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The global prevalence of overweight and obesity is a significant public health concern that also largely affects women of childbearing age. Human epidemiological studies indicate that prenatal exposure to excessive maternal weight or excessive gestational weight gain is linked to various neurodevelopmental disorders in children, including attention deficit hyperactivity disorder, autism spectrum disorder, internalizing and externalizing problems, schizophrenia, and cognitive/intellectual impairment. Considering that inadequate maternal body mass can induce serious disorders in offspring, it is important to increase efforts to prevent such outcomes. In this paper, we review human studies linking excessive maternal weight and the occurrence of mental disorders in children.
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Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Criança , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Ganho de Peso na Gestação , Obesidade/epidemiologiaRESUMO
Aim: Schizophrenia involves complex interactions between biological and environmental factors, including childhood trauma, cognitive impairments, and premorbid adjustment. Predicting its severity and progression remains challenging. Biomarkers like glial cell line-derived neurotrophic factor (GDNF) and miRNA-29a may bridge biological and environmental aspects. The goal was to explore the connections between miRNAs and neural proteins and cognitive functioning, childhood trauma, and premorbid adjustment in the first episode of psychosis (FEP). Method: This study included 19 FEP patients who underwent clinical evaluation with: the Childhood Trauma Questionnaire (CTQ), the Premorbid Adjustment Scale (PAS), the Positive and Negative Syndrome Scale (PANSS), and the Montreal Cognitive Assessment Scale (MoCA). Multiplex assays for plasma proteins were conducted with Luminex xMAP technology. Additionally, miRNA levels were quantitatively determined through RNA extraction, cDNA synthesis, and RT-qPCR on a 7500 Fast Real-Time PCR System. Results: Among miRNAs, only miR-29a-3p exhibited a significant correlation with PAS-C scores (r = -0.513, p = 0.025) and cognitive improvement (r = -0.505, p = 0.033). Among the analyzed proteins, only GDNF showed correlations with MoCA scores at the baseline and after 3 months (r = 0.533, p = 0.0189 and r = 0.598, p = 0.007), cognitive improvement (r = 0.511, p = 0.025), and CTQ subtests. MIF concentrations correlated with the PAS-C subscale (r = -0.5670, p = 0.011). Conclusion: GDNF and miR-29a-3p are promising as biomarkers for understanding and addressing cognitive deficits in psychosis. This study links miRNA and MIF to premorbid adjustment and reveals GDNF's unique role in connection with childhood trauma.
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The problem of an unbalanced diet, overly rich in fats, affects a significant proportion of the population, including women of childbearing age. Negative metabolic and endocrine outcomes for offspring associated with maternal high-fat diet during pregnancy and/or lactation are well documented in the literature. In this paper, we present our findings on the little-studied effects of this diet on NMDA receptors and cognitive functions in offspring. The subject of the study was the rat offspring born from dams fed a high-fat diet before mating and throughout pregnancy and lactation. Using a novel object location test, spatial memory impairment was detected in adolescent offspring as well as in young adult female offspring. The recognition memory of the adolescent and young adult offspring remained unaltered. We also found multiple alterations in the expression of the NMDA receptor subunits, NMDA receptor-associated scaffolding proteins, and selected microRNAs that regulate the activity of the NMDA receptor in the medial prefrontal cortex and the hippocampus of the offspring. Sex-dependent changes in glutamate levels were identified in extracellular fluid obtained from the medial prefrontal cortex and the hippocampus of the offspring. The obtained results indicate that a maternal high-fat diet during pregnancy and lactation can induce in the offspring memory disturbances accompanied by alterations in NMDA receptor expression.
