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Drug addiction therapies commonly fail because continued drug use promotes the release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential as a target for drug misuse therapies.
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Mepirapim is a novel synthetic cannabinoid that first appeared on the illicit drug market in 2013. In recent years, recreational abuse of Mepirapim has caused serious emergencies, posing a threat to public health. However, there are no legal regulations to prohibit the use of Mepirapim, as there is no scientific evidence for the dangerous pharmacological effects of the drug. In the present study, we investigated the dangerous neurotoxic effects of Mepirapim through behavioral and molecular experiments in mice (ICR/CD1, male, 25-30 g). In particular, based on a previous study that Mepirapim activates the dopamine system, we evaluated whether high-dose Mepirapim [single (15, 30, or 60 mg·kg-1, i.p.) or multiple (8, 15, or 30 mg·kg-1, i.p. × 4 at 2 h intervals)] treatment causes Parkinson's disease-related symptoms through damage to the dopamine system. In the result, we found that Mepirapim treatment caused comprehensive Parkinson's disease-related symptoms, including motor impairment, cognitive deficits and mood disorders. Furthermore, we confirmed the maladaptation in dopamine-related neurochemicals, including decreased dopamine levels, decreased tyrosine hydroxylase expression, and increased α-synuclein expression, in the brains of mice treated with Mepirapim. Taken together, these results indicate that Mepirapim has dangerous neurotoxic effects that induces Parkinson's disease-related behaviors by causing maladaptation of the dopamine system in the brain. Based on these findings, we propose the strict regulation of recreational abuse and therapeutic misuse of Mepirapim.
Assuntos
Transtornos Cognitivos , Síndromes Neurotóxicas , Doença de Parkinson , Masculino , Animais , Camundongos , Camundongos Endogâmicos ICR , Dopamina , EncéfaloRESUMO
2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.
Assuntos
Drogas Desenhadas/toxicidade , Síndromes Neurotóxicas/etiologia , Fenetilaminas/toxicidade , Animais , Drogas Desenhadas/administração & dosagem , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/patologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/fisiopatologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Fenetilaminas/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg-1]; SA [0.01, 0.03, 0.1 mg kg-1]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg-1]; repeated high dose [4 × 8, 15, 30 mg kg-1]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.
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Comportamento Aditivo/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Fenetilaminas/toxicidade , Psicotrópicos/toxicidade , Transtornos Relacionados ao Uso de Substâncias/etiologia , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Proteínas de Ligação ao Cálcio/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/metabolismo , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Teste de Campo Aberto/efeitos dos fármacos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.
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Canabinoides/química , Receptores de Canabinoides/química , Cannabis/química , Dronabinol/química , Modelos Moleculares , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , SoftwareRESUMO
Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p.âo.) significantly improved amyloid beta25â-â35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p.âo.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25â-â35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25â-â35 in mice.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lespedeza/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Peptídeos beta-Amiloides , Animais , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Fragmentos de Peptídeos , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: Abnormal reward sensitivity is a risk factor for psychiatric disorders, including eating disorders such as overeating and binge-eating disorder, but the brain structural mechanisms that underlie it are not completely understood. Here, we sought to investigate the relationship between multimodal whole-brain structural features and reward sensitivity in nonhuman primates. METHODS: Reward sensitivity was evaluated through behavioral economic analysis in which monkeys (adult rhesus macaques; 7 female, 5 male) responded for sweetened condensed milk (10%, 30%, 56%), Gatorade, or water using an operant procedure in which the response requirement increased incrementally across sessions (i.e., fixed ratio 1, 3, 10). Animals were divided into high (n = 6) or low (n = 6) reward sensitivity groups based on essential value for 30% milk. Multimodal magnetic resonance imaging was used to measure gray matter volume and white matter microstructure. Brain structural features were compared between groups, and their correlations with reward sensitivity for various stimuli was investigated. RESULTS: Animals in the high sensitivity group had greater dorsolateral prefrontal cortex, centromedial amygdaloid complex, and middle cingulate cortex volumes than animals in the low sensitivity group. Furthermore, compared with monkeys in the low sensitivity group, high sensitivity monkeys had lower fractional anisotropy in the left dorsal cingulate bundle connecting the centromedial amygdaloid complex and middle cingulate cortex to the dorsolateral prefrontal cortex, and in the left superior longitudinal fasciculus 1 connecting the middle cingulate cortex to the dorsolateral prefrontal cortex. CONCLUSIONS: These results suggest that neuroanatomical variation in prefrontal-limbic circuitry is associated with reward sensitivity. These brain structural features may serve as predictive biomarkers for vulnerability to food-based and other reward-related disorders.
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Macaca mulatta , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Recompensa , Animais , Masculino , Feminino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Vias Neurais/fisiologia , Vias Neurais/diagnóstico por imagem , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/fisiologia , Substância Branca/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiologia , Condicionamento Operante/fisiologiaRESUMO
BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH-induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild-type and TRPA1 knock-out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. KEY RESULTS: TRPA1 antagonism blunted METH self-administration and drug-primed reinstatement of METH-seeking behaviour. Further, development of METH-induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock-out mice. Similarly, molecular studies revealed METH-induced increases in dopamine levels and expression of dopamine system-related proteins in wild-type, but not in TRPA1 knock-out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. CONCLUSION AND IMPLICATIONS: This study demonstrates that TRPA1 is involved in the abuse-related behavioural effects of METH, potentially through its modulatory role in METH-induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder.
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Proteínas da Membrana Plasmática de Transporte de Dopamina , Metanfetamina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canal de Cátion TRPA1 , Animais , Metanfetamina/farmacologia , Metanfetamina/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Canal de Cátion TRPA1/metabolismo , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/antagonistas & inibidores , Masculino , Camundongos , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Autoadministração , Ratos Sprague-Dawley , Estimulantes do Sistema Nervoso Central/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. EXPERIMENTAL APPROACH: We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. KEY RESULTS: CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. CONCLUSION AND IMPLICATIONS: These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.
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Proteínas Adaptadoras de Transdução de Sinal , Cocaína , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Núcleo Accumbens , Recompensa , Animais , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Cocaína/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Camundongos , Masculino , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação , Comportamento Animal/efeitos dos fármacosRESUMO
2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.
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Drogas Desenhadas , Alucinógenos , Ratos , Camundongos , Animais , Drogas Desenhadas/farmacologia , Dopamina/metabolismo , Recompensa , Alucinógenos/metabolismo , Núcleo Accumbens/metabolismoRESUMO
BACKGROUND: Methamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. METHODS: We first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. RESULTS: Treatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. CONCLUSION: Our findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.
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Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.
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Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcementenhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.
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BACKGROUND: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. METHODS: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. RESULTS: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. CONCLUSION: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.
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BACKGROUND AND PURPOSE: Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. EXPERIMENTAL APPROACH: Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours. KEY RESULTS: Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. CONCLUSIONS AND IMPLICATIONS: We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.
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Comportamento Aditivo , Esquizofrenia , Animais , Comportamento Aditivo/induzido quimicamente , Encéfalo , Camundongos , Piperidinas , RatosRESUMO
Daidzein, one of the important isoflavones, is extensively metabolized in the human body following consumption. In particular, 6,7,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, has been the focus of recent investigations due to its various health benefits, such as anti-cancer and anti-obesity effects. However, the protective effects of 6,7,4'-THIF have not yet been studied in models of Parkinson's disease (PD). Therefore, the present study aimed to investigate the protective activity of 6,7,4'-THIF on 6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells. Pretreatment of SH-SY5Y cells with 6,7,4'-THIF significantly inhibited 6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive oxygen species production. In addition, 6,7,4'-THIF significantly attenuated reductions in 6-OHDA-induced superoxide dismutase activity and glutathione content. Moreover, 6,7,4'-THIF attenuated alterations in Bax and Bcl-2 expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore, 6,7,4'-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2. Additionally, 6,7,4'-THIF effectively prevented 6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results suggest that 6,7,4'-THIF, a major metabolite of daidzein, may be an attractive option for treating and/or preventing neurodegenerative disorders such as PD.
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Antineoplásicos/farmacologia , Isoflavonas/metabolismo , Isoflavonas/farmacologia , Neuroblastoma/tratamento farmacológico , Neurônios/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoflavonas/química , Estrutura Molecular , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/prevenção & controle , Células Tumorais CultivadasRESUMO
Daidzein isolated from soybean (Glycine max) has been widely studied for its antioxidant and anti-inflammatory activities. However, the protective effects of 7,8,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, on 6-hydroxydopamine (OHDA)-induced neurotoxicity are not well understood. In the current study, 7,8,4'-THIF significantly inhibited neuronal cell death and lactate dehydrogenase (LDH) release induced by 6-OHDA in SH-SY5Y cells, which were used as an in vitro model of Parkinson' disease (PD). Moreover, pretreatment with 7,8,4'-THIF significantly increased the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) and decreased malondialdehyde (MDA) activity in 6-OHDA-induced SH-SY5Y cells. In addition, 7,8,4'-THIF significantly recovered 6-OHDA-induced cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), increased Bax, and decreased Bcl-2 levels. Additionally, 7,8,4'-THIF significantly restored the expression levels of phosphorylated c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3 beta (GSK-3ß) in 6-OHDA-induced SH-SY5Y cells. Further, 7,8,4'-THIF significantly increased the reduced tyrosine hydroxylase (TH) level induced by 6-OHDA in SH-SY5Y cells. Collectively, these results suggest that 7,8,4'-THIF protects against 6-OHDA-induced neuronal cell death in cellular PD models. Also, these effects are mediated partly by inhibiting activation of the MAPK and PI3K/Akt/GSK-3ß pathways.
RESUMO
New psychoactive substances that have been modified and developed to mimic the effects of already prohibited drugs are an increasingly global problem. Among them, 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine (25 N-NBOMe) belonging to the N-methoxybenzyl-phenethylamines (NBOMes) class has recently emerged as a new psychoactive substance. However, the rewarding effects of 25 N-NBOMe have not yet been studied. Here, we investigated the addictive potential of 25 N-NBOMe using conditioned place preference and self-administration in rodents. We also evaluated the effects of 25 N-NBOMe on the dopaminergic system using Western blot analysis. We found that 25 N-NBOMe at 3 mg/kg significantly increased conditioned place preference in mice and 25 N-NBOMe at 0.01 mg/kg/infusion significantly enhanced self-administration in rats. In addition, repeated administration of 25 N-NBOMe did not affect the expression of the dopamine 1 receptor but significantly reduced the expression of the dopamine 2 receptor in both the nucleus accumbens (NAc) and the dorsal striatum (DSt). We also found that 25 N-NBOMe significantly decreased the expression of the dopamine transporter only in the NAc, while increasing the expression of the phosphorylated dopamine transporter in both the NAc and the DSt. Furthermore, 25 N-NBOMe significantly reduced the expression of tyrosine hydroxylase in the NAc but not in the DSt. Taken together, these findings suggest that 25 N-NBOMe has abuse potential via dopaminergic system.
Assuntos
Drogas Desenhadas/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Dopamina , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Alucinógenos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Fenetilaminas , Ratos , Ratos Sprague-Dawley , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismoRESUMO
In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.