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Introduction: The chronic use of psychostimulants increases the risk of addiction and, there is no specific pharmacologic treatment for psychostimulant addiction. The vasopressin (AVP) system is a possible pharmacological target in drug addiction. Previous results obtained in our laboratory showed that amphetamine (AMPH) treatment decreases lateral septum (LS) AVP levels in male rats, and AVP microinjection in LS decreases addictive-like behavior. The aim of the present work was to investigate the effect of AMPH treatment on LS AVP levels and the effect of LS AVP administration on the expression of AMPH-conditioned place preference (CPP) in female rats. The secondary objectives were to study the effect of LS AVP administration on LS GABA and glutamate release in male and female rats and on nucleus accumbens (NAc) dopamine (DA) release in female rats. Methods: Female rats were conditioned with AMPH (1.5 mg/kg i.p.) or saline for 4 days. Results: Conditioning with AMPH did not change LS AVP content in females. However, AVP microinjection into the LS decreased the expression of conditioned place preference (CPP) to AMPH. Glutamate and GABA extracellular levels in the LS induced by AVP were studied in males and females. NAc GABA and DA extracellular levels induced by LS AVP microinjection in female rats were measured by microdialysis. In males, AVP perfusion produced a significant increase in LS GABA extracellular levels; however, a decrease in GABA extracellular levels was observed in females. Both in males and females, LS AVP perfusion did not produce changes in LS glutamate extracellular levels. Microinjection of AVP into the LS did not change GABA or DA extracellular levels in the NAc of females. Discussion: Therefore, AVP administration into the LS produces different LS-NAc neurochemical responses in females than males but decreases CPP to AMPH in both sexes. The behavioral response in males is due to a decrease in NAc DA levels, but in females, it could be due to a preventive increase in NAc DA levels. It is reasonable to postulate that, in females, the decrease in conditioning produced by AVP microinjection is influenced by other factors inherent to sex, and an effect on anxiety cannot be discarded.
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Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that the neural circuits underlying the regulation and expression of social behaviors are highly overlapped with those targeted by psychostimulants, which in most cases have strong rewarding and, consequently, addictive properties. In the present work, we provide an overview regarding the effects of illicit and prescription psychostimulants, such as cocaine, amphetamine-type stimulants, methylphenidate or modafinil, upon social behaviors such as social play, maternal behavior, aggression, pair bonding and social cognition and how psychostimulants in both animals and humans alter them. Finally, we discuss why these effects can vary depending on numerous variables such as the type of drug considered, acute versus long-term use, clinical versus recreational consumption, or the presence or absence of concomitant risk factors.
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Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.
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Anfetamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Angiotensina II , Benzimidazóis , Compostos de Bifenilo , Corpo Estriado , Dopamina , Animais , Anfetamina/farmacologia , Masculino , Dopamina/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Benzimidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ratos Wistar , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Interação Social/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.
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Antioxidantes , Doxiciclina , Hipocampo , Mania , Neurônios , Animais , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Antioxidantes/farmacologia , Mania/induzido quimicamente , Mania/tratamento farmacológico , Doxiciclina/farmacologia , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Anfetamina/farmacologia , Anfetamina/toxicidade , Modelos Animais de Doenças , Estimulantes do Sistema Nervoso Central/toxicidade , Monoaminas Biogênicas/metabolismo , Dextroanfetamina/farmacologia , Dextroanfetamina/toxicidade , Antimaníacos/farmacologia , Fármacos Neuroprotetores/farmacologiaRESUMO
The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1ß, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.
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Anfetamina , Sepse , Ratos , Animais , Ratos Wistar , Anfetamina/farmacologia , Punções , Modelos Animais de DoençasRESUMO
RATIONALE: Relapse into substance use is often triggered by exposure to drug-related environmental cues. The magnitude of drug seeking depends on the duration of abstinence, a phenomenon known as the incubation of drug craving. Clinical and preclinical research shows that the insular cortex is involved in substance use disorders and cue-induced drug seeking. However, the role of the insula on memory retrieval and motivational integration for cue-elicited drug seeking remains to be determined. OBJECTIVES: We investigated the role of the anterior insular cortex (aIC) and its glutamatergic projection to amygdala nuclei (aIC-AMY) on the expression of conditioned place preference (CPP) during early and late abstinence. METHODS: Male adult C57BL/6J mice underwent amphetamine-induced CPP, and their preference was tested following 1 or 14 days of abstinence. aIC and aIC-AMY functional role in CPP expression was assessed at both abstinence periods by employing optogenetic silencing and behavioral pharmacology. RESULTS: Compared to a single day, an exacerbated preference for the amphetamine-paired context was observed after 14 days of abstinence. Photoinhibition of either aIC or aIC-AMY projection reduced CPP expression following late but not early abstinence. Similarly, the antagonism of aIC NMDA receptors reduced CPP expression after 14 days of abstinence but not 1 day. CONCLUSIONS: These results suggest that aIC and its glutamatergic output to amygdala nuclei constitute critical neurobiological substrates mediating enhanced motivational cue reactivity during the incubation of amphetamine craving rather than contextual memory recall. Moreover, cortical NMDA receptor signaling may become sensitized during abstinence, ultimately modulating disproportioned drug seeking.
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Córtex Insular , Memória , Camundongos , Animais , Masculino , Camundongos Endogâmicos C57BL , Memória/fisiologia , Tonsila do Cerebelo , Anfetamina/farmacologiaRESUMO
The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.
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Glucagon , Neuropeptídeos , Peptídeos , Camundongos , Animais , Masculino , Proteína Relacionada com Agouti , Glucagon/metabolismo , Camundongos Obesos , Pró-Opiomelanocortina/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , Hipotálamo/metabolismo , Neuropeptídeo Y/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismoRESUMO
Algunas situaciones ponen en riesgo a Cuba en cuanto al uso de drogas, entre ellas el aumento del turismo, las relaciones con países que poseen altas tasas de consumo, la ubicación geográfica en corredores de narcotraficantes y la alta prevalencia de drogas porteras. Al respecto, el Sistema Nacional de Salud debe estar preparado para la prevención del problema y la atención a los afectados, de manera que resulta necesario mantener una información actualizada sobre los factores de riesgo y los principales productos utilizados por los consumidores. En la presente revisión bibliográfica sobre el tema se busca llamar la atención de los trabajadores de la salud en tal sentido, se ofrecen datos sobre la magnitud del problema y se abordan elementos de sus antecedentes, así como de la clasificación de las drogas, los factores de riesgo asociados a su consumo y las bases jurídicas para su control en Cuba.
Some situations put Cuba at risk for drug use, such as an increase in tourism, relations with countries that have high rates of substance abuse, the geographic location in drug trafficking corridors, and the high prevalence of "opening doors" drugs. In this regard, the National Health System must be prepared to prevent the problem and care for those affected, so it is necessary to maintain updated information on risk factors and main products used by consumers. In the present literature review on the subject, it is sought to draw the attention of health workers to this point, data on the magnitude of the problem and elements of its background are offered, as well as drug classification, the risk factors associated with its use and the legal bases for its control in Cuba.
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Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Usuários de Drogas , Cannabis , Fatores de Risco , Cocaína , Cuba , Anfetamina , MetanfetaminaRESUMO
The actual illicit market for synthetic drugs is characterized by a wide variety of psychoactive substances of different chemical and pharmacological classes, such as amphetamine-type stimulants and new psychoactive substances. The knowledge about its chemical composition, as well as the nature and quantity of the active substances present, is important for emergency care in intoxication cases by these substances and to establish adequate chemical and toxicological analysis procedures in forensic laboratories. The aim of this work was to study the prevalence of amphetamine-type stimulants and new psychoactive substances in the states of Bahia and Sergipe, in the northeast region of Brazil, involving samples of drugs seized by the local police forces from 2014 to 2019. In a total of 121 seized and analyzed samples, in which ecstasy tablets predominated (n = 101), nineteen substances were identified using GC-MS and 1D NMR techniques, comprising classical synthetic drugs and new psychoactive substances (NPS). In order to determine the composition of ecstasy tablets, an analytical method based on GC-MS was applied after validation. Analyzes of 101 ecstasy tablets showed that MDMA was the main substance, being found in 57% of the samples, in amounts between 27.3 and 187.1 mg per tablet. In addition, mixtures of MDMA, MDA, synthetic cathinones and caffeine were observed in 34 samples. These results demonstrate that the variety of substances found and the composition of seized materials in northeast Brazil is similar to other studies carried out previously in other Brazilian regions.
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Estimulantes do Sistema Nervoso Central , Drogas Ilícitas , N-Metil-3,4-Metilenodioxianfetamina , Medicamentos Sintéticos , N-Metil-3,4-Metilenodioxianfetamina/análise , Brasil , Cromatografia Gasosa-Espectrometria de Massas , Drogas Ilícitas/análise , Estimulantes do Sistema Nervoso Central/análise , Anfetamina/análise , Comprimidos , Psicotrópicos/análiseRESUMO
PURPOSE: New psychoactive substances (NPS) are not controlled under the Single Convention on Narcotic Drugs of 1961 or the 1971 Convention, but they may pose a public health threat. Knowledge of the main properties and toxicological effects of these substances is lacking. According to the current Drugs Law (Law n. 11.343/2006), the Brazilian Surveillance Agency issues directives for forbidden substances in Brazil, and structural classes of synthetic cannabinoids, cathinones, and phenylethylamines are considered illicit drugs. Considering that data on these controlled substances are scattered, the main objective of this work was to collect and organize data to generate relevant information on the toxicological properties of NPS. METHODS: We carried out a literature review collecting information on the acute, chronic, and post-mortem toxicity of these classes of NSP. We searched info in five scientific databases considering works from 2017 to 2021 and performed a statistical evaluation of the data. RESULTS: Results have shown a general lack of studies in this field given that many NPS have not had their toxicity evaluated. We observed a significant difference in the volume of data concerning acute and chronic/post-mortem toxicity. Moreover, studies on the adverse effects of polydrug use are scarce. CONCLUSIONS: More in-depth information about the main threats involving NPS use are needed.
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Canabinoides , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Humanos , Psicotrópicos/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Drogas Ilícitas/toxicidade , Canabinoides/toxicidade , Substâncias ControladasRESUMO
The use of psychostimulant drugs can modify brain function by inducing changes in the reward system, mainly due to alterations in dopaminergic and glutamatergic transmissions in the mesocorticolimbic pathway. However, the etiopathogenesis of addiction is a much more complex process. Previous data have suggested that microglia and other immune cells are involved in events associated with neuroplasticity and memory, which are phenomena that also occur in addiction. Nevertheless, how dependent is the development of addiction on the activity of these cells? Although the mechanisms are not known, some pathways may be involved. Recent data have shown psychoactive substances may act directly on immune cells, alter their functions and induce various inflammatory mediators that modulate synaptic activity. These could, in turn, be involved in the pathological alterations that occur in substance use disorder. Here, we extensively review the studies demonstrating how cocaine and amphetamines modulate microglial number, morphology, and function. We also describe the effect of these substances in the production of inflammatory mediators and a possible involvement of some molecular signaling pathways, such as the toll-like receptor 4. Although the literature in this field is scarce, this review compiles the knowledge on the neuroimmune axis that is involved in the pathogenesis of addiction, and suggests some pharmacological targets for the development of pharmacotherapy.
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Estimulantes do Sistema Nervoso Central , Cocaína , Transtornos Relacionados ao Uso de Substâncias , Humanos , Microglia , Cocaína/farmacologia , Anfetaminas/farmacologiaRESUMO
Introducción: el consumo de estimulantes de tipo anfetamínico (ETA) y sus derivados está cada vez más presente en los estudiantes universitarios y, en particular, en los programas de medicina. El objetivo principal de este estudio fue revisar la literatura sobre el uso de ETA y sus derivados en estudiantes de medicina latinoamericanos. Materiales y método: se realizó una revisión de la literatura disponible, utilizando las bases de datos PubMed, SciELO y LILACS. Se encontraron un total de 1.054 artículos, de los cuales 17 fueron seleccionados para esta revisión. Resultados: la revisión muestra, en general, una mayor frecuencia de uso de ETA en estudiantes de medicina de América Latina en comparación con la población general y estudiantes de otras carreras universitarias. También existe una tendencia a un mayor uso en hombres, de mayor nivel socioeconómico y en cursos posteriores del programa. La razón más informada para usar ETA fue aumentar el rendimiento académico. Como factor protector se destacaron los deportes, el tiempo en familia y la profesión de alguna creencia religiosa. De los artículos seleccionados, no se encontraron estudios sobre las consecuencias a largo plazo del uso de ETA en estudiantes de medicina. Discusión: en resumen, los estudiantes de medicina latinoamericanos tienen un alto consumo de ETA, por lo que es evidente la necesidad de nuevos estudios para mejorar la precisión estadística, determinar factores de riesgo específicos, estudiar las consecuencias a largo plazo y establecer políticas de prevención y tratamiento.
Introduction: the consumption of amphetamine-type stimulants (ATS) and their derivatives are increasingly present in university students and in particular in medical programs. The main objective of this study was to review the literature on the use of ATS and their derivatives in Latin American medical students. Materials and method: a review of the literature available was performed, using PubMed, SciELO, and LILACS databases. A total of 1054 articles were found, of which 17 were selected for this review. Results: the review generally shows a higher frequency of use of ATS in medical students of Latin America compared to the general population and students from other university degrees. There is also a tendency of a higher use in men, from higher socioeconomic status, and in later courses of the program. The most reported reason for using ATS was to increase the academic performance. As a protective factor, sports, family time and professing some religious belief stood out. Of the selected articles, no studies were found on the long-term consequences of the use of ATS in medical students. Discussion: in summary, Latin American medical students have a high consumption of ATS, and therefore there is an evident need for new studies to improve statistical precision, to determine specific risk factors, to study long-term consequences, and to stablish prevention policies and treatment.
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Humanos , Estudantes de Medicina , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Anfetaminas/administração & dosagem , Desempenho Acadêmico , Estimulantes do Sistema Nervoso Central/administração & dosagem , América Latina , Metilfenidato/administração & dosagemRESUMO
Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.
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Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.
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Estimulantes do Sistema Nervoso Central , Metilfenidato , Transtornos Relacionados ao Uso de Substâncias , Propionato de Testosterona , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/farmacologia , Estradiol/farmacologia , Feminino , Masculino , Metilfenidato/farmacologia , Atividade Motora , Núcleo Accumbens , RatosRESUMO
Background and aim: This study investigated the effect of Kava extract (Piper methysticum), a medicinal plant that has been worldly used by its anxiolytic effects, on monoamine oxidase (MAO) activity of mice brain after 21 days of treatment as well as anxiolytic and locomotor behavior. Furthermore, the in vitro inhibitory profile of Kava extract on MAO-B activity of mouse brain was evaluated. Experimental procedure: Mice were treated with Kava extract (10, 40, 100 and 400 mg/kg) for 21 days by gavage. After behavioral analysis (plus maze test and open field), MAO activity in different mouse brain structures (cortex, hippocampus, region containing the substantia nigra and striatum) were performed. MAO-B inhibitory profile was characterized in vitro. Results: The treatment with Kava extract (40 mg/kg) increased the percentage of entries of mice into the open arms. Ex vivo analysis showed an inhibition on MAO-B activity caused by Kava extract in cortex (10 mg/kg) and in the region containing the substantia nigra (10 and 100 mg/kg). In vitro, Kava extract also reversibly inhibited MAO-B activity with IC50 = 14.62 µg/mL and, increased Km values at the concentrations of 10 and 30 µg/mL and decreased Vmax value at 100 µg/mL. Conclusion: Kava extract showed different effects on MAO-B isoform depending on the brain structure evaluated. Therefore, the use of Kava extract could be promissory in pathologies where MAO-B is the pharmacological target.
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Prenatal exposure to amphetamine induces changes in dopamine receptors in mesolimbic areas and alters locomotor response to amphetamine during adulthood. Sex differences have been reported in amphetamine-induced brain activity and stress sensitivity. We evaluated the effects of prenatal amphetamine exposure on locomotor activity, dopamine receptors and tyrosine hydroxylase mRNA expression in nucleus accumbens and caudate-putamen in response to amphetamine challenge in adult female and male rats. The role of estrogen in the response to restraint stress was analyzed in ovariectomized, prenatally amphetamine-exposed rats. Pregnant rats were treated with D-amphetamine during days 15-21 of gestation. Nucleus accumbens and caudate-putamen were processed for mRNA determination by real-time PCR. In nucleus accumbens, higher mRNA dopamine (D3) receptor expression was found in basal and D-amphetamine-challenge conditions in female than male, and prenatal amphetamine increased the difference. No sex differences were observed in caudate-putamen. Basal saline-treated females showed higher locomotor activity than males. Amphetamine challenge in prenatally amphetamine-exposed rats increased locomotor activity in males and reduced it in females. In nucleus accumbens, estrogen diminished mRNA D1, D2 and D3 receptor expression in basal, and D1 and D3 in ovariectomized stressed rats. Estrogen prevented the increase in tyrosine hydroxylase expression induced by stress in ovariectomized prenatally exposed rats. In conclusion, estrogen modulates mRNA levels of D1, D2 and D3 receptors and tyrosine hydroxylase expression in nucleus accumbens; prenatal amphetamine-exposure effects on D3 receptors and behavioral responses were gender dependent.
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Anfetamina , Dopamina , Anfetamina/farmacologia , Animais , Dopamina/metabolismo , Estrogênios/farmacologia , Feminino , Masculino , Núcleo Accumbens/metabolismo , Gravidez , Ratos , Receptores Dopaminérgicos , Receptores de Dopamina D3/metabolismoRESUMO
Trigeminal neuropathic pain has been modeled in rodents through the constriction of the infraorbital nerve (CCI-ION). Sensory alterations, including spontaneous pain, and thermal and mechanical hyperalgesia are well characterized, but there is a notable lack of evidence about the affective pain component in this model. Evaluation of the emotional component of pain in rats has been proposed as a way to optimize potential translational value of non-clinical studies. In rats, 22 and 50 kHz ultrasonic vocalizations (USVs) are considered well-established measures of negative and positive emotional states, respectively. Thus, this study tested the hypothesis that trigeminal neuropathic pain would result, in addition to the sensory alterations, in a decrease of 50 kHz USV, which may be related to altered function of brain areas involved in emotional pain processing. CCI-ION surgery was performed on 60-day-old male Wistar rats. 15 days after surgery, von Frey filaments were applied to detect mechanical hyperalgesia, and USV was recorded. At the same timepoint, systemic treatment with d,l-amphetamine (1 mg/kg) allowed investigation of the involvement of the dopaminergic system in USV emission. Finally, brain tissue was collected to assess the change in tyrosine hydroxylase (TH) expression in the nucleus accumbens (NAc) and c-Fos expression in brain areas involved in emotional pain processing, including the prefrontal cortex (PFC), amygdala, and NAc. The results showed that CCI-ION rats presented mechanical hyperalgesia and a significant reduction of environmental-induced 50 kHz USV. Amphetamine caused a marked increase in 50 kHz USV emission in CCI-ION rats. In addition, TH expression was lower in constricted animals and c-Fos analysis revealed an increase in neuronal activation. Taken together, these data indicate that CCI-ION causes a reduction in the emission of environmental-induced appetitive calls concomitantly with facial mechanical hyperalgesia and that both changes may be related to a reduction in the mesolimbic dopaminergic activity.
Assuntos
Neuralgia , Neuralgia do Trigêmeo , Animais , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Neuralgia do Trigêmeo/complicaçõesRESUMO
ABSTRACT. Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems. Objective: The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD. Methods: The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020. Results: The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids. Conclusions: The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.
RESUMO. Déficit de atenção e hiperatividade (TDAH) é uma das mais frequentes condições psiquiátricas da infância. Objetivo: O objetivo deste artigo foi identificar, sintetizar os resultados e avaliar criticamente todas as revisões sistemáticas (RS) da Cochrane sobre as intervenções farmacológicas para crianças e adolescentes (até 18 anos de idade) diagnosticados com transtorno do déficit de atenção com hiperatividade. Métodos: A pesquisa foi realizada na base de dados Cochrane de Revisões Sistemáticas — CDSR (via Wiley) em julho de 2020. Resultados: A estratégia de busca resultou em quatro RS de alta qualidade metodológica, que analisavam 51 ensaios clínicos randomizados (9.013 participantes). Comparado ao placebo, o tratamento com antidepressivos tricíclicos (desipramina), anfetamina e metilfenidato apresentou melhora nos sintomas, como dificuldade de concentração, impulsividade e hiperatividade no curto prazo (até seis meses). Houve aumento na ocorr≖ncia de eventos adversos, como redução do apetite, dificuldade para dormir e dor abdominal. Foram encontradas evid≖ncias insuficientes para apoiar os efeitos da suplementação com ácidos graxos poli-insaturados. Conclusões: Com base nos resultados de revisões sistemáticas Cochrane, o uso de antidepressivos tricíclicos, anfetamina e metilfenidato em crianças e adolescentes com TDAH parece apresentar efeitos positivos e taxas mais elevadas de eventos adversos menores quando comparado ao placebo. Dado o alto risco de viés nos estudos primários incluídos nessas RS, ainda são necessários novos ensaios clínicos randomizados com rigor metodológico para apoiar esses achados.
Assuntos
Humanos , Criança , Adolescente , Transtorno do Deficit de Atenção com HiperatividadeRESUMO
Attention deficit/Hyperactivity disorder (ADHD) is one of the most diagnosed psychiatric disorders nowadays. The core symptoms of the condition include hyperactivity, impulsiveness and inattention. The main pharmacological treatment consists of psychostimulant drugs affecting Dopamine Transporter (DAT) function. We have previously shown that genetically modified mice lacking p35 protein (p35KO), which have reduced Cdk5 activity, present key hallmarks resembling those described in animal models useful for studying ADHD. The p35KO mouse displays spontaneous hyperactivity and shows a calming effect of methylphenidate or amphetamine treatment. Interestingly, dopaminergic neurotransmission is altered in these mice as they have an increased Dopamine (DA) content together with a low DA turnover. This led us to hypothesize that the lack of Cdk5 activity affects DAT expression and/or function in this animal model. In this study, we performed biochemical assays, cell-based approaches, quantitative fluorescence analysis and functional studies that allowed us to demonstrate that p35KO mice exhibit decreased DA uptake and reduced cell surface DAT expression levels in the striatum (STR). These findings are supported by in vitro observations in which the inhibition of Cdk5 activity in N2a cells induced a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization to recycling endosomes. Taken together, these data provide evidences regarding the role of Cdk5/p35 in DAT expression and function, thus contributing to the knowledge of DA neurotransmission physiology and also providing therapeutic options for the treatment of DA pathologies such as ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Quinase 5 Dependente de Ciclina/deficiência , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/biossíntese , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Linhagem Celular , Quinase 5 Dependente de Ciclina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Ativação Enzimática/fisiologia , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive-compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3 g lo /CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3 g lo /CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3 g lo /CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3 g lo /CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3 g lo /CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3 g lo /CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3 g lo /CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3 g lo /CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.