Publications by authors named "Aurelijus Burokas"

20 Publications

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Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways.

Gut 2021 Jan 29. Epub 2021 Jan 29.

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain

Background: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits.

Methods: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics.

Results: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism ( exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice.

Conclusion: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.
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http://dx.doi.org/10.1136/gutjnl-2020-323371DOI Listing
January 2021

The Microbiota-Gut-Brain Axis and Alzheimer's Disease: Neuroinflammation Is to Blame?

Nutrients 2020 Dec 24;13(1). Epub 2020 Dec 24.

Life Sciences Center, Department of Biological Models, Institute of Biochemistry, Vilnius University, Sauletekio Ave. 7, LT-10257 Vilnius, Lithuania.

For years, it has been reported that Alzheimer's disease (AD) is the most common cause of dementia. Various external and internal factors may contribute to the early onset of AD. This review highlights a contribution of the disturbances in the microbiota-gut-brain (MGB) axis to the development of AD. Alteration in the gut microbiota composition is determined by increase in the permeability of the gut barrier and immune cell activation, leading to impairment in the blood-brain barrier function that promotes neuroinflammation, neuronal loss, neural injury, and ultimately AD. Numerous studies have shown that the gut microbiota plays a crucial role in brain function and changes in the behavior of individuals and the formation of bacterial amyloids. Lipopolysaccharides and bacterial amyloids synthesized by the gut microbiota can trigger the immune cells residing in the brain and can activate the immune response leading to neuroinflammation. Growing experimental and clinical data indicate the prominent role of gut dysbiosis and microbiota-host interactions in AD. Modulation of the gut microbiota with antibiotics or probiotic supplementation may create new preventive and therapeutic options in AD. Accumulating evidences affirm that research on MGB involvement in AD is necessary for new treatment targets and therapies for AD.
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http://dx.doi.org/10.3390/nu13010037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824474PMC
December 2020

Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.

Cell Metab 2020 Oct;32(4):548-560.e7

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain; Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain; Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, Girona University, Girona, Spain. Electronic address:

The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.
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http://dx.doi.org/10.1016/j.cmet.2020.09.002DOI Listing
October 2020

Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status.

Microbiome 2020 09 20;8(1):136. Epub 2020 Sep 20.

Department of Endocrinology, Diabetes and Nutrition, Departament de Ciències Mèdiques, Hospital of Girona "Dr JosepTrueta", Girona Biomedical Research Institute (IdibGi), University of Girona, Carretera de França s/n, 17007, Girona, Spain.

Background: Gonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids.

Results: No significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor's testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor's gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status.

Conclusions: The present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00913-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504665PMC
September 2020

Gut bacterial ClpB-like gene function is associated with decreased body weight and a characteristic microbiota profile.

Microbiome 2020 04 30;8(1):59. Epub 2020 Apr 30.

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Carretera de França s/n, 17007, Girona, Spain.

Background: The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans.

Results: Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10-2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10), Rikenellaceae (r = 0.702, p = 3.9 × 10), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = - 0.445, p = 0.038) and Prevotellaceae RA (r = - 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function.

Conclusions: In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193372PMC
April 2020

Time-course and dynamics of obesity-related behavioral changes induced by energy-dense foods in mice.

Addict Biol 2018 03 10;23(2):531-543. Epub 2018 Jan 10.

Cellular and Systems Neurobiology, Systems Biology Program, The Barcelona Institute of Science and Technology, Centre for Genomic Regulation (CRG), Spain.

Obesity represents an important risk factor contributing to the global burden of disease. The current obesogenic environment with easy access to calorie-dense foods is fueling this obesity epidemic. However, how these foods contribute to the progression of feeding behavior changes that lead to overeating is not well understood and needs systematic assessment. Using novel automated methods for the high-throughput screening of behavior, we here examine mice meal pattern upon long-term exposure to a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity induced by unhealthy food regularly consumed in our societies. We identified rapid diet-specific behavioral changes after exposure to those high-caloric diets. Mice fed with high-fat chow, showed long-lasting meal pattern disturbances, which initiate with a stable loss of circadian feeding rhythmicity. Mice receiving a chocolate-mixture showed qualitatively similar changes, though less marked, consisting in a transient disruption of the feeding behavior and the circadian feeding rhytmicity. Strikingly, compulsive-like eating behavior is triggered immediately after exposure to both high-fat food and chocolate-mixture diet, well before any changes in body weight could be observed. We propose these changes as behavioral biomarkers of prodromal states of obesity that could allow early intervention.
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http://dx.doi.org/10.1111/adb.12595DOI Listing
March 2018

Extinction and reinstatement of an operant responding maintained by food in different models of obesity.

Addict Biol 2018 03 28;23(2):544-555. Epub 2017 Dec 28.

Laboratori de Neurofarmacologia. Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

A major problem in treating obesity is the high rate of relapse to abnormal food-taking habits after maintaining an energy balanced diet. Alterations of eating behavior such as compulsive-like behavior and lack of self-control over food intake play a critical role in relapse. In this study, we used an operant paradigm of food-seeking behavior on two different diet-induced obesity models, a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity or for unhealthy food regularly consumed in our societies. A reduced operant performance and motivation for the hedonic value of palatable chocolate pellets was revealed in both obesity mouse models. However, only mice exposed to high-fat diet showed an increased compulsive-like behavior in the absence of the reinforcer further characterized by impaired operant learning, enhanced impulsivity and intensified inflexibility. We used principal component analysis to globally identify the specific behaviors responsible for the differences among diet groups. Learning impairment and inflexible behaviors contributed to a first principal component, explaining the largest proportion of the variance in the high-fat diet mice phenotype. Reinforcement, impulsion and compulsion were the main contributors to the second principal component explaining the differences in the chocolate-mixture mice behavioral phenotype. These behaviors were not exclusive of chocolate group because some high-fat individuals showed similar values on this component. These data indicate that extended access to hypercaloric diets differentially modifies operant behavior learning, behavioral flexibility, impulsive-like and compulsive-like behavior, and these effects were dependent on the exposure to each specific diet.
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http://dx.doi.org/10.1111/adb.12597DOI Listing
March 2018

Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism.

EBioMedicine 2017 Oct 21;24:166-178. Epub 2017 Sep 21.

APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland. Electronic address:

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR TItpr3/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut - namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
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http://dx.doi.org/10.1016/j.ebiom.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652137PMC
October 2017

Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice.

Biol Psychiatry 2017 Oct 24;82(7):472-487. Epub 2017 Feb 24.

APC Microbiome Institute, University College Cork, Cork; Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork; Department of Anatomy and Neuroscience, University College Cork, Cork. Electronic address:

Background: The realization that the microbiota-gut-brain axis plays a critical role in health and disease, including neuropsychiatric disorders, is rapidly advancing. Nurturing a beneficial gut microbiome with prebiotics, such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), is an appealing but underinvestigated microbiota manipulation. Here we tested whether chronic prebiotic treatment modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior.

Methods: C57BL/6J male mice were administered FOS, GOS, or a combination of FOS+GOS for 3 weeks prior to testing. Plasma corticosterone, microbiota composition, and cecal short-chain fatty acids were measured. In addition, FOS+GOS- or water-treated mice were also exposed to chronic psychosocial stress, and behavior, immune, and microbiota parameters were assessed.

Results: Chronic prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic effects. Moreover, the administration of GOS and the FOS+GOS combination reduced stress-induced corticosterone release. Prebiotics modified specific gene expression in the hippocampus and hypothalamus. Regarding short-chain fatty acid concentrations, prebiotic administration increased cecal acetate and propionate and reduced isobutyrate concentrations, changes that correlated significantly with the positive effects seen on behavior. Moreover, FOS+GOS reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota.

Conclusions: Taken together, these data strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.
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http://dx.doi.org/10.1016/j.biopsych.2016.12.031DOI Listing
October 2017

Epigenetic and Proteomic Expression Changes Promoted by Eating Addictive-Like Behavior.

Neuropsychopharmacology 2015 Nov 6;40(12):2788-800. Epub 2015 May 6.

Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

An increasing perspective conceptualizes obesity and overeating as disorders related to addictive-like processes that could share common neurobiological mechanisms. In the present study, we aimed at validating an animal model of eating addictive-like behavior in mice, based on the DSM-5 substance use disorder criteria, using operant conditioning maintained by highly palatable chocolate-flavored pellets. For this purpose, we evaluated persistence of food-seeking during a period of non-availability of food, motivation for food, and perseverance of responding when the reward was associated with a punishment. This model has allowed identifying extreme subpopulations of mice related to addictive-like behavior. We investigated in these subpopulations the epigenetic and proteomic changes. A significant decrease in DNA methylation of CNR1 gene promoter was revealed in the prefrontal cortex of addict-like mice, which was associated with an upregulation of CB1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/kg; i.p.) of CB1 receptor during the late training period reduced the percentage of mice that accomplished addiction criteria, which is in agreement with the reduced performance of CB1 knockout mice in this operant training. Proteomic studies have identified proteins differentially expressed in mice vulnerable or not to addictive-like behavior in the hippocampus, striatum, and prefrontal cortex. These changes included proteins involved in impulsivity-like behavior, synaptic plasticity, and cannabinoid signaling modulation, such as alpha-synuclein, phosphatase 1-alpha, doublecortin-like kinase 2, and diacylglycerol kinase zeta, and were validated by immunoblotting. This model provides an excellent tool to investigate the neurobiological substrate underlying the vulnerability to develop eating addictive-like behavior.
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http://dx.doi.org/10.1038/npp.2015.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864655PMC
November 2015

Microbiota regulation of the Mammalian gut-brain axis.

Adv Appl Microbiol 2015 11;91:1-62. Epub 2015 Mar 11.

Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.

The realization that the microbiota-gut-brain axis plays a critical role in health and disease has emerged over the past decade. The brain-gut axis is a bidirectional communication system between the central nervous system (CNS) and the gastrointestinal tract. Regulation of the microbiota-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The routes of this communication are not fully elucidated but include neural, humoral, immune, and metabolic pathways. A number of approaches have been used to interrogate this axis including the use of germ-free animals, probiotic agents, antibiotics, or animals exposed to pathogenic bacterial infections. Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiota-brain interactions is an exciting area of research which may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior, and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia. Finally, the concept of psychobiotics, bacterial-based interventions with mental health benefit, is also emerging.
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http://dx.doi.org/10.1016/bs.aambs.2015.02.001DOI Listing
August 2015

Frustrated expected reward induces differential transcriptional changes in the mouse brain.

Addict Biol 2015 Jan 6;20(1):22-37. Epub 2014 Oct 6.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, PRBB, Universitat Pompeu Fabra, Spain.

Frustration represents a particular aspect of the addictive process that is related to loss of control when the expected reward is not obtained. We aim to study the consequences of frustrated expected reward on gene expression in the mouse brain. For this purpose, we used an operant model of frustration using palatable food as reward combined with microarrays. Transcriptomic profiles of frontal cortex, ventral striatum and hippocampus were analysed in five groups of mice: (1) positive control receiving palatable food and the cue light as conditioned stimulus; (2) frustrated group only receiving the cue light; (3) extinction learning group that did not receive palatable food nor the light; (4) negative control that never received the reinforcer nor the light during the whole experiment; and (5) yoked that received palatable food passively. Gene expression changes produced by frustration were revealed in the frontal cortex and ventral striatum, but not in the hippocampus. Most of the changes, such as the modification of the dopamine-DARPP-32 signalling pathway, were common in both areas and estimated to have neuronal origin. Extinction learning induced transcriptional changes only in the ventral striatum, with most genes showing down-regulation and without alteration in the dopamine-DARPP-32 signalling pathway. Active palatable food-seeking behaviour induced changes in gene expression in ventral striatum mainly affecting cell communication. In conclusion, frustration behaviour-induced changes in frontal cortex and ventral striatum mainly related to dopamine-DARPP-32 signalling that could play an important role in the loss of behavioural control during the addictive processes.
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http://dx.doi.org/10.1111/adb.12188DOI Listing
January 2015

Effects of genetic deletion of endogenous opioid system components on the reinstatement of cocaine-seeking behavior in mice.

Neuropsychopharmacology 2014 Dec 19;39(13):2974-88. Epub 2014 Jun 19.

Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

The repeated cycles of cessation of consumption and relapse remain the major clinical concern in treating drug addiction. The endogenous opioid system is a crucial component of the reward circuit that participates in the adaptive changes leading to relapse in the addictive processes. We have used genetically modified mice to evaluate the involvement of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) and their main endogenous ligands, the enkephalins derived from proenkephalin (PENK) and prodynorphin (PDYN), in the reinstatement of cocaine-seeking behavior. Constitutive knockout mice of MOR, DOR, PENK, and PDYN, and their wild-type littermates were trained to self-administer cocaine or to seek for palatable food, followed by a period of extinction and finally tested on a cue-induced reinstatement of seeking behavior. The four lines of knockout mice acquired operant cocaine self-administration behavior, although DOR and PENK knockout mice showed less motivation for cocaine than wild-type littermates. Moreover, cue-induced relapse was significantly decreased in MOR and DOR knockout mice. In contrast, PDYN knockout mice showed a slower extinction and increased relapse than wild-type littermates. C-Fos expression analysis revealed differential activation in brain areas related with memory and reward in these knockout mice. No differences were found in any of the four genotypes in operant responding to obtain palatable food, indicating that the changes revealed in knockout mice were not due to unspecific deficit in operant performance. Our results indicate that MOR, DOR, and PDYN have a differential role in cue-induced reinstatement of cocaine-seeking behavior.
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http://dx.doi.org/10.1038/npp.2014.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229567PMC
December 2014

Relationships between serotonergic and cannabinoid system in depressive-like behavior: a PET study with [11C]-DASB.

J Neurochem 2014 Jul 30;130(1):126-35. Epub 2014 Apr 30.

Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

Chronic stress represents a major environmental risk factor for mood disorders in vulnerable individuals. The neurobiological mechanisms underlying these disorders involve serotonergic and endocannabinoid systems. In this study, we have investigated the relationships between these two neurochemical systems in emotional control using genetic and imaging tools. CB1 cannabinoid receptor knockout mice (KO) and wild-type littermates (WT) were exposed to chronic restraint stress. Depressive-like symptoms (anhedonia and helplessness) were produced by chronic stress exposure in WT mice. CB1 KO mice already showed these depressive-like manifestations in non-stress conditions and the same phenotype was observed after chronic restraint stress. Chronic stress similarly impaired long-term memory in both genotypes. In addition, brain levels of serotonin transporter (5-HTT) were assessed using positron emission tomography. Decreased brain 5-HTT levels were revealed in CB1 KO mice under basal conditions, as well as in WT mice after chronic stress. Our results show that chronic restraint stress induced depressive-like behavioral alterations and brain changes in 5-HTT levels similarly to those revealed in CB1 KO mice in non-stressed conditions. These results underline the relevance of chronic environmental stress on serotonergic and endocannabinoid transmission for the development of depressive symptoms. Chronic restraint stress induces depressive-like behavior and reduced 5-HTT levels in WT mice similar to those revealed in non-stressed CB1-KO mice. Reduced 5-HTT in both genotypes increases synaptic 5-HT concentration. The 5-HT release is modulated through CB1 receptors and the absence of inhibitory CB1 receptor causes decreased inhibition of 5-HT release resulting in high synaptic 5-HT concentration that are not further enhanced by stress.
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http://dx.doi.org/10.1111/jnc.12716DOI Listing
July 2014

Sex-dependent psychoneuroendocrine effects of THC and MDMA in an animal model of adolescent drug consumption.

PLoS One 2013 4;8(11):e78386. Epub 2013 Nov 4.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain ; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.

Ecstasy is a drug that is usually consumed by young people at the weekends and frequently, in combination with cannabis. In the present study we have investigated the long-term effects of administering increasing doses of delta-9-tetrahydrocannabinol [THC; 2.5, 5, 10 mg/kg; i.p.] from postnatal day (pnd) 28 to 45, alone and/or in conjunction with 3,4-methylenedioxymethamphetamine [MDMA; two daily doses of 10 mg/kg every 5 days; s.c.] from pnd 30 to 45, in both male and female Wistar rats. When tested one day after the end of the pharmacological treatment (pnd 46), MDMA administration induced a reduction in directed exploration in the holeboard test and an increase in open-arm exploration in an elevated plus maze. In the long-term, cognitive functions in the novel object test were seen to be disrupted by THC administration to female but not male rats. In the prepulse inhibition test, MDMA-treated animals showed a decrease in prepulse inhibition at the most intense prepulse studied (80 dB), whereas in combination with THC it induced a similar decrease at 75 dB. THC decreased hippocampal Arc expression in both sexes, while in the frontal cortex this reduction was only evident in females. MDMA induced a reduction in ERK1/2 immunoreactivity in the frontal cortex of male but not female animals, and THC decreased prepro-orexin mRNA levels in the hypothalamus of males, although this effect was prevented when the animals also received MDMA. The results presented indicate that adolescent exposure to THC and/or MDMA induces long-term, sex-dependent psychophysiological alterations and they reveal functional interactions between the two drugs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078386PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817254PMC
August 2014

Operant model of frustrated expected reward in mice.

Addict Biol 2012 Jul 20;17(4):770-82. Epub 2012 Jan 20.

Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Spain.

One aspect of the addictive process that has not been thoroughly investigated is the consequence of the frustrated state occurring when the drug is not available. The present study aimed to validate a novel operant model of frustrated expected reward in mice. C57BL/6J mice were trained in operant conditioning maintained by chocolate-flavoured pellets or cocaine. After the completion of high rates of responding on a progressive ratio schedule, the reward was unexpectedly withheld. The consequences of this frustrated behaviour on anxiety, aggressiveness, perseveration, extinction and reinstatement were investigated. Mice exposed to the frustrated event perseverated in the operant responses and showed increased aggressiveness in the resident-intruder test. These animals also showed higher rates of cue-induced reinstatement of drug seeking. The present study provides a reliable operant model in mice to evaluate a frustrated state following reward unavailability. This animal model could be useful to study the behavioural and neurochemical consequences related to the emotional states generated during the omission of a highly expected reward.
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http://dx.doi.org/10.1111/j.1369-1600.2011.00423.xDOI Listing
July 2012

Positron emission tomographic imaging of the cannabinoid type 1 receptor system with [¹¹C]OMAR ([¹¹C]JHU75528): improvements in image quantification using wild-type and knockout mice.

Mol Imaging 2011 Dec;10(6):481-7

Institut d’Alta Tecnologia, Parc de Recerca Biomèdica de Barcelona, CRC Corporació Sanitària, Barcelona, Spain.

In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [¹¹C]OMAR ([¹¹C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) and CB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [¹¹C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals.
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December 2011

New operant model of reinstatement of food-seeking behavior in mice.

Psychopharmacology (Berl) 2011 May 14;215(1):49-70. Epub 2010 Dec 14.

Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

Rationale: A major problem in treating obesity is the high rate of relapse to abnormal food-taking behavior when maintaining diet.

Objectives: The present study evaluates the reinstatement of extinguished palatable food-seeking behavior induced by cues previously associated with the palatable food, re-exposure to this food, or stress. The participation of the opioid and dopamine mechanisms in the acquisition, extinction, and cue-induced reinstatement was also investigated.

Materials And Methods: C57BL/6 mice were first trained on a fixed-ratio-1 schedule of reinforcement to obtain chocolate-flavored pellets during 20 days, which was associated to a stimulus light. Operant behavior was then extinguished during 20 daily sessions. mRNA levels of opioid peptide precursors and dopamine receptors were evaluated in the brain by in situ hybridization and RT-PCR techniques.

Results: A reinstatement of food-seeking behavior was only obtained after exposure to the food-associated cue. A down-regulation of prodynorphin mRNA was found in the dorsal striatum and nucleus accumbens after the acquisition, extinction, and reinstatement of the operant behavior. Extinction and reinstatement of this operant response enhanced proenkephalin mRNA in the dorsal striatum and/or the nucleus accumbens core. Down-regulation of D2 receptor expression was observed in the dorsal striatum and nucleus accumbens after reinstatement. An up-regulation of PDYN mRNA expression was found in the hypothalamus after extinction and reinstatement.

Conclusions: This study provides a new operant model in mice for the evaluation of food-taking behavior and reveals specific changes in the dopamine and opioid system associated to the behavioral responses directed to obtain a natural reward.
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http://dx.doi.org/10.1007/s00213-010-2110-6DOI Listing
May 2011

Effects of chronic nicotine on food intake and anxiety-like behaviour in CB(1) knockout mice.

Eur Neuropsychopharmacol 2010 Jun 26;20(6):369-78. Epub 2010 Feb 26.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB Barcelona, Spain.

We have evaluated the effects of chronic nicotine administration and withdrawal in food intake and preference, metabolic parameters and anxiety-like behaviour in CB(1) knockout mice and wild-type littermates. Mutant mice showed lower levels of glucose, insulin and cholesterol after two weeks of high fat diet and reduced preference for saccharin solution when compared with wild-type mice. Nicotine reduced body weight and induced anxiogenic-like effects in wild-type, but not in CB(1) knockout mice. Our results suggest a modulatory role of the endocannabinoid system on the effects induced by nicotine on metabolic parameters and anxiety-like responses.
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http://dx.doi.org/10.1016/j.euroneuro.2010.02.003DOI Listing
June 2010

Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant.

J Neurochem 2010 Mar 17;112(5):1338-13351. Epub 2009 Dec 17.

Laboratori de Neurofarmacologia, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.
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http://dx.doi.org/10.1111/j.1471-4159.2009.06549.xDOI Listing
March 2010