RESUMEN
Cytochrome P450 2D (CYP2D) is important in psychopharmacology as it is engaged in the metabolism of drugs, neurosteroids and neurotransmitters. An unbalanced maternal diet during pregnancy and lactation can cause neurodevelopmental abnormalities and increases the offspring's predisposition to neuropsychiatric diseases. The aim of the present study was to evaluate the effect of maternal modified types of diet: a high-fat diet (HFD) and high-carbohydrate diet (HCD) during pregnancy and lactation on CYP2D in the liver and brain of male offspring at 28 (adolescent) or 63 postnatal days (young adult). The CYP2D activity and protein level were measured in the liver microsomes and the levels of mRNAs of CYP2D1, 2D2 and 2D4 were investigated both in the liver and brain. In the liver, both HFD and HCD increased the mRNA levels of all the three investigated CYP2D genes in adolescents, but an opposite effect was observed in young adults. The CYP2D protein level increased in adolescents but not in young adults. In contrast, young adults showed significantly decreased CYP2D activity. Similar effect of HFD on the CYP2D mRNAs was observed in the prefrontal cortex, while the effect of HCD was largely different than in the liver (the CYP2D2 expression was not affected, the CYP2D4 expression was decreased in young adults). In conclusion, modified maternal diets influence the expression of individual CYP2D1, CYP2D2 and CYP2D4 genes in the liver and brain of male offspring, which may affect the metabolism of CYP2D endogenous substrates and drugs and alter susceptibility to brain diseases and pharmacotherapy outcome.
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Encéfalo , Dieta Alta en Grasa , Lactancia , Hígado , Efectos Tardíos de la Exposición Prenatal , Animales , Embarazo , Femenino , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Encéfalo/metabolismo , Ratas , Masculino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Familia 2 del Citocromo P450/metabolismo , Familia 2 del Citocromo P450/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Microsomas Hepáticos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Ratas WistarRESUMEN
The lack of selective pharmacological tools has limited the full unraveling of G protein-coupled receptor 18 (GPR18) functions. The present study was aimed at discovering the activities of three novel preferential or selective GPR18 ligands, one agonist (PSB-KK-1415) and two antagonists (PSB-CB-5 and PSB-CB-27). We investigated these ligands in several screening tests, considering the relationship between GPR18 and the cannabinoid (CB) receptor system, and the control of endoCB signaling over emotions, food intake, pain sensation, and thermoregulation. We also assessed whether the novel compounds could modulate the subjective effects evoked by Δ9-tetrahydrocannabinol (THC). Male mice or rats were pretreated with the GPR18 ligands, and locomotor activity, depression- and anxiety-like symptoms, pain threshold, core temperature, food intake, and THC-vehicle discrimination were measured. Our screening analyses indicated that GPR18 activation partly results in effects that are similar to those of CB receptor activation, considering the impact on emotional behavior, food intake, and pain activity. Thus, the orphan GPR18 may provide a novel therapeutic target for mood, pain, and/or eating disorders, and further investigation is warranted to better discern its function.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Roedores , Ratas , Masculino , Ratones , Animales , Ligandos , Dolor/tratamiento farmacológico , Receptores de Cannabinoides , Dronabinol/farmacología , Receptor Cannabinoide CB1 , Relación Dosis-Respuesta a Droga , Receptores Acoplados a Proteínas GRESUMEN
A maternal high-fat diet (HFD) provokes changes in the offspring's brain's structure, function, and development. These changes may cause neuropsychiatric disorders in the early life of offspring the basis of which may be memory impairment. In this study, the effects of maternal HFD during pregnancy and lactation on the short-term memory in adolescent and young adult offspring were evaluated. We analyzed the expression of genes encoding the glutamatergic transporters in the hippocampus to verify the association between changes in glutamatergic transporters and behavioral changes in offspring. Next, we examined whether maternal diet-induced changes in the mRNA levels of genes encoding the NMDA receptor subunits and the AMPA receptor subunits, as well as BDNF in this structure in offspring. All significant changes were validated at the protein level. We found that a maternal HFD during pregnancy and lactation disrupts short-term memory in adolescent and young adult females. The latter change is likely related to the dysregulation of hippocampal levels of GluN2B subunit of NMDA receptors and of reduced levels of BDNF. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several changes within the glutamatergic system in the hippocampus of rat offspring, which may be related to producing behavioral changes in offspring.
