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1.
PLoS One ; 18(1): e0273888, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36598915

RESUMO

Methamphetamine (METH) can induce spermatogenesis impairment, testicular apoptosis, and abnormal sperm quality. It also promotes changes in the expression of receptors for sex hormones and neurotransmitters, including GABA receptors in the testis. Proteomic assessment focusing on proteins involved in the calcium signalling pathway in the testis can facilitate diagnostic factors contributing to testicular and sperm functions, especially those related to spermatogenesis and fertilisation. In this study, we proposed to determine the localisation and differential expression of GABA A receptor alpha 1 subunit (GABA A-α1) in the spermatozoa of METH-administered rats. The differential proteomic profile of the testis was also observed by focusing on proteins in the KEGG pathways belonging to the calcium signalling pathway. There were 212 differentially expressed proteins in the rat testis, based on the cut-off value of 1.2-fold change. Most of those proteins, 13 proteins, were classified in the calcium signalling pathway, including 4 down-regulated and 9 up-regulated proteins. An immunolocalisation study of the GABA A-α1 receptor and calbindin revealed their localisation in the equatorial segment of the head in the rat spermatozoa. The expression of calbindin is also found in the middle piece of sperm. An increase in GABA A-α1 receptor in rat spermatozoa was correlated with an increase in abnormal sperm motility and morphology after methamphetamine exposure. Moreover, calbindin expression in sperm decreased in METH-administered rats. All our findings demonstrate that METH influences intracellular calcium homeostasis by acting through the calcium signalling pathway-associated proteins. Moreover, it might disrupt ion homeostasis in sperm through the GABA A-α1 receptor and calbindin, triggering a change in intracellular calcium and chloride ions. These changes may cause abnormalities in spermatogenesis, testicular apoptosis, and sperm quality impairment.


Assuntos
Metanfetamina , Testículo , Masculino , Ratos , Animais , Testículo/metabolismo , Receptores de GABA-A/metabolismo , Metanfetamina/farmacologia , Proteômica , Cálcio/metabolismo , Motilidade Espermática , Sêmen/metabolismo , Espermatozoides/metabolismo , Espermatogênese/fisiologia , Ácido gama-Aminobutírico/metabolismo
2.
BMC Neurosci ; 24(1): 2, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631757

RESUMO

BACKGROUND: The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT2A receptor agonists such as ( ±)- 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT1A receptors, but enhanced DOI-evoked c-fos expression. d-Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d-fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d-fenfluramine-evoked c-fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors would prevent suppressive effect of MA on d-fenfluramine-induced HTR. RESULTS: EMD 281014 (0.001-0.05 mg/kg) or MA (0.1-5 mg/kg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT1A antagonist WAY 100635 countered the inhibitory effect of MA on d-fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ2 antagonist RS 79948 reversed MA's inhibitory effect in both 20- and 30- day old mice. d-Fenfluramine significantly increased c-fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d-fenfluramine-evoked c-fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d-fenfluramine-induced c-fos expression, but significantly increased it in one PFC region (PrL at - 2.68 mm). CONCLUSION: EMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT2A- and the inhibitory 5-HT1A- and ɑ2-receptors. MA-evoked increases in c-fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d-fenfluramine-evoked changes in c-fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.


Assuntos
Fenfluramina , Metanfetamina , Humanos , Camundongos , Animais , Fenfluramina/metabolismo , Fenfluramina/farmacologia , Metanfetamina/farmacologia , Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Córtex Pré-Frontal , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Envelhecimento
3.
Life Sci Alliance ; 6(3)2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36669783

RESUMO

For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Metanfetamina , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Metanfetamina/farmacologia , Neoplasias Hepáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus
4.
Drug Alcohol Depend ; 242: 109719, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36521236

RESUMO

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Ratos , Animais , Metanfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Glutamato Carboxipeptidase II/uso terapêutico , Riluzol/uso terapêutico , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Glutamatos/uso terapêutico
5.
Neurosci Lett ; 792: 136952, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36336087

RESUMO

Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Animais , Camundongos , Metanfetamina/farmacologia , Trocador de Sódio e Cálcio/metabolismo , Núcleo Accumbens/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Recompensa , Estimulantes do Sistema Nervoso Central/farmacologia
6.
Brain Res Bull ; 193: 47-58, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36516898