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Dieta Hiperlipídica , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Lactação/metabolismo , Transtornos da Memória , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato , Memória EspacialRESUMO
A high-calorie diet has contributed greatly to the prevalence of overweight and obesity worldwide for decades. These conditions also affect pregnant women and have a negative impact on the health of both the woman and the fetus. Numerous studies indicate that an unbalanced maternal diet, rich in sugars and fats, can influence the in utero environment and, therefore, the future health of the child. It has also been shown that prenatal exposure to an unbalanced diet might permanently alter neurotransmission in offspring. In this study, using a rat model, we evaluated the effects of a maternal high-sugar diet on the level of extracellular glutamate and the expression of key transporters crucial for maintaining glutamate homeostasis in offspring. Glutamate concentration was assessed in extracellular fluid samples collected from the medial prefrontal cortex and hippocampus of male and female offspring. Analysis showed significantly increased glutamate levels in both brain structures analyzed, regardless of the sex of the offspring. These changes were accompanied by altered expression of the EAAT1, VGLUT1, and xc- proteins in these brain structures. This animal study further confirms our previous findings that a maternal high-sugar diet has a detrimental effect on the glutamatergic system.
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Ácido Glutâmico , Efeitos Tardios da Exposição Pré-Natal , Animais , Encéfalo/metabolismo , Dieta , Dieta Hiperlipídica , Feminino , Ácido Glutâmico/metabolismo , Homeostase , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , AçúcaresRESUMO
Cognitive impairment affects patients suffering from various neuropsychiatric diseases, which are often accompanied by changes in the glutamatergic system. Epidemiological studies indicate that predispositions to the development of neuropsychiatric diseases may be programmed prenatally. Mother's improper diet during pregnancy and lactation may cause fetal abnormalities and, consequently, predispose to diseases in childhood and even adulthood. Considering the prevalence of obesity in developed countries, it seems important to examine the effects of diet on the behavior and physiology of future generations. We hypothesized that exposure to sugar excess in a maternal diet during pregnancy and lactation would affect memory as the NMDA receptor-related processes. Through the manipulation of the sugar amount in the maternal diet in rats, we assessed its effect on offspring's memory. Then, we evaluated if memory alterations were paralleled by molecular changes in NMDA receptors and related modulatory pathways in the prefrontal cortex and the hippocampus of adolescent and young adult female and male offspring. Behavioral studies have shown sex-related changes like impaired recognition memory in adolescent males and spatial memory in females. Molecular results confirmed an NMDA receptor hypofunction along with subunit composition abnormalities in the medial prefrontal cortex of adolescent offspring. In young adults, GluN2A-containing receptors were dominant in the medial prefrontal cortex, while in the hippocampus the GluN2B subunit contribution was elevated. In conclusion, we demonstrated that a maternal high-sugar diet can affect the memory processes in the offspring by disrupting the NMDA receptor composition and regulation in the medial prefrontal cortex and the hippocampus.
Assuntos
Disfunção Cognitiva/patologia , Açúcares da Dieta/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Memória Espacial/efeitos dos fármacos , Animais , Disfunção Cognitiva/induzido quimicamente , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Glutamate transmission is an important mediator of the development of substance use disorders, particularly with regard to relapse. The present review summarizes the changes in glutamate levels in the reward system (the prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, and ventral tegmental area) observed in preclinical studies at different stages of cocaine exposure and withdrawal as well as after reinstatement of cocaine-seeking behavior. We also summarize changes in the glutamate transporters xCT and GLT-1 and metabotropic glutamate receptors mGlu2/3, mGlu1, and mGlu5 based on preclinical and clinical studies with an emphasis on their role in cocaine-seeking. Glutamate transporters, such as GLT-1 and xc-, play a key role in maintaining glutamate homeostasis. In preclinical models, agents reversing cocaine-induced decreases in GLT-1 and xc- in the nucleus accumbens attenuate relapse. Very recent studies indicate that other mechanisms of action, such as reversing the mGlu2 receptor downregulation, contribute to these compounds' anti-relapse efficacy. In preclinical models, antagonism of mGlu5 receptors and stimulation of mGlu2/3 autoreceptors decrease relapse. Therefore, analysis of the above glutamatergic adaptations seems to be crucial because, so far, there are no prognostic biomarkers that can forecast relapse vulnerability in clinical practice, which would be helpful in alleviating or suppressing this phenomenon. Moreover, these receptor sites can be molecular targets for the development of effective medication for cocaine use disorder.
Assuntos
Sistema X-AG de Transporte de Aminoácidos , Transtornos Relacionados ao Uso de Cocaína , Receptores de Glutamato Metabotrópico , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Receptores de Glutamato Metabotrópico/metabolismo , RecidivaRESUMO
In this published article, Fig. 5 contained a mistake-graphs on the right.
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BACKGROUND: Several studies strongly support the role of the dopamine D2-like and glutamate mGlu5 receptors in psychostimulant reward and relapse. METHODS: The present study employed cocaine or MDMA self-administration with yoked-triad procedure in rats to explore whether extinction training affects the drug-seeking behavior and the D2-like and mGlu5 receptor Bmax and Kd values in several regions of the animal brain. RESULTS: Both cocaine and MDMA rats developed maintenance of self-administration, but MDMA evoked lower response rates and speed of self-administration acquisition. During reinstatement tests, cocaine or MDMA seeking behavior was produced by either exposure to the drug-associated cues or drug-priming injections. The extinction training after cocaine self-administration did not alter significantly D2-like receptor expression the in the limbic and subcortical brain areas, while MDMA yoked rats showed a decrease of the D2-like binding density in the nucleus accumbens and increase in the hippocampus and a rise of affinity in the striatum and hippocampus. Interestingly, in the prefrontal cortex a reduction in the mGlu5 receptor density in cocaine- or MDMA-abstinent rats was demonstrated, with significant effects being observed after previous MDMA exposure. Moreover, rats self-administered cocaine showed a rise in the density of mGlu5 receptor for the nucleus accumbens. CONCLUSION: This study first time shows that abstinence followed extinction training after cocaine or MDMA self- or passive-injections changes the D2-like and mGlu5 density and affinity. The observed changes in the expression of both receptors are brain-region specific and related to either pharmacological and/or motivational features of cocaine or MDMA.
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Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Cocaína/administração & dosagem , Masculino , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Ratos Wistar , Esquema de Reforço , AutoadministraçãoRESUMO
Literature data show diverse vulnerability to the rewarding effects of cocaine in human as well as in laboratory animals. The molecular mechanisms of these differences have not been discovered yet. While the initial effects of cocaine depend primarily on the dopamine system, numerous studies have shown that adaptation within the glutamatergic system is responsible for the development of addiction. In this paper, we used the unbiased conditioned place preference (CPP) to identify rats showing a vulnerable or resistant phenotype to the rewarding effects of cocaine. Next, we investigated the expression of membrane glutamate transporter proteins: GLT-1 and xCT in selected brain structures in the above-mentioned groups of rats. Moreover, we determined the nuclear level of NF-κB and Nrf2 to verify whether changes in GLT-1 and xCT expression correlate with NF-κB and Nrf2 levels, respectively. In addition, we determined GLT-1, NF-κB, xCT and Nrf2 mRNA levels to verify the involvement of transcriptional mechanisms. We also analyzed the ability of the ß-lactam antibiotic, ceftriaxone, to attenuate the persistence of CPP after a cocaine-free period in animals showing vulnerability to cocaine rewarding effects, and furthermore we determined GLT-1, xCT, NF-κB and Nrf2 protein expression. Our findings demonstrated molecular and neurochemical differences in the response to cocaine administration that are characteristic of the phenotype vulnerable or resistant to the rewarding effects of cocaine. Moreover, repeated administrations of ceftriaxone during cocaine-free perios attenuated CPP persistence and normalized GLT-1 level in the NAc. The results suggest the a lack of NF-κB involvement in the regulation of GLT-1 expression by ceftriaxone in the NAc. Additionally, we are the first to report that ceftriaxone strongly upregulates the GLT-1 in the HIP in a transcriptional mechanism involving the Nf-κB transcription factor. Future experiments may resolve the question concerning whether modulation exclusively of the GLT-1 expression in the HIP may attenuate cocaine-induced place preference or relapse.