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Dieta Alta en Grasa , Efectos Tardíos de la Exposición Prenatal , Embarazo , Ratas , Animales , Femenino , Humanos , Dieta Alta en Grasa/efectos adversos , Memoria a Corto Plazo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Lactancia , Hipocampo/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos/fisiologíaRESUMEN
Recent years have provided more and more evidence confirming the important role of Wnt/ß-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding ß-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and ß-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder.
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Trastornos Relacionados con Cocaína , Cocaína , MicroARNs , Animales , Ratas , Masculino , Cocaína/farmacología , beta Catenina/genética , beta Catenina/metabolismo , Preparaciones Farmacéuticas , Vía de Señalización Wnt , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/metabolismo , Hipocampo/metabolismoRESUMEN
Drug addiction is a devastating disorder with a huge economic and social burden for modern society. Although an individual may slip into drug abuse throughout his/her life, adolescents are at higher risk, but, so far, only a few studies have attempted to elucidate the underlying cellular and molecular bases of such vulnerability. Indeed, preclinical evidence indicates that psychostimulants and adolescence interact and contribute to promoting a dysfunctional brain. In this review, we have focused our attention primarily on changes in neuroplasticity brought about by cocaine, taking into account that there is much less evidence from exposure to cocaine in adolescence, compared with that from adults. This review clearly shows that exposure to cocaine during adolescence, acute or chronic, as well as contingent or non-contingent, confers a vulnerable endophenotype, primarily, by causing changes in neuroplasticity. Given the close relationship between drug abuse and psychiatric disorders, we also discuss the translational implications providing an interpretative framework for clinical studies involving addictive as well as affective or psychotic behaviours. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.
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Cocaína , Trastornos Mentales , Adolescente , Cocaína/efectos adversos , Femenino , Humanos , Masculino , Modelos Teóricos , Plasticidad NeuronalRESUMEN
Epidemiological and preclinical studies suggest that maternal obesity increases the risk of autism spectrum disorder (ASD) in offspring. Here, we assessed the effects of exposure to modified maternal diets limited to pregnancy and lactation on brain development and behavior in rat offspring of both sexes. Among the studied diets, a maternal high-fat diet (HFD) disturbed the expression of ASD-related genes (Cacna1d, Nlgn3, and Shank1) and proteins (SHANK1 and TAOK2) in the prefrontal cortex of male offspring during adolescence. In addition, a maternal high-fat diet induced epigenetic changes by increasing cortical global DNA methylation and the expression of miR-423 and miR-494. As well as the molecular changes, behavioral studies have shown male-specific disturbances in social interaction and an increase in repetitive behavior during adolescence. Most of the observed changes disappeared in adulthood. In conclusion, we demonstrated the contribution of a maternal HFD to the predisposition to an ASD-like phenotype in male adolescent offspring, while a protective effect occurred in females.
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Alimentación Animal/efectos adversos , Trastorno Autístico/etiología , Exposición a Riesgos Ambientales/efectos adversos , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Animales , Metilación de ADN , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Epigénesis Genética , Femenino , Edad Gestacional , Lactancia , Fenotipo , Embarazo , Ratas , Factores SexualesRESUMEN
Autism spectrum disorder (ASD) is a disruptive neurodevelopmental disorder manifested by abnormal social interactions, communication, emotional circuits, and repetitive behaviors and is more often diagnosed in boys than in girls. It is postulated that ASD is caused by a complex interaction between genetic and environmental factors. Epigenetics provides a mechanistic link between exposure to an unbalanced maternal diet and persistent modifications in gene expression levels that can lead to phenotype changes in the offspring. To better understand the impact of the early development environment on the risk of ASD in offspring, we assessed the effect of maternal high-fat (HFD), high-carbohydrate, and mixed diets on molecular changes in adolescent and young adult offspring frontal cortex and hippocampus. Our results showed that maternal HFD significantly altered the expression of 48 ASD-related genes in the frontal cortex of male offspring. Moreover, exposure to maternal HFD led to sex- and age-dependent changes in the protein levels of ANKRD11, EIF4E, NF1, SETD1B, SHANK1 and TAOK2, as well as differences in DNA methylation levels in the frontal cortex and hippocampus of the offspring. Taken together, it was concluded that a maternal HFD during pregnancy and lactation periods can lead to abnormal brain development within the transcription and translation of ASD-related genes mainly in male offspring.