RESUMO

Methamphetamine (METH) is a potent and highly addictive psychostimulant and one of the most widely used illicit drugs, the abuse of which has become a severe public health problem worldwide. A growing amount of evidence has indicated potential connections between gut microbiota and mental disorders induced by METH and associations with neural and metabolic pathways. The present study aimed to explore the relationship between fecal microbial alterations and neuropsychiatric diseases in METH addictions. Thus, mental disorders and gut microbial alterations were analyzed by self-rating depression (SDS) and anxiety (SAS) scales and 16 S rRNA gene sequencing, respectively. Our results showed that increased SDS and SAS indices and decreased alpha diversity indicated more serious mental disorders and lower bacterial diversity in METH users than in the age-matched healthy control group. The gut microbial composition in female METH users was also significantly altered, with reductions in hydrogen-producing bacteria, including Bacteroides and Roseburia. Molecular hydrogen (H2) is spontaneously produced by intestinal bacteria in the process of anaerobic metabolism, which is the main pathway for H2 production in vivo. Numerous studies have shown that hydrogen intervention can significantly improve neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease. Our results showed that hydrogen intervention, including drinking and inhaling, significantly alleviated mental disorders induced by METH abuse, and the inhalation of hydrogen also altered gut microbiota profiles in the METH abusers. These results suggest that hydrogen intervention has potential therapeutic applicability in the treatment of mental disorders in METH abusers.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Microbioma Gastrointestinal , Metanfetamina , Humanos , Feminino , Metanfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia
7.
Peptides ; 160: 170926, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565856

RESUMO

The present study, regarding the orexin receptors having a pivotal role in reward-related psychostimulant use disorder (PUD), aimed to investigate the role of orexin-2 (OX2) receptors in the CA1 region of the hippocampus (HPC) in the extinction and reinstatement of methamphetamine (METH)-induced conditioned place preference (CPP). In the first set of investigations, to determine the role of OX2 receptors in the extinction of METH-induced CPP, rats were daily given (during the extinction) bilaterally intra-CA1 region different doses of TCS OX2 29 (1, 3, 10, and 30 nmol/0.5 µl 12% DMSO) as the selective OX2 receptor antagonist. Then, to demonstrate the role of OX2 receptors in the reinstatement of METH-induced CPP after the extinction was established, each rat bilaterally received TCS OX2 29 at the same doses in the CA1 region before injection of the sub-threshold (priming) dose of METH (0.25 mg/kg, sc) on the reinstatement day. The data revealed that the administration of TCS OX2 29 in the CA1 region reduces the mean extinction latency and suppresses the reinstatement of METH-seeking behavior in extinguished rats. Additionally, the potency of TCS OX2 29 to inhibit the reinstatement phase was higher compared to the potency of this drug to modulate the extinction phase of METH-induced CPP. Accordingly, it could be concluded that the blockade of the OX2 receptors in this area might be an essential application and potential therapeutics in treating METH use disorder.


Assuntos
Extinção Psicológica , Metanfetamina , Ratos , Animais , Orexinas/farmacologia , Metanfetamina/farmacologia , Receptores de Orexina/metabolismo , Ratos Wistar , Morfina/farmacologia , Hipocampo/metabolismo
8.
Dev Psychobiol ; 65(1): e22350, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36567658

RESUMO

Methamphetamine use by women, even throughout pregnancy, is common. But there is limited knowledge about the effects in prenatally methamphetamine-exposed children. This study investigated how prenatal methamphetamine exposure in rats, via maternal i.v. self-administration, affected the sensitivity of adult offspring to methamphetamine in comparison with controls. The offspring were generated from dams either self-administering methamphetamine daily under limited-access conditions prior to and throughout pregnancy, or their respective saline-yoked control dams. Spontaneous and methamphetamine-induced locomotor activity was assessed in male and female offspring of both exposure groups after a range of methamphetamine doses. In a separate group of offspring, acquisition of i.v. methamphetamine self-administration, responding under fixed and progressive ratio schedules of methamphetamine reinforcement, and reinstatement of extinguished drug-seeking behavior were assessed. Methamphetamine dose-dependently increased locomotor activity in both exposure groups. However, methamphetamine-exposed males showed significantly enhanced locomotor activity compared with controls at 1 mg/kg, and methamphetamine-exposed females showed significantly enhanced locomotor activity compared with controls at 3.2 mg/kg. Methamphetamine-exposed offspring of both sexes acquired methamphetamine self-administration faster and showed overall higher levels of methamphetamine-induced reinstatement compared with controls. Taken together, these results indicate that prenatal methamphetamine exposure to relatively low levels alters methamphetamine sensitivity in male and female adult offspring.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Ratos , Feminino , Masculino , Animais , Metanfetamina/farmacologia , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração , Estimulantes do Sistema Nervoso Central/farmacologia
9.
Addict Biol ; 28(1): e13255, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36577725