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Ceftriaxona/farmacologia , Cocaína/metabolismo , Transportador 2 de Aminoácido Excitatório/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Biomarcadores Farmacológicos/metabolismo , Encéfalo/efeitos dos fármacos , Ceftriaxona/metabolismo , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/genética , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Recompensa , AutoadministraçãoRESUMO
There is strong support for the role of the endocannabinoid system and the noncannabinoid lipid signaling molecules, N-acylethanolamines (NAEs), in cocaine reward and withdrawal. In the latest study, we investigated the changes in the levels of the above molecules and expression of cannabinoid receptors (CB1 and CB2) in several brain regions during cocaine-induced reinstatement in rats. By using intravenous cocaine self-administration and extinction procedures linked with yoked triad controls, we found that a priming dose of cocaine (10 mg/kg, i.p.) evoked an increase of the anadamide (AEA) level in the hippocampus and prefrontal cortex only in animals that had previously self-administered cocaine. In the same animals, the level of 2-arachidonoylglycerol (2-AG) increased in the hippocampus and nucleus accumbens. Moreover, the drug-induced relapse resulted in a potent increase in NAEs levels in the cortical areas and striatum and, at the same time, a decrease in the tissue levels of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) was noted in the nucleus accumbens, cerebellum, and/or hippocampus. At the level of cannabinoid receptors, a priming dose of cocaine evoked either upregulation of the CB1 and CB2 receptors in the prefrontal cortex and lateral septal nuclei or downregulation of the CB1 receptors in the ventral tegmental area. In the medial globus pallidus we observed the upregulation of the CB2 receptor only after yoked chronic cocaine treatment. Our findings support that in the rat brain, the endocannabinoid system and NAEs are involved in cocaine induced-reinstatement where these molecules changed in a region-specific manner and may represent brain molecular signatures for the development of new treatments for cocaine addiction.
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Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/farmacologia , Endocanabinoides/metabolismo , Etanolaminas/metabolismo , Animais , Biomarcadores , Cromatografia Líquida , Transtornos Relacionados ao Uso de Cocaína/etiologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Expressão Gênica , Imuno-Histoquímica , Masculino , Ratos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Environmental conditions have an important function in substance use disorder, increasing or decreasing the risks of relapse. Several studies strongly support the role of the dopamine D2-like and metabotropic glutamate type 5 receptors in maladaptive neurobiological responses to cocaine reward and relapse. AIMS: The present study employed cocaine self-administration with yoked-triad procedure in rats to explore whether drug abstinence in different housing conditions affects the drug-seeking behaviour and the dopamine D2-like and metabotropic glutamate type 5 receptor density and affinity in several regions of the animal brain. METHODS: Rats were trained to self-administer cocaine and later they were forced to abstain either in: (a) enriched environment or (b) isolation cage conditions to evaluate the effect of housing conditions on the drug-seeking behaviour and to assess changes concerning receptors in animals brain. RESULTS: Our results show that exposure to enriched environment conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated a significant increase in the dopamine D2-like receptor density in the prefrontal cortex in animals following drug abstinence in isolation cage or enriched environment conditions, and the reduction in their density in the dorsal striatum provoked by isolation cage conditions. The metabotropic glutamate type 5 receptor density decreased only in the prefrontal cortex after isolation cage and enriched environment abstinence. CONCLUSIONS: This study shows the different impacts caused by the type of housing conditions during abstinence from cocaine self-administration on drug-seeking behaviour in rats. The observed changes in the dopamine D2-like and metabotropic glutamate type 5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of cocaine.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Encéfalo/metabolismo , Comportamento de Procura de Droga/fisiologia , Abrigo para Animais , Masculino , Ratos , Ratos Wistar , Recidiva , Recompensa , AutoadministraçãoRESUMO
The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad-yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p < 0.01), nucleus accumbens (p < 0.01), and medial globus pallidus (p < 0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus.