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Ascomicetos/efectos de los fármacos , Ascomicetos/metabolismo , Trastorno del Espectro Autista/etiología , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos de la Nutrición Prenatal , Envejecimiento , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Embarazo , ARN/genética , ARN/metabolismo , Distribución Aleatoria , Ratas , Factores de Riesgo , Maduración Sexual , TranscriptomaRESUMEN
In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring's brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.
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Depresión/genética , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales Maternos/genética , Efectos Tardíos de la Exposición Prenatal/genética , Receptor Cannabinoide CB1/metabolismo , Animales , Conducta Animal , Encéfalo/metabolismo , Epigénesis Genética , Femenino , Expresión Génica , Lactancia/genética , Masculino , Embarazo , RatasRESUMEN
BACKGROUND: Recent studies have shown a relationship between the composition of the maternal diet and acquiring a risk of mental illnesses through changes in the offspring's brain. This study assessed the role of a modified maternal diet on the levels of serotonin (5-HT)2C and 5-HT2A receptors in the offspring brain. METHODS: Wistar rat dams during gestation and lactation were maintained either on a standard (SD) or special diets: high-fat (HFD), high-carbohydrate (rich in sucrose, HCD) or mixed (MD). Offspring were weaned to SD after lactation, and at postnatal days (PNDs) 28 and 63 changes in the 5-HT2C and 5-HT2A receptor levels were evaluated in their prefrontal cortex (PFCx), nucleus accumbens (NAc), dorsal striatum (DSTR) and hippocampus (HIP). RESULTS: Maternal HFD reduced the expression of 5-HT2C receptors in male rats at PND 28 in the PFCx, NAc, and DSTR but increased it at PND 63 in male animals in the NAc and DSTR. HCD induced a decrease in the expression of 5-HT2C receptors in male offspring at PND 28 but increased it in female rats at PND 63 in the PFCx. MD reduced 5-HT2C receptor expression in males at PND 28 in the PFCx and increased it in male and female offspring at PND 28 in the HIP. Moreover, maternal HFD reduced 5-HT2A receptor levels within the PFCx in adolescent male offspring. CONCLUSION: Our findings indicate that a modified maternal diet induces age- and sex-specific adaptive changes mainly in 5-HT2C receptors, which may contribute to disturbances in the offspring brain.
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Encéfalo/metabolismo , Conducta Alimentaria/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , Serotonina/metabolismoRESUMEN
A balanced maternal diet is essential for proper fetal development, and the consumption of a nutritionally inadequate diet during intrauterine development and early childhood is associated with a significantly increased risk of metabolic and brain disorders in offspring. The current literature indicates that maternal exposure to a high-fat diet exerts an irreversible influence on the general health of the offspring. This review of preclinical research examines the relationship between a maternal high-fat diet during pregnancy or lactation and metabolic changes, molecular alterations in the brain, and behavioral disorders in offspring. Animal models indicate that offspring exposed to a maternal high-fat diet during pregnancy and lactation manifest increased depressive-like and aggressive behaviors, reduced cognitive development, and symptoms of metabolic syndrome. Recently, epigenetic and molecular studies have shown that maternal nutrition during pregnancy and the suckling period modifies the development of neurotransmitter circuits and many other factors important to central nervous system development. This finding confirms the importance of a balanced maternal diet for the health of offspring.