RESUMO

Methamphetamine (METH) is a commonly abused addictive psychostimulant, and METH-induced neurotoxic and behavioural deficits are in a sex-specific manner. However, there is lack of biomarkers to evaluate METH addiction in clinical practice, especially for gender differences. We utilized ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to detect the serum metabolomics in METH addicts and controls, specially exploring the sex-specific metabolic alterations by METH abuse. We found that many differently expressed metabolites in METH addicts related to metabolisms of amino acid, energy, vitamin and neurological disorders. Further, METH abuse caused different patterns of metabolomics in a sex-specific manner. As to amino acid metabolism, L-phenylalanine, L-tryptophan and L-histidine in serum of male addicts and betaine in serum of female addicts were significantly changed by METH use. In addition, it seemed that purine and pyrimidine-related metabolites (e.g., xanthosine and adenosine 5'-monophosphate) in male and the metabolites of hormone (e.g., cortisol) and folate biosynthesis (e.g., 7,8-dihydrobiopterin and 4-hydroxybenzoic acid) in female were more sensitive to METH addiction. Our findings revealed that L-glutamic acid, L-aspartic acid, alpha-ketoglutarate acid and citric acid may be potential biomarkers for monitoring METH addiction in clinic. Considering sex-specific toxicity by METH, the metabolites of purine and pyrimidine metabolism in male and those of stress-related hormones in female may be used to facilitate the accurate diagnosis and treatment for METH addicts of different genders.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Metanfetamina , Feminino , Masculino , Humanos , Metanfetamina/farmacologia , Espectrometria de Massas em Tandem , Biomarcadores/metabolismo , Purinas , Aminoácidos , Pirimidinas
10.
Behav Brain Res ; 437: 114109, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36108778

RESUMO

Human immunodeficiency virus (HIV) continues to infect millions worldwide, negatively impacting neurobehavioral function. Further understanding of the combined effects of HIV and methamphetamine use is crucial, as methamphetamine use is prevalent in people with HIV. The HIV-associated protein Tat may contribute to cognitive dysfunction, modeled preclinically in mice using doxycycline (DOX)-inducible Tat expression (iTat). Tat may exert its effects on cognitive function via disruption of the dopamine transporter, similar to the action of methamphetamine. Additionally, Tat and methamphetamine both decrease interneuron populations, including those expressing calbindin. It is important to understand the combined effects of Tat and methamphetamine in preclinical models of HIV infection. Here, we used iTat transgenic mice and a chronic binge regimen of methamphetamine exposure to determine their combined impact on reward learning and motivation. We also measured calbindin expression in behavior-relevant brain regions. Before induction with DOX, iTat mice exhibited no differences in behavior. Chronic methamphetamine exposure before Tat induction impaired initial reward learning but did not affect motivation. Furthermore, DOX-induced Tat expression did not alter behavior, but slowed latencies to retrieve rewards. This effect of Tat, however, was not observed in methamphetamine-treated mice, indicative of a potential protective effect. Finally, Tat expression was associated with an increase in calbindin-expressing cells in the VTA, while methamphetamine exposure did not alter calbindin numbers. These findings may indicate a protective role of methamphetamine in HIV neuropathology, which in turn may help in our understanding of why people with HIV use methamphetamine at disproportionately higher rates.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Infecções por HIV , Metanfetamina , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Animais , Humanos , Camundongos , Calbindinas/metabolismo , Modelos Animais de Doenças , Infecções por HIV/complicações , Infecções por HIV/psicologia , Metanfetamina/efeitos adversos , Metanfetamina/farmacologia , Camundongos Transgênicos , Recompensa , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo
11.
Brain Behav Immun ; 107: 47-52, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36174884

RESUMO

P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned place preference (CPP), and intracranial self-stimulation (ICSS) assays, we tested the hypothesis that methamphetamine (METH) reward and acute locomotor activation requires P2X7 receptor activity. We also investigated effects of P2X7 blockade on METH-induced changes in cytokine levels in brain reward regions. A438079 (5, 10, 50 mg/kg), a P2X7 antagonist, did not affect spontaneous locomotor activity but reduced hyperlocomotion caused by acute METH (1 mg/kg) exposure. A438079 (10 mg/kg) also prevented expression of METH CPP without causing aversive or rewarding effects. For ICSS experiments, METH (1 mg/kg) facilitated brain reward function as interpreted from reductions in baseline threshold. In the presence of A438079 (50 mg/kg), METH-induced facilitation of ICSS was reduced. Repeated METH exposure (1 mg/kg × 7 d) caused enhancement of IL-17A levels in the prefrontal cortex (PFC) that was normalized by A438070 (10 mg/kg × 7 d). The present data suggest that P2X7 receptor activity contributes to rewarding and locomotor-stimulant effects of METH through a potential mechanism involving IL-17A, which has recently been implicated in anxiety.


Assuntos
Metanfetamina , Animais , Camundongos , Metanfetamina/farmacologia , Receptores Purinérgicos P2X7 , Antagonistas do Receptor Purinérgico P2X , Interleucina-17
12.
F1000Res ; 11: 1018, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226037

RESUMO

The last 50 years have witnessed extraordinary discoveries in the field of circadian rhythms. However, there are still several mysteries that remain. One of these chronobiological mysteries is the circadian rