute geriatric unit: the OCTA-COVID study.

PURPOSE: To determine predictors of in-hospital mortality related to COVID-19 in oldest-old patients. DESIGN: Single-center observational study. SETTING AND PARTICIPANTS: Patients ≥ 75 years admitted to an Acute Geriatric Unit with COVID-19. METHODS: Data from hospital admission were retrieved from the electronic medical records: demographics, geriatric syndromes (delirium, falls, polypharmacy, functional and cognitive status) co-morbidities, previous treatments, clinical, laboratory, and radiographic characteristics. Cox proportional hazard models were used to evaluate in-hospital mortality. RESULTS: Three hundred patients were consecutively included (62.7% females, mean age of 86.3 ± 6.6 years). Barthel Index (BI) was < 60 in 127 patients (42.8%) and 126 (42.0%) had Charlson Index CI ≥ 3. Most patients (216; 72.7%) were frail (Clinical Frailty Scale ≥ 5) and 134 patients (45.1%) had dementia of some degree. The overall in-hospital mortality rate was 37%. The following factors were associated with higher in-hospital mortality in a multi-variant analysis: CURB-65 score = 3-5 (HR 7.99, 95% CI 3.55-19.96, p < 0.001), incident delirium (HR 1.72, 1.10-2.70, p = 0.017) and dementia (HR 3.01, 95% CI 1.37-6.705, p = 0.017). Protective factors were concurrent use of angiotensin-converting enzyme inhibitors (HR 0.42, 95% CI 0.25-0.72, p = 0.002) or prescription of hydroxychloroquine (HC 0.37 95% CI 0.22-0.62, p < 0.001) treatment during admission. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that recognition of geriatric syndromes together with the CURB-65 score may be useful tools to help clinicians establish the prognosis of oldest-old patients admitted to hospital with COVID-19.

Predictive Factors of Pulmonary Embolism in Older Patients with SARS-CoV-2: The OCTA-COVID-19 Study.

BACKGROUND: The risk of pulmonary embolism (PE) has not been studied in older patients affected by COVID-19. We aimed to assess PE incidence and risk factors in a population of older patients infected with SARS-CoV-2. METHODS: An ambispective, observational cohort study. A total of 305 patients ≥ 75 years old had the SARS-CoV-2 infection from March to May 2020. The incidence rate of PE was estimated as the proportion of new cases within the whole sample. Youden's index was used to assess the cutoff point of D-dimer. To select factors associated with the risk of PE, time-to-event analyses were performed using cause-specific hazard models. RESULTS: In total, 305 patients with a median age of 87 years (62.3% female) were studied; 67.9% were referred from nursing homes and 90.4% received any type of anticoagulation. A total of 64.9% showed frailty and 44% presented with dementia. The PE incidence was 5.6%. The cutoff value of a D-dimer level over 2.59 mg/L showed a sensitivity of 82.4% and specificity of 73.8% in discriminating a PE diagnosis. In the multivariate analysis, the factors associated with PE were previous oncological events and D-dimer levels. CONCLUSIONS: The PE incidence was 5.6%, and major risk factors for PE were oncological antecedents and increased plasma D-dimer levels.

Prevalence of potentially inappropriate prescription in community-dwelling patients with advanced dementia and palliative care needs.

OBJECTIVE: To establish the prevalence of potentially inappropriate prescription (PIP) in older people with advanced dementia, monitored by a Geriatric Home Care Unit (GHC), as well as the associated risk factors and costs. METHODS: Community-dwelling patients ≥65 years with an advanced dementia diagnosis (GDS-FAST≥7a) and poor 1-year vital prognosis (Frail-VIG≥0.6) were included. Pharmacotherapy history was reviewed retrospectively, collecting functional and cognitive status, on the first GHC visit, of patients assessed January 2016-January 2019. Potentially inappropriate medication was defined following STOPP-Frail criteria. RESULTS: 100 patients included (76% women, 89.15±5.8 years). Total medications prescribed 760 (7.63±3.4 drugs per patient). 85% patients were given at least one drug considered to be PIP. 26% (196) of the total drugs registered were PIPs. Patients who were prescribed an inappropriate drug showed a higher number of total prescribed drugs (7.92±3.42 vs 6.00±2.24; p 0.04) and a higher frequency of polypharmacy (84.7% vs 60%; p 0.025). Risk of receiving inappropriate medication increased by 24% for each additional drug prescribed (OR 1.24; 95% CI 1.01-1.52; p 0.04). The costs associated with PIP were 113.99 euros per 100 patients/day; 41,606.35 euros per 100 patients/year. CONCLUSIONS: Prescription of PIP to community-dwelling patients with severe dementia and poor vital prognosis is common and is associated with high economic impact in this population group.

A combination of circulating chemokines as biomarkers of obesity-induced insulin resistance at puberty.

BACKGROUND: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR). OBJECTIVE: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity. METHODS: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR. RESULTS: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR. CONCLUSIONS: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.

Atypical symptoms of COVID-19 in hospitalised oldest old adults / Síntomas atípicos de COVID-19 en el adulto mayor hospitalizado

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Potential association of plasma lysophosphatidic acid (LPA) species with cognitive impairment in abstinent alcohol use disorders outpatients.

Lysophosphatidic acid (LPA) species are bioactive lipids participating in neurodevelopmental processes. The aim was to investigate whether the relevant species of LPA were associated with clinical features of alcohol addiction. A total of 55 abstinent alcohol use disorder (AUD) patients were compared with 34 age/sex/body mass index-matched controls. Concentrations of total LPA and 16:0-LPA, 18:0-LPA, 18:1-LPA, 18:2-LPA and 20:4-LPA species were quantified and correlated with neuroplasticity-associated growth factors including brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-2, and neurotrophin-3 (NT-3). AUD patients showed dysexecutive syndrome (22.4%) and memory impairment (32.6%). Total LPA, 16:0-LPA, 18:0-LPA and 18:1-LPA concentrations, were decreased in the AUD group compared to control group. Total LPA, 16:0-LPA, 18:2-LPA and 20:4-LPA concentrations were decreased in men compared to women. Frontal lobe functions correlated with plasma LPA species. Alcohol-cognitive impairments could be related with the deregulation of the LPA species, especially in 16:0-LPA, 18:1-LPA and 20:4-LPA. Concentrations of BDNF correlated with total LPA, 18:2-LPA and 20:4-LPA species. The relation between LPA species and BDNF is interesting in plasticity and neurogenesis functions, their involvement in AUD might serve as a biomarker of cognitive impairment.

COX-2 Inhibition Antagonizes Intra-Accumbens 2-Arachidonoylglycerol-Mediated Reduction in Ethanol Self-Administration in Rats.

BACKGROUND: Ethanol (EtOH) self-administration is particularly sensitive to the modulation of CB1 signaling in the nucleus accumbens (NAc) shell, and EtOH consumption increases extracellular levels of the endogenous cannabinoid CB1 receptor agonist 2-arachidonoyl glycerol (2-AG) in this brain region. Stimulation of CB1 receptor with agonists increases EtOH consumption, suggesting that EtOH-induced increases in 2-AG might sustain motivation for EtOH intake. METHODS: In order to further explore this hypothesis, we analyzed the alterations in operant EtOH self-administration induced by intra-NAc shell infusions of 2-AG itself, the CB1 inverse agonist SR141716A, the 2-AG clearance inhibitor URB602, anandamide, and the cyclooxygenase-2 (COX-2) inhibitor nimesulide. RESULTS: Surprisingly, self-administration of 10% EtOH was dose-dependently reduced by either intra-NAc shell SR141716A or 2-AG infusions. Similar effects were found by intra-NAc shell infusions of URB602, suggesting again a role for accumbal 2-AG on the modulation of EtOH intake. Intra-NAc shell anandamide did not alter EtOH self-administration, pointing to a specific role for 2-AG in the modulation of EtOH self-administration. Finally, the inhibitory effect of intra-NAc shell 2-AG on EtOH intake was significantly reversed by pretreatment with nimesulide, suggesting that oxidative metabolites of 2-AG might mediate these inhibitory effects on operant self-administration. CONCLUSIONS: We propose that 2-AG signaling in the NAc exerts an inhibitory influence on EtOH consumption through a non-CB1 receptor mechanism involving the COX-2 pathway.

Variation in chemokines plasma concentrations in primary care depressed patients associated with Internet-based cognitive-behavioral therapy.

How the presence of inflammation has repercussions for brain function is a topic of active research into depression. Signals released from immune system-related cells, including chemokines, might be indicative of active depression and can, hypothetically, serve as biomarkers of response to interventions, both pharmacological and psychological. The objective of this study is to analyze the peripheral plasma concentrations of CXCL12, CCL11, CX3CL1 and CCL2 in a cohort of depressed primary-care patients, as well as their evolution after an internet-based cognitive-behavioral intervention. The concentrations of those chemokines were measured in 66 primary-care patients with mild and moderate depression, before and after the intervention, as well as 60 controls, using multiplex immunoassays. Concentrations of CXCL12 and CCL2 were significantly higher in the clinical sample in comparison with controls. A stable multivariate discriminative model between both groups was found. Concentrations of all chemokines decreased after the internet-based psychological intervention. These findings support the implication of chemokines in depression, even in a sample of patients with mild and moderate severity. Furthermore, they demonstrate the need for further multidisciplinary research that confirms how biomarkers such as plasma chemokines can serve as a marker for depression and are sensitive to non-pharmacological interventions.

Plasma concentrations of oleoylethanolamide in a primary care sample of depressed patients are increased in those treated with selective serotonin reuptake inhibitor-type antidepressants.

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models.

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory.

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 -receptor-deficient mice were acutely infused with LPA, which revealed that LPA1 -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.

Neuroplastic and cognitive impairment in substance use disorders: a therapeutic potential of cognitive stimulation.

Drug addiction is a chronic and relapsing disorder in which repeated drug exposure compromises brain neuroplasticity. Brain areas normally involved in learning and goal-directed behaviors become corrupted, which may lead to cognitive deficits that coexist with other addiction symptoms and predict a worse treatment outcome. New learning experiences that are not motivated by drugs may improve both cognitive deficits and drug-induced symptoms by promoting adaptive neuroplastic changes that could alleviate or reverse those involved in addiction. The present review will focus on whether potentiating healthy cognitive function, either by formal cognitive training or non-drug related environmental experiences, could exert beneficial effects in the therapeutics of addiction. Although additional studies are needed, the available clinical and preclinical evidence suggests that cognitive stimulation may provide a valuable adjuvant intervention in drug addiction.

Ethanol-induced alterations in endocannabinoids and relevant neurotransmitters in the nucleus accumbens of fatty acid amide hydrolase knockout mice.

Deletion of fatty acid amide hydrolase (FAAH), enzyme responsible for degrading endocannabinoids, increases alcohol consumption and preference. However, there is a lack of data on neurochemical events in mice exposed to alcohol in the absence of FAAH. Extracellular levels of endocannabinoids and relevant neurotransmitters were measured by in vivo microdialysis in the nucleus accumbens (NAc) of FAAH knockout (KO) and wild-type (WT) mice during an ethanol (EtOH; 2 g/kg, ip) challenge in EtOH-naive and repeated (r) EtOH-treated mice. In both genotypes, EtOH treatment caused no changes in baseline endocannabinoid levels, although FAAH KO mice displayed higher baseline N-arachidonoylethanolamine levels than WT mice. EtOH challenge caused a sustained increase in 2-arachidonoylglycerol (2-AG) levels in EtOH-naive WT mice but not in FAAH KO mice. In contrast, 2-AG levels were decreased following EtOH challenge in (r)EtOH-treated mice in both genotypes. Whereas (r)EtOH-treated mice showed higher baseline dopamine and serotonin levels than EtOH-naive mice in WT mice, these differences were attenuated in FAAH KO mice. Significant differences in baseline γ-aminobutyric acid (GABA) and glutamate levels by EtOH history were observed in WT mice but not in FAAH KO mice. Moreover, opposed effects on glutamate response were observed after EtOH challenge in EtOH-naive and (r)EtOH-treated FAAH KO mice. Finally, FAAH deletion failed to show EtOH-induced locomotion sensitivity. These data provide evidence of a potential influence of 2-AG in the neurochemical response to EtOH exposure in the NAc.

Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake.

Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA. Additionally, we evaluated the inhibition of endocannabinoids clearance enzymes [monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase] on anxiety-like behavior and alcohol consumption in alcohol-dependent rats and mice. Results revealed that alcohol dependence produced decreases in baseline 2-AG dialysate levels and increases in baseline levels of glutamate and GABA. Acute alcohol abstinence induced an enhancement of these dependence-induced effects and the levels of 2-AG and GABA were restored upon alcohol re-exposure. Additional studies showed that the increased CeA 2-AG levels induced by restraint stress and alcohol self-administration were blunted in alcohol-dependent rats. Pharmacological studies in rats and mice showed that anxiety-like behavior and alcohol consumption were increased in alcohol-dependent animals, and these behavioral effects were attenuated mainly by MAGL inhibitors [MJN110 (10 and 20 mg/kg) in rats and JZL184 (1 and 3 mg/kg) in mice]. The present results suggest a key role for endocannabinoid signaling in motivational neuroadaptations during alcohol dependence, in which a deficiency in CeA 2-AG signaling in alcohol-dependent animals is linked to stress and excessive alcohol consumption.

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.

Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior.

The systemic administration of lysophosphatidic acid (LPA) LPA1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA1/3 receptor antagonist (intraperitoneal ki16425, 20 mg/kg) on ethanol-related behaviors as well as on brain and plasma correlates. Acute administration of ki16425 reduced motivation for ethanol but not for saccharine in ethanol self-administering Wistar rats. Mouse experiments were conducted in two different strains. In Swiss mice, ki16425 treatment reduced both ethanol-induced sedation (loss of righting reflex, LORR) and ethanol reward (escalation in ethanol consumption and ethanol-induced conditioned place preference, CPP). Furthermore, in the CPP-trained Swiss mice, ki16425 prevented the effects of ethanol on basal c-Fos expression in the medial prefrontal cortex and on adult neurogenesis in the hippocampus. In the c57BL6/J mouse strain, however, no effects of ki16425 on LORR or voluntary drinking were observed. The c57BL6/J mouse strain was then evaluated for ethanol withdrawal symptoms, which were attenuated when ethanol was preceded by ki16425 administration. In these animals, ki16425 modulated the expression of glutamate-related genes in brain limbic regions after ethanol exposure; and peripheral LPA signaling was dysregulated by either ki16425 or ethanol. Overall, these results suggest that LPA1/3 receptor antagonists might be a potential new class of drugs that are suitable for treating or preventing alcohol use disorders. A pharmacokinetic study revealed that systemic ki16425 showed poor brain penetration, suggesting the involvement of peripheral events to explain its effects.

Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens.

Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p < 0.001) and resulted in a strong post-nicotine elevation in DA levels (p < 0.01). However, there were no differences between the genotypes at higher doses. Furthermore, FAAH KO mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.05), with no differences between the genotypes at higher doses. Compared with vehicle-pretreated mice, mice pretreated with PF-3845 displayed an enhancement of the effect of low-dose nicotine on NAc DA release (p < 0.001), which resulted in a sustained increase in DA levels (p < 0.05). Similar to FAAH KO mice, PF-3845-pretreated mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.01). These observations in mice suggest that enhanced nicotine-induced NAc DA release might contribute to increased sensitivity to the conditioned rewarding effects of low-dose nicotine following FAAH inhibition, which has been previously reported. Future studies combining behavioral and neurochemical approaches are needed to elucidate the precise mechanism of these effects.