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Dieta Alta en Grasa , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal , Animales , Lactancia Materna/estadística & datos numéricos , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Lactancia/fisiología , EmbarazoRESUMEN
Environmental factors such as maternal diet, determine the pathologies that appear early in life and can persist in adulthood. Maternally modified diets provided through pregnancy and lactation increase the predisposition of offspring to the development of many diseases, including obesity, diabetes, and neurodevelopmental and mental disorders such as depression. Fetal and early postnatal development are sensitive periods in the offspring's life in which maternal nutrition influences epigenetic modifications, which results in changes in gene expression and affects molecular phenotype. This study aimed to evaluate the impact of maternal modified types of diet, including a high-fat diet (HFD), high-carbohydrate diet (HCD) and mixed diet (MD) during pregnancy and lactation on phenotypic changes in rat offspring with respect to anhedonia, depressive- and anxiety-like behavior, memory impairment, and gene expression profile in the frontal cortex. Behavioral results indicate that maternal HFD provokes depressive-like behavior and molecular findings showed that HFD leads to persistent transcriptomics alterations. Moreover, a HFD significantly influences the expression of neuronal markers specific to excitatory and inhibitory cortical neurons. Collectively, these experiments highlight the complexity of the impact of maternal modified diet during fetal programming. Undoubtedly, maternal HFD affects brain development and our findings suggest that nutrition exerts significant changes in brain function that may be associated with depression.
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Efectos Tardíos de la Exposición Prenatal , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Fenotipo , Embarazo , Ratas , Ratas WistarRESUMEN
Cocaine induces neuronal changes as well as non-neuronal (astrocytes, microglia, oligodendroglia) mechanisms, but these changes can also be modulated by various types of drug abstinence. Due to the very complex and still incompletely understood nature of cocaine use disorder, understanding of the mechanisms involved in addictive behavior is necessary to further search for effective pharmacotherapy of this disease. The aim of this study was to investigate changes at the gene and protein levels associated with glial cell activity after cocaine exposure, as well as during early cocaine abstinence (3 days) with extinction training or in home cage isolation. Cocaine self-administration significantly decreased myelin regulatory factor (MYRF) and cyclic nucleotide phosphodiesterase (CNP) expression in the hippocampus as well as pleckstrin (PLEK) and T-lymphocyte activation antigen (CD86) in the rat striatum. Depending on cocaine abstinence conditions, microglial PLEK expression was increased through extinction training but did not change in the home cage isolation. In addition, downregulation of gene expression associated with oligodendrocytes (CNP, MYRF) and microglia regulator of G protein signaling 1 (RGS1) was observed in the hippocampus, regardless of the type of drug abstinence, while downregulation of myelin and lymphocyte protein (MAL) expression was found only in rats exposed to abstinence in the home cage. Taken together, the presented results strongly suggest that cocaine abstinence evokes significant changes in gene expression associated with the proper functioning of glial cells, suggesting their significant involvement in adaptive changes in the brain associated with cocaine exposure. Interestingly, drug abstinence conditions are important factors influencing observed changes at the transcript levels of selected genes, which may be of clinical interest.
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Trastornos Relacionados con Cocaína/metabolismo , Cocaína/efectos adversos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/efectos de los fármacos , Neuroglía/metabolismo , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/genética , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/metabolismo , Animales , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Trastornos Relacionados con Cocaína/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Extinción Psicológica , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Neuroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismo , Ratas , Autoadministración , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Depression and cocaine use disorder represent frequent co-current diagnoses and the GABAB receptors are involved in both conditions. This research involved the application of the animal model of depression (bulbectomy, OBX) and cocaine use disorder (self-administration) to assess the efficiency of GABAB receptor agonists, baclofen and SKF-97541, on cocaine rewarding property and reinforcement of seeking-behaviors in rats with depressive phenotype. Additionally, we applied immunoreactive techniques to determine changes in the expression of GABAB receptor subunit 1 and 2 in rats with depression and cocaine addiction. The results obtained the study illustrate that the GABAB receptor agonists reduced the rewarding property of cocaine in both OBX and control (SHAM) rats. Both agonists significantly reduced cue- and cocaine-induced reinstatement in both groups. This is the first report demonstrating a different impact of cocaine abuse on GABAB receptor levels in depressed animals. It was documented that the expression of GABAB1 subunit in the infralimbic cortex increased during self-administration and extinction training in OBX animals. The lower level of expression for this subunit in addictive SHAM rats during self-administration, and increased in extinguished addictive OBX rats was found in the ventrolateral striatum. The expression of GABAB2 subunit changed only in the case of cocaine self-administration paradigm, as a decline of the subunit level in the nucleus accumbens and ventral hippocampus was observed only in OBX rats. The relevance of GABAB receptors in depression and addiction comorbidity is clearly implicated and can open a new era of drug discovery for individuals with dual diagnosis.
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Baclofeno/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/farmacología , Depresión/metabolismo , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Agonistas de Receptores GABA-B/farmacología , Compuestos Organofosforados/farmacología , Receptores de GABA-B/efectos de los fármacos , Refuerzo en Psicología , Animales , Conducta Adictiva/metabolismo , Conducta Adictiva/fisiopatología , Conducta Adictiva/psicología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Depresión/fisiopatología , Depresión/psicología , Modelos Animales de Enfermedad , Masculino , Ratas Wistar , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , RecompensaRESUMEN
Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopamine (DA) neurotransmission within the mesocorticolimbic circuitry of the brain followed by the activation of DA receptors. D2 receptors were proposed as important molecular targets for SUD. The findings showed that D2 receptors formed heteromeric complexes with other GPCRs, which forced the addiction research area in new directions. In this review, we updated the view on the brain D2 receptor complexes with adenosine (A)2A receptors (A2AR) and discussed the role of A2AR in different aspects of addiction phenotypes in laboratory animal procedures that permit the highly complex syndrome of human drug addiction. We presented the current knowledge on the neurochemical in vivo and ex vivo mechanisms related to cocaine use disorder (CUD) and discussed future research directions for A2AR heteromeric complexes in SUD.
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Cocaína/efectos adversos , Receptor de Adenosina A2A/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Animales , Conducta , Encéfalo/metabolismo , Modelos Animales de Enfermedad , HumanosRESUMEN
Maternal diet significantly influences the proper development of offspring in utero. Modifications of diet composition may lead to metabolic and mental disorders that may predispose offspring to a substance use disorder. We assessed the impact of a maternal high-sugar diet (HSD, rich in sucrose) consumed during pregnancy and lactation on the offspring phenotype in the context of the rewarding and motivational effects of cocaine and changes within the central melanocortin (MC) system. Using an intravenous cocaine self-administration model, we showed that maternal HSD leads to increased relapse of cocaine-seeking behavior in male offspring. In addition, we demonstrated that cocaine induces changes in the level of MC-4 receptors in the offspring brain, and these changes depend on maternal diet. These studies also reveal that an MC-4 receptor antagonist reduces the reinstatement of cocaine-seeking behavior, and offspring exposed to maternal HSD are more sensitive to its effects than offspring exposed to the maternal control diet. Taken together, the results suggest that a maternal HSD and MC-4 receptors play an important role in cocaine relapse.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Cocaína/administración & dosificación , Dieta/efectos adversos , Comportamiento de Búsqueda de Drogas , Extinción Psicológica , Receptor de Melanocortina Tipo 4/metabolismo , Azúcares/toxicidad , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Trastornos Relacionados con Cocaína/patología , Femenino , Masculino , Exposición Materna/efectos adversos , Embarazo , Ratas Wistar , Receptor de Melanocortina Tipo 4/genética , AutoadministraciónRESUMEN
Recent studies have emphasized the role of the maternal diet in the development of mental disorders in offspring. Substance use disorder is a major global health and economic burden. Therefore, the search for predisposing factors for the development of this disease can contribute to reducing the health and social damage associated with addiction. In this study, we focused on the impact of the maternal diet on changes in melanocortin-4 (MC-4) receptors as well as on behavioral changes related to cocaine addiction. Rat dams consumed a high-fat diet (HFD), high-sugar diet (HSD, rich in sucrose), or mixed diet (MD) during pregnancy and lactation. Using an intravenous cocaine self-administration model, the susceptibility of female offspring to cocaine reward and cocaine-seeking propensities was evaluated. In addition, the level of MC-4 receptors in the rat brain structures related to cocaine reward and relapse was assessed. Modified maternal diets did not affect cocaine self-administration in offspring. However, the maternal HSD enhanced cocaine-seeking behavior in female offspring. In addition, we observed that the maternal HSD and MD led to increased expression of MC-4 receptors in the nucleus accumbens, while increased MC-4 receptor levels in the dorsal striatum were observed after exposure to the maternal HSD and HFD. Taken together, it can be concluded that a maternal HSD is an important factor that triggers cocaine-seeking behavior in female offspring and the expression of MC-4 receptors.
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Dieta/efectos adversos , Comportamiento de Búsqueda de Drogas/fisiología , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Conducta Animal/fisiología , Cocaína , Dieta/métodos , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , RecompensaRESUMEN
BACKGROUND: There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder. METHODS: The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin. RESULTS: Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597. CONCLUSIONS: In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.
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Antidepresivos/farmacología , Núcleo Accumbens/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Acetilcisteína/farmacología , Animales , Autorradiografía , Benzamidas/farmacología , Encéfalo/metabolismo , Carbamatos/farmacología , Citalopram/farmacología , Imipramina/farmacología , Ketanserina , Masculino , Ratas , Ratas Wistar , Tiazepinas/farmacologíaRESUMEN
Preclinical data indicate that ethanol produces behavioral effects that can be regulated by many neurotransmitters and neuromodulators like adenosine (A). The most important receptors with respect to the rewarding effects of ethanol seem to be the A2A receptors. This study used a transgenic strategy, specifically rats overexpressing the A2A receptor, to characterize the neurobiological mechanisms of ethanol consumption as measured by intermittent access to 20% ethanol in a two-bottle choice paradigm. In this model, no change in ethanol consumption was observed in transgenic animals compared to wild type controls during the acquisition/maintenance phase. Following alcohol deprivation, only transgenic rats overexpressing the A2A receptor exhibited escalation of ethanol consumption and drank more (by ca. 90%), but not significantly, ethanol than did the wild type rats. During ethanol withdrawal, the immobility time of rats overexpressing the A2A receptor in the forced swim test was lower than that of wild type rats. Moreover, transgenic rats withdrawn from ethanol, compared to the drug-naive transgenic animals, exhibited an increase above 70% in locomotion. The results indicated that the overexpression of A2A receptors may be a risk factor for the escalation of ethanol consumption despite the reduction in depression-like signs of ethanol withdrawal.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Consumo de Bebidas Alcohólicas/efectos adversos , Etanol/farmacología , Locomoción/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Adenosina/farmacología , Animales , Masculino , Ratas Transgénicas , Receptor de Adenosina A2A , Síndrome de Abstinencia a Sustancias/etiologíaRESUMEN
The endocannabinoid (eCB) system plays a significant role in the pathophysiology of depression. The potential participation of this system in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the expression of cannabinoid (CB) receptors using Western blot and CB1 receptor density using autoradiography after acute or chronic administration of antidepressant drugs [imipramine (IMI, 15mg/kg), escitalopram (ESC, 10mg/kg) and tianeptine (TIA, 10mg/kg)]. Antidepressants given chronically elevated CB1 receptor density in the cortical structures and hippocampal areas, while a decrease of CB1 receptor density was observed in the striatum after IMI and ESC treatment. The CB1 receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC or the receptor rise in the hippocampus after chronic ESC and TIA treatment were confirmed using Western blot analyses. An increase in the CB2 receptor expression was observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression was noted in the striatum and cerebellum after chronic IMI treatment. Our results provide clear evidence that the antidepressant exposures provoke some modulations within the eCB system through CB receptors.
Asunto(s)
Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Animales , Autorradiografía , Encéfalo/anatomía & histología , Masculino , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismoRESUMEN
A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB1 receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB2 receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB1 receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).