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Encéfalo/efeitos dos fármacos , Cocaína/administração & dosagem , Cocaína/farmacologia , Extinção Psicológica/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Autoadministração , Estatísticas não ParamétricasRESUMO
BACKGROUND: In the cocaine addiction the development from transient into persistent neuroplastic changes strongly involves the glutamatergic system. In this respect, among glutamatergic receptors special attention is paid to the group II of metabotropic glutamatergic receptors (mGlu2/3R) which are involved in the transition from drug use to drug addiction including the relapse mechanisms. METHODS: The present study employed radioligand binding and Western blot assays to study mGlu2/3R density, affinity and protein expression in selected rat brain areas after cocaine self-administration, extinction training and cocaine-induced reinstatement. Rats were randomly assigned in triads to one of three conditions: contingent cocaine intravenous self-administration, non-contingent injections of cocaine (yoked cocaine), or saline yoked to the intake of the self-administering subject. RESULTS: Cocaine self-administration and yoked cocaine delivery resulted in a significant increase in the mGlu2/3R density in the prefrontal cortex and the dorsal striatum, while 10-day extinction training provoked a reduction in the prefrontal cortex and the nucleus accumbens. Cocaine abstinence also enhanced an increase in the [3H]ligand binding to mGlu2/3R in the prefrontal cortex. During reinstatement the cocaine challenge dose (10mg/kg, ip) led to important elevation in the mGlu2/3R density in the prefrontal cortex. CONCLUSIONS: Our study demonstrated the role of mGlu2/3R localized in the prefrontal cortex-striatum pathways to cocaine repeated exposure.
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Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Plasticidade Neuronal/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Membrana Celular , Extinção Psicológica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos , Masculino , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/genéticaRESUMO
One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.
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Sistemas de Transporte de Aminoácidos Acídicos/genética , Isquemia Encefálica/tratamento farmacológico , Transportador 2 de Aminoácido Excitatório/genética , Ácido Glutâmico/metabolismo , Acetilcisteína/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Ceftriaxona/administração & dosagem , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Infarto da Artéria Cerebral Média , Ratos , Transmissão Sináptica/efeitos dos fármacosRESUMO
Several behavioral findings highlight the importance of glutamatergic transmission and its metabotropic receptor type 5 (mGlu5) in the controlling of cocaine reward and seeking behaviors. The molecular or neurochemical nature of such interactions is not well recognized, so in the present paper we determine if cocaine self-administration and extinction/reinstatement models with the yoked triad control procedure alter mGlu5 receptor density in rats. [³H]MPEP was used to evaluate mGlu5 receptors density and affinity in selected brain structures, while immunofluorescence analysis was used to detect changes in mGlu5 receptors' brain location. Cocaine self-administration and yoked cocaine delivery evoked a significant elevation in mGlu5 receptors' density in the dorsal striatum, while receptor protein expression was importantly elevated in the substantia nigra and reduced in the nucleus accumbens shell. Cocaine administration followed by 10 extinction training sessions resulted in biphasic mGlu5 receptor density changes in the prefrontal cortex-nucleus accumbens pathway. mGlu5 receptors' up-regulation was noted for cocaine self-administration and extinction training in the hippocampus and in yoked cocaine controls following drug abstinence in the dorsal striatum. A cocaine priming dose (but not a saline priming) resulted in a significant decrease of mGlu5 receptors' density in the nucleus accumbens of rats previously treated with the drug and in the hippocampus of rats previously self-administered cocaine. The latter decrease in mGlu5 receptors' density and protein expression in the hippocampus was parallel to an increase in [³H]MPEP affinity and opposite to a rise observed after single cocaine administration (ip) to drug-naïve yoked saline controls. Additionally, we also observed a significant elevation in the protein expression of the tested receptors in the limbic cortex in both cocaine groups. The present results shown modality dependent and brain-region specific changes in mGlu5 receptors' localization and membrane specific binding.
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Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Extinção Psicológica/fisiologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Análise de Variância , Animais , Encéfalo/patologia , Transtornos Relacionados ao Uso de Cocaína/patologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios , Imunofluorescência , Masculino , Piridinas , Ensaio Radioligante , Compostos Radiofarmacêuticos , Ratos Wistar , Recidiva , Autoadministração , TrítioRESUMO
Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism.
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Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Etanol/uso terapêutico , Homeostase/genética , Esfingolipídeos/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Depressão/genética , Etanol/sangue , Preferências Alimentares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esfingomielina Fosfodiesterase/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Neurotensin is a tridecapeptide originally identified in extracts of bovine hypothalamus. This peptide has a close anatomical and functional relationship with the mesocorticolimbic and nigrostriatal dopamine system. Neural circuits containing neurotensin were originally proposed to play a role in the mechanism of action of antipsychotic agents. Additionally, neurotensin-containing pathways were demonstrated to mediate some of the rewarding and/or sensitizing properties of drugs of abuse.This review attempts to contribute to the understanding of the role of neurotensin and its receptors in drug abuse. In particular, we will summarize the potential relevance of neurotensin, its related compounds and neurotensin receptors in substance use disorders, with a focus on the preclinical research.
Assuntos
Neurotensina/metabolismo , Receptores de Neurotensina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Dopamina/metabolismo , Humanos , RecompensaRESUMO
In human addicts and in animal models, chronic cocaine use leads to numerous alterations in glutamatergic transmission, including its receptors. The present study focused on metabotropic glutamatergic receptors type 5 (mGluR(5)) and N-methyl-D-aspartate receptor subunits (NMDAR: GluN1, GluN2A, GluN2B) proteins during cocaine self-administration and after 10-day of extinction training in rats. To discriminate the contingent from the non-contingent cocaine delivery, we employed the "yoked"-triad control procedure. Protein expression in rat prefrontal cortex, nucleus accumbens, hippocampus, and dorsal striatum was determined. We also examined the Homer1b/c protein, a member of the postsynaptic density protein family that links NMDAR to mGluR(5). Our results revealed that cocaine self-administration selectively increased GluN1 and GluN2A subunit in the rat hippocampus and dorsal striatum, respectively, while mGluR(5) protein expression was similarly increased in the dorsal striatum of both experimental groups. Withdrawal from both contingent and non-contingent cocaine delivery induced parallel increases in prefrontal cortical GluN2A protein expression, hippocampal mGluR(5), and GluN1 protein expression as well as in accumbal GluN1 subunit expression, while the mGluR(5) expression was reduced in the prefrontal cortex. Extinction training in animals with a history of cocaine self-administration resulted in an elevation of the hippocampal GluN2A/GluN2B subunits and accumbal mGluR(5), and in a 50 % decrease of mGluR(5) protein expression in the dorsal striatum. The latter reduction was associated with Homer1b/1c protein level decrease. Our results showed that both contingent and non-contingent cocaine administration produces numerous, brain region specific, alterations in the mGluR(5), NMDA, and Homer1b/1c protein expression which are dependent on the modality of cocaine administration.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cocaína/toxicidade , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Proteínas de Transporte/metabolismo , Cocaína/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Proteínas de Arcabouço Homer , Masculino , Subunidades Proteicas/metabolismo , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
Ethylene glycol ethers (EGEs) are components of many industrial and household products. Their hemolytic and gonadotoxic effects are relatively well known while their potential adverse effects on the central nervous system have not yet been clearly demonstrated. The aim of the present study was to examine the effects of 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE) and 2-ethoxyethanol (EE) on the total antioxidant capacity, activity of some antioxidant enzymes, such as the superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase and lipid peroxidation in the frontal cortex and hippocampus in the rat. These studies showed that BE and PHE decreased the total antioxidant activity, SOD and GPX activity, while increased lipid peroxidation in the frontal cortex. Like in the frontal cortex, also in the hippocampus BE and PHE attenuated the total antioxidant activity, however, lipid peroxidation was increased only in animals which received BE while reduction in GPX activity was present in rats administered PHE. The obtained data indicated that 4-week administration of BE and PHE, but not EE, reduced the total antioxidant activity and enhanced lipid peroxidation in the brain. In the frontal cortex, adverse effects of PHE and BE on lipid peroxidation probably depended on reduction in SOD and GPX activity, however, in the hippocampus the changes in the total antioxidant activity and lipid peroxidation were not connected with reduction of the investigated antioxidant enzyme activity.
Assuntos
Etilenoglicóis/toxicidade , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Catalase/metabolismo , Lobo Frontal/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs.