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Official websites use. Share sensitive information only on official, secure websites. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The combination of substance use and psychiatric disorders is one of the most common comorbidities. The objective of this study was to perform a genome-wide association study of this comorbidity Com , substance use alone Subs , and psychiatric symptomatology alone Psych in the Mexican population. The study included individuals of Mexican descent. Genotyping was carried out using the PsychArray microarray and genome-wide correlations were calculated. Genome-wide associations were analyzed using multiple logistic models, polygenic risk scores PRSs were evaluated using multinomial models, and vertical pleiotropy was evaluated by generalized summary-data-based Mendelian randomization. Genome-wide correlation and vertical pleiotropy were found between all traits. The SNPs associated with each trait were independent, and the individuals with high PRSs had a higher prevalence of tobacco and alcohol use. Epidemiological studies have found high rates of substance use disorders in individuals with psychiatric disorders, and vice versa 1 — 6. The etiopathological mechanisms of this comorbidity have yet to be clarified, but there are some general hypotheses 12 , One of these is the diathesis-stress model, which holds that there must be a vulnerability such as a genetic variability in a stressful environment such as a socioeconomic or family situation for a comorbidity to appear With the help of technologies for analyzing genetic information, genome-wide association studies have identified a genetic predisposition to many psychiatric disorders, demonstrating a pleiotropic effect 14 , However, these genetic studies have focused on exploring associations with a single phenotype, without investigating the question of comorbidity There has been little study of genetic variants related to the appearance of comorbidity. Recent genome-wide analyses of psychiatric disorders have also included little representation of Latin American populations The majority of studies are of Europeans, but Latin American populations, including that of Mexico, have a high degree of genetic mixing, and could thus be the source of new associations for some phenotypes 17 — A recent study in India, for example, found an association for schizophrenia that had not previously been reported in European populations Other studies have identified differences in non-Europeans from the polygenic risk scores PRSs derived from genetic associations based on European ancestry 16 , Because of the high degree of genetic mixing in Mexico, there is a need to find loci associated with the comorbidity. The objective of this study was thus to carry out an analysis of genome-wide association with the comorbidity of psychiatric symptomatology and substance use, substance use alone, and psychiatric symptomatology alone, in the Mexican population. The individuals were divided into four groups: i individuals with comorbidity Com , psychiatric symptomatology and substance use , ii individuals with substance use alone Subs , iii individuals with psychiatric symptomatology alone Psych , and iv individuals without symptomatology or substance use Cont. Gustavo A. It includes patients with diagnoses of bipolar disorder, schizophrenia, and major depressive disorder. All participants provided written informed consent or assent, and the protocol complied with international norms and the Helsinki Declaration. Quality control was performed with Plink software To correct for cryptic relationships, all individual pairs with an identity-by-state value greater than 1. Three models of explained variance were proposed, comparing: 1 Com with Cont , 2 Psych with Cont , and 3 Subs with Cont. All of the models were adjusted for age, sex, and ten principal components of global ancestry. Estimation of global ancestry was performed with a principal components analysis using previously reported algorithms 33 and the PC-AiR package Only independent SNPs were included in this estimation; for this reason a process of linkage disequilibrium pruning LD pruning was carried out, using the following parameters: a window size of 50 kb, a step of 2, and a variance inflation factor of 5. The genetic associations were carried out by means of multiple logistic regressions, adjusted for age, sex, and ten components of global ancestry as covariables. A p -value of 5. The logistic regressions were carried out in Plink After statistical contrasts, all of the variants were removed that had a MAF lower than 5. In addition, the allelic frequencies of the associated variants were compared with the Genome Aggregation Database GnomAD A search in the GWAS atlas of the associated SNPs was performed for associations with brain-related phenotypes psychiatric, substance use, and neurological disorders. A clustering of paths was also performed Next, the standardized residual of the PRS was regressed on the ten principal components of global ancestry. These analyses considered only the individuals from the MxGDAR, because these had a more in-depth phenotyping. Next, the accuracy of the PRSs to predict the phenotypes Com , Subs , Psych , and Cont was calculated with a multinomial regression using the nnet package. A multinomial regression of the phenotypes in the training sample was performed on the three PRSs constructed, and the phenotype was then predicted in the test sample. A contrast table of the phenotype in the test sample and those predicted by the model were compared using the caret package, and the accuracy was calculated. The possible functional impact of the associated SNPs on the brain was assessed by calculating brain methylation quantitative loci brain meQTL , using a previously published database 43 — 45 that included a total of 48 brain samples from individuals of Mexican descent. These were genotyped and DNA methylation levels were measured with microarrays. To explore whether the associated variants could perform vertical pleiotropy in the phenotypes with one exposure to an outcome, the following models were tested: a Subs exposure to the Com outcome, b Psych exposure to the Com outcome, c Subs exposure to the Psych outcome, d Psych exposure to the Subs outcome, e Com exposure to the Subs outcome, and f Com exposure to the Psych outcome. The genome-wide explained variance in the Com group was No enriched pathways were found. The only SNP reported in the GWAS atlas associated with a brain-associated phenotype was rs, associated with being a morning person. Of these, 26 were intergenic, 13 were intronic, and one was a missense polymorphism. No enriched pathways were found grouping these genes. The following SNPs have been associated with other brain-associated phenotypes: rs chronotype , rs insomnia and intelligence , rs educational attainment , rs right superior frontal diusivities , and rs superior corona radiata radial diusivities. Of the 17 SNPs, seven were intergenic, nine were intronic, and one was a missense polymorphism. The missense polymorphism was a change of glutamine for glutamic acid in the position of the SHPK p. The GWAS atlas search found five SNPs rs, rs, rs, rs, and rs previously associated with psychiatric or substance use phenotypes in other populations. The SNPs rs, rs, and rs were associated with past tobacco smoking, weekly alcohol consumption, and frequency of failure in the past year to fulfill normal expectations due to drinking, while rs and rs were associated with ease of getting up in the morning and being a morning person. Subs- PRS explained 1. In the multinomial model, there was a statistically significant association of the three PRSs with every group Supplementary Table S1. The three PRSs had an accuracy of Next, the individuals were grouped based on PRS, and the differences in psychiatric symptoms and substance use patterns in individuals with different PRSs were evaluated Table 3 ; these analyses included only individuals from the MxGDAR. There were statistically significant differences between individuals with different PRSs in lifetime prevalence of anxiety, lifetime smoking of at least cigarettes, and problematic use of alcohol excessive alcohol consumption, possible abuse or dependence on alcohol in the previous year, or having stopped drinking because of problems with its use. The brain meQTLs associated with Subs , rs, rs, rs, and rs, had an effect on CpG sites, 48 of which were annotated to the gene promoter Table 4 a. The greatest association was for rs affecting cg, annotated to the promoter of HSBP1 Table 4 a. Of the 40 SNPs associated with Psych , 19 rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, rs, and rs had a cis or trans effect on CpGs sites, of which 61 were annotated to the gene promoter, with the greatest effect for the rs associated with cg, annotated to SKI Table 4 b. Of the 17 SNPs associated with the Com , seven rs, rs, rs, rs, rs, rs, and rs had an effect on 91 CpGs sites, of which 25 were associated with the gene promoter. There were no enriched pathways for the genes where the brain meQTL associated with Com had an effect. Of the 64 SNPs associated with any phenotype at nominal significance, 29 The comorbidity between psychiatric symptomatology and substance use leads to a significant impairment in affected individuals, but the evaluation of the phenotype has been little explored in genome-wide studies. Ours is one of the first genome-wide association studies to explore variants associated with this comorbidity, along with substance use and psychiatric symptoms alone, in the Mexican population. Our study found that the evaluation of different phenotypes Subs , Psych , and Com could identify different patterns of associated variants, but that these associated variants are highly correlated and could also have pleiotropy, the effect of a single variant on different phenotypes or traits Genome-wide association studies have found a high degree of correlation between psychiatric disorders 49 , possibly because many of the associated genes could have pleiotropic effects between different psychiatric phenotypes. In this study we found vertical pleiotropy and genome-wide correlation of all phenotypes, suggesting that the associated variants could have an effect in Subs , Psych , and Com. These have been reported recently in a genome-wide study of lifelong cannabis use, which found a genetic correlation of the phenotype with different substance use disorders as well as with other mental disorders, meaning that many of the associated genes could show a pleiotropic effect in these phenotypes Other studies have suggested that the categorization of individuals into discrete diagnoses may neglect the consideration of these individuals in terms of a broader phenotype, which may be occurring in comorbidity studies 50 — The use of genetic analysis could help us to better categorize individuals with comorbidity, as in our finding that individuals with higher polygenic risk scores had a higher prevalence of having smoked more than cigarettes in their life and a higher prevalence of risky alcohol use. This may be the result of the larger sample size in our study of individuals using alcohol or tobacco. We thus believe that genome-wide association studies of comorbidity might include a greater diversity of substance use disorders in order to explore this phenotype-dependent difference in GWAS signals. If so, PRS results could be used in a clinical setting to screen for individuals with a greater risk of developing the comorbidity. In order to assess the possible effects of the associated SNPs on the brain, we performed brain meQTL analysis of a previously published database of individuals of Mexican ancestry 43 — Some polymorphisms showed greater evidence of association with brain phenotypes, including rs, rs, and rs The first, the intron SNP in the gene DPP10 , for which we found an association with psychiatric disorders, has been associated with chronotype 55 — These results suggest that the comorbidity could be associated with chronotype. The rs in this study was a brain meQTL, associated in trans to a CpG site in the ELF2 gene, which has been suggested as a sensor for the elevation of extrasynaptic glutamate, modifying the growth of functional dendritic spines Glutamatergic signaling is a regulator in the reward regions of the brain that maintain the habits of psychoactive substance use The increase in excitotoxicity could generate changes in neuroplasticity, leading to an increase in drug-seeking behaviors and in the memories associated with drugs PCBP1 is part of the DISC1 interactome 66 , which is essential in the development of brain cells, and alterations in this area could lead to neurodegenerative disorders 66 — Peripheral levels of DISC1 have been proposed as a marker of nicotine exposure 69 , supporting the possibility of an association between rs and tobacco-related behavior. Those associated with Subs modified the insulin signaling pathway, while those associated with Psych modified the Fc gamma receptor mediated phagocytosis. Insulin signaling in the periphery plays a crucial role in the homeostasis of plasma glucose levels, but the effect of insulin on the central nervous system is less recognized. The insulin pathway has been associated with substance addiction in animal and human studies, and in integrative bioinformatics analysis of different omic data The mechanism underlying the effect of insulin in substance use is not fully elucidated, but evidence points to a dysregulation of dopamine in brain reward circuits 75 — The Fc gamma receptor mediated phagocytosis pathway, for which we found brain meQTLs associated with psychiatric symptoms, was recently associated with schizophrenia and bipolar disorder through analysis of transcriptomes and co-localization of GWAS signals Zhao et al. The genome-wide estimated variance in the Com group was greater than in those who presented only one disorder, suggesting that the risk from genetic variability could be greater in this group. Interestingly, the explained variance in the Subs group was close to zero. This lesser explained variance could mean that the effects of the common variants analyzed in the microarray are not sufficient to capture the genetic effect in this group, possibly because of an underestimation, possibly because of the effects of uncommon variants not explored in this study. An examination of these phenotypes with other sources of genetic variation is thus needed, and of the way in which this genetic risk could interact with environmental factors such as exposure to trauma and social tolerance of substance use in producing the comorbidity. Although this study identified associations that could be the basis for future functional studies of the relationship between genetic variability and comorbidity, some limitations should be noted. The main one is the use of two samples, one a population sample and the other clinical, where the criteria for defining the phenotype could be a source of heterogeneity. However, the inclusion of both populations increases the sample size and facilitates the identification of associations. Even with these limitations, we believe that this study, with the sample size it offers for investigation of the genome-wide association, provides important information for the understanding of the comorbidity between psychiatric symptomatology and substance use in the Mexican population. This study found genetic associations of SNPs that modulate brain DNA methylation levels in genes involved in the insulin signaling pathway and Fc gamma receptor phagocytosis with the comorbidity between psychiatric symptomatology and substance use in the Mexican population. These results suggest new paradigms for understanding how genetic variability regulates comorbidity. We wish to thank the work committee and the field coordination team of the Encodat , headed by Aurora Franco. All authors reviewed the manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Sci Rep. Find articles by Alma Delia Genis-Mendoza. Find articles by Carlos Alfonso Tovilla-Zarate. Find articles by Emmanuel Sarmiento. Find articles by Erasmo Saucedo. Find articles by Clara Fleiz-Bautista. Find articles by Beatriz Camarena. Find articles by Alejandro Aguilar. Find articles by Thelma Beatriz Gonzalez-Castro. Find articles by Humberto Nicolini. Received Sep 28; Accepted Mar 8; Collection date Overview of the Sociodemographic and Clinical Characteristics of the Samples. Open in a new tab. Genetic loci associated with Subs , Psych , and Com. HisAsp c Com rs 1p Supplementary Table S1. Supplementary Table S2. Supplementary Table S3. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
Anorexigenic drugs. Water intake. Conditioned taste aversion. Amphetamine. Fenfluramine. Methamphetamine. p-Chloromethamphetamine. Chlorphentermine. Cocaine.
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The acute behavioral effects of cocaine were evaluated in open-field, elevated plus-maze and forced swimming tests. Results were compared between a group of 80 mice consuming a balanced diet and a high-fat diet, and a group of 80 mice fed a commercially available rodent chow formula Ralston Purina but receiving recombinant leptin rLeptin or saline ip. These results suggest that anxiolytic effects and increased general activity were induced by leptin in cocaine-treated mice and that low leptin levels are associated with behavioral depression. Chronic changes in diet composition producing high leptin levels or rLeptin treatment may result in an altered response to cocaine in ethologic tests that measure degrees of anxiety and depression, which could be attributed to an antagonistic effect of leptin. Behavioral changes induced by cocaine in mice are modified by a hyperlipidic diet or recombinant leptin. Correspondence and Footnotes E. Erhardt, L. Zibetti, J. Godinho, B. Bacchieri and H. It is currently recognized that appetite expression, body adiposity control, beginning of puberty, behavioral and affective changes, among other functions, are chemically coded in the hypothalamus. The derangement of neurochemical signaling in the hypothalamus by environmental, genetic and hormonal factors may produce hyperphagia, anorexia and anomalies of sexual development and gonadal function 1. Leptin, our study target, is a recently discovered hormone which was initially considered to be a feeding regulator 2,3. Leptin is produced in many organs and secreted mainly by adipose tissue. It plays an important role in the control of food ingestion, in the reproductive system and in several steps involved in metabolism, such as insulin secretion, lipolysis and glucose transport. However, one of its most important physiological roles is to signal the nutritional status during periods of food deprivation Leptin levels vary widely among individuals with similar body compositions and in depressed and anorectic patients, suggesting that factors other than body adiposity modulate leptin secretion In fact, the fat content of a meal and habitual dietary fat content, but not carbohydrate or protein intake, are important factors that can modify leptin secretion It has been observed that body mass index BMI, the quotient of weight kg divided by the square of the height m 2 can be correlated with serum leptin levels linearly in both men and women This relation was not seen in depressed patients, suggesting a disturbed regulation of leptin secretion in mood disorders In fact, these patients present more intense leptin secretion during the night when compared to normal subjects, despite a reported weight loss by the majority of patients A sexual dimorphism was seen between depressed and normal patients, with higher leptin levels in females There are other factors that suggest a role of leptin in mood disorders. Leptin stimulates the sympathetic nervous system whereas both galanin and neuropeptide Y NPY reduce sympathetic tone NPY has anxiolytic activity, and leptin, which antagonizes the action of NPY, may have anxiogenic effects In addition, leptin administration inhibits diencephalic nitric oxide synthase, thus increasing serotonin metabolism in mice Since serotonin has a role in depressive diseases, it is possible that leptin may play a role in mood regulation 13, The elevated consumption of foods rich in calories such as high-fat food, associated with low physical activity, have led to an increase in obesity in the developing world, particularly among children and adolescents 20, In addition, cocaine addiction represents another important problem in modern society and the consumption of this drug has been increasing among teenagers It has been extensively reported that cocaine alters the reward system, thus impairing the effects of natural rewards, such as eating, drinking, sex, and social interactions On this basis, it is important to determine a possible interaction between high-fat foods as enhancers of leptin production and behavioral changes induced by cocaine. Thus, the objective of the present study was to determine whether the acute behavioral effects of cocaine are influenced by exogenous treatment with leptin or by enhanced endogenous production of leptin through a high-fat diet. Animals were randomly divided into two groups of 40 animals each. During this period, the animals were weighed three times a week. According to the method reported by Lin et al. Drugs were administered 60 min before the open-field test, 30 min before the plus-maze test, and 24, 5, and 1 h before the forced swim test. Behavioral tests were applied once a day starting on the 46th day of the special diet, in the following order: open-field, elevated plus-maze and forced swimming test. The cages were carried to test rooms, illuminated with a red fluorescent light on the ceiling, and each test was recorded on a video recording system for further analysis. Thumbnail Table 1. Composition of the balanced and high-fat diets in macronutrients offered to the animals diet contained minerals and vitamins. Drugs were administered according to the same schedule as in Experiment 1. After an adaptation time of 1 week in our laboratory, mice were submitted to the behavioral tests in the same daily sequence as described in Experiment 1, i. All tests were performed in a quiet and dark room lighted by a red ceiling fluorescent lamp and behaviors were recorded on a video recording system for later analysis. The animal is placed inside a lighted arena from which it cannot escape, and patterns of ambulation and behaviors such as rearing, grooming, and defecation are observed for brief periods of time. The open-field used was a circular arena 90 cm in diameter, with a center circle 40 cm in diameter with cm high acrylic walls covered with white paper. The mouse was placed in the center of the arena and allowed to explore for 5 min The elevated plus-maze consisted of a black acrylic cross of two closed arms 30 x 5 x 15 cm and two open arms 30 x 5 cm raised 50 cm above the floor. For each test, the mouse was placed in the center of the cross facing an open arm and was allowed to explore the maze for 5 min. Behavior was recorded for analysis during the last 4 min of the test. It was noted that, if mice are forced to swim in an inevitable situation, first they present a vigorous attitude, as if looking for an exit, and later they remain immobile, performing only the movements necessary to keep their heads out of water. When significant differences were found, subgroup analysis was performed with the Student-Newman-Keuls test using the statistical package Sigma Stat for Windows, version 2. No difference in body weight gain was observed between mice that received a balanced diet and mice that received a high-fat diet. High-fat-fed mice were less susceptible to the stimulant effects of cocaine when compared to mice that received a balanced diet. The latter presented an increase in locomotion and exploration when compared to the former. In Experiment 2 there was no interaction between leptin and cocaine. Administration of leptin did not alter the locomotor stimulant effects of cocaine. Regarding grooming behavior, in Experiment 1, the group of mice that received a high-fat diet showed lower intensity compared to the group of mice maintained on a balanced diet Table 2. However, in Experiment 2, administration of leptin did not change the increase in grooming that followed cocaine administration Table 3. Interaction between cocaine and the hormonal condition was observed for some behaviors. Thumbnail Table 2. Ethologic evaluation of anxiety signs in mice fed a balanced or high-fat diet and exposed to cocaine. Open-field test experiment 1. Thumbnail Table 3. Ethologic evaluation of anxiety signs in mice exposed to different cocaine and recombinant leptin rLeptin doses. Open-field test. Thumbnail Table 4. Evaluation of the anxiolytic effects of a balanced or high-fat diet in mice exposed to cocaine. Plus-maze test experiment 1. Thumbnail Table 5. Evaluation of the anxiolytic effects of different recombinant leptin rLeptin doses in mice exposed to cocaine. Plus-maze test experiment 2. Thumbnail Table 6. Behavioral evaluation of the antidepressant activities of a balanced or high-fat diet in mice exposed to cocaine. Forced swimming test experiment 1. Thumbnail Table 7. Behavioral evaluation of the antidepressant activities of different doses of recombinant leptin rLeptin in mice exposed to cocaine. Forced swimming test experiment 2. In rodents, high-fat intake may be associated with increased serum leptin and obesity, and these leptin levels are related to the amount of body lipid 13, It was our objective to compare data for high-fat-fed mice with those for mice receiving a dose of rLeptin, in behavioral tests in order to detect changes in animal behavior due to leptin. In contrast to other methods used to study anxious behavior in rodents, such as the elevated plus-maze, the open-field test allows a comprehensive description of the animal's behavior, since more behaviors can be readily observed and quantified 30, Locomotion, a behavioral that can be interpreted as an adaptation to a stressful situation, was affected by an interaction between high-fat or balanced diets and cocaine or saline treatments in the first experiment. In Experiment 2, mice that had received cocaine also showed significant hyperactivity and leptin decreased this effect. Therefore, the results demonstrate that mice treated with cocaine display higher locomotion and that a high-fat diet or leptin treatment decrease this behavioral effect This could be interpreted as an antagonism of leptin against the effects of cocaine. It might be suggested that the effect of leptin is an adaptation to stressful situations. Grooming behavior might also be considered to be an index of behavioral adaptation to a stressful situation. Increased grooming behavior has been related to fear or an increased emotional response, and has been associated with conflict or frustration in different species. Cocaine treatment induces an increase in grooming, but this effect was dependent on the diet. The mice fed a high-fat diet displayed lower frequencies of grooming compared to mice fed a balanced diet. Leptin treatment also decreased grooming behaviors after cocaine treatment. All of these results point to a possible anxiolytic effect of leptin in the open-field test. As pointed out by Rogerio and Takahashi 35 in their experiment about the anxiogenic action of cocaine in mice, the ability of cocaine to induce anxiogenic effects in mice may depend, at least in part, on the animals' emotional state. They proposed that repeated handling made animals less anxious and more susceptible to the anxiogenic effects of cocaine. They concluded that a single cocaine injection induces anxiogenic-like effects in handling-habituated mice, while repeated injections of the drug did not alter the indices of anxiety as measured in the elevated plus-maze. This could be the case for our mice on special diets that were handled every two or three days. However, our animals showed the opposite effect with cocaine - an 'anxiolytic' effect in mice on a high-fat diet or receiving leptin spent more time in the open arms. Also important to note is that the anxiolytic effect of leptin became more evident in those animals exposed to the highest dose of cocaine, i. This effect has been rarely reported by other laboratories, but has been seen with Wistar rats in our laboratory Loebens M and Barros HMT, unpublished data on other occasions. The explanation for this effect still needs to be determined. We believe that cocaine decreases risk evaluation by the animals and induces open-arm entries in spite of the risk involved, due to the impulsivity-induced effect. High-fat-fed animals showed less immobility, spent more time swimming and climbing, and presented higher values of swimming frequency compared to mice fed a balanced diet. These results are consistent with the findings of Collin et al. In addition, a clinical study performed by Kraus and colleagues 37 showed low levels of leptin in depressed patients. In contrast, we found no difference in immobility between mice treated or not with leptin. Frederich and co-workers 29 demonstrated that a high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, and high levels of leptin have been shown to increase energy expenditure. However, it is important to point out that, when animals on each diet type were divided into two groups - above or below the mean weight gain of control animals - no differences in behavior were detected between these groups. Leptin exerts its action through several other hormones in a cascade of reactions involving, for example, cocaine- and amphetamine-regulated transcripts CART. These CART peptides are neurotransmitters that have received much attention as mediators of feeding behavior and body weight regulation in mammals, and animal studies have demonstrated that CART expression is regulated by both leptin and glucocorticoids CART have also been implicated in the behavioral and neuroendocrine effects of leptin On the other hand, CART peptides have a role in drug abuse. It is important to note that injection of CART peptides into the VTA caused a small increase in locomotor activity and promoted conditioned place preference, suggesting that CART has psychostimulant-like effects. However, co-treatment of the animals with both intra-VTA CART and systemic cocaine produced only partially additive effects, and this additivity seemed to occur at lower concentrations of the drugs. At higher doses, CART tended to oppose the locomotor activity induced by systemic cocaine, acting as a functional 'partial agonist' in the VTA Also, we observed an increased anxiolytic effect as shown by an increase in percent time spent in the open arms in the elevated plus-maze test with increasing doses of cocaine and leptin. Mice that had received cocaine and no leptin showed higher locomotion values. Thus, we may conclude that leptin can change the effects of cocaine in mice by increasing CART expression, as reported in other studies. We have demonstrated that animals exposed to high leptin levels evoked by a high-fat diet or to rLeptin treatment can change the behavioral effects induced by cocaine in ethologic tests that measure degrees of anxiety and depression. Further studies are necessary to validate these findings and establish a link between cocaine effects and nutritional status in humans. Address for correspondence: E. Neuza G. Brizola, , Apto. E-mail: eerhardt terra. Received May 18, Accepted August 21, Open menu Brazil. Brazilian Journal of Medical and Biological Research. Open menu. Text EN Text English. Mice; Cocaine; Leptin; Hyperlipidic diet; Interaction. Braz J Med Biol Res, December , Volume 39 12 Behavioral changes induced by cocaine in mice are modified by a hyperlipidic diet or recombinant leptin Correspondence and Footnotes E. Key words: Mice, Cocaine, Leptin, Hyperlipidic diet, Interaction Introduction It is currently recognized that appetite expression, body adiposity control, beginning of puberty, behavioral and affective changes, among other functions, are chemically coded in the hypothalamus. Experiment 1: high-fat diet Animals were randomly divided into two groups of 40 animals each. Table 1. Table 2. Table 3. Table 4. Table 5. Table 6. Table 7. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev ; Endocrinology ; Inui A. 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Neuroendocrinology ; Suomalainen M, Mannisto PT. Lack of effect of leptin on the behaviour of mice predicting the level of anxiety and depression. Pharmacol Toxicol ; J Diabetes Complications ; Trends in drug use among students in Brazil: analysis of four surveys in , , and Braz J Med Biol Res ; Blockade of the leptin-sensitive pathway markedly reduces alcohol consumption in mice. Alcohol Clin Exp Res ; Accessed October 12, Leptin: genes, concepts and clinical perspective. Horm Res ; Manual of therapeutics for addictions 1st edn. Pharmacokinetics of human leptin in mice and rhesus monkeys. Harro J. Measurement of exploratory behavior in rodents. J Neurosci Methods ; Andreatini R, Bacellar LF. The relationship between anxiety and depression in animal models: a study using the forced swimming test and elevated plus-maze. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med ; 1: An animal model for measuring behavioral responses to anxiogenic and anxiolytic manipulations. Pharmacol Biochem Behav ; Animal models of anxiety: an ethological perspective. Leptin decreases feeding and exploratory behaviour via interactions with CCK 1 receptors in the rat. Neuropharmacology ; The effects of GABAergic drugs on grooming behaviour in the open field. Lister RG. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology ; Rogerio R, Takahashi RN. Anxiogenic action of acute but not repeated cocaine administration in handling-habituated mice in the plus-maze test. Brain Res Mol Brain Res ; Low leptin levels but normal body mass indices in patients with depression or schizophrenia. CART in feeding and obesity. Effect of leptin administration versus re-feeding on hypothalamic neuropeptide gene expression in fasted male rats. Can J Physiol Pharmacol ; Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets. History Received 18 May Accepted 21 Aug This work is licensed under a Creative Commons Attribution 4. Tables 7. Stay informed of issues for this journal through your RSS reader. PDF English. Google Google Scholar.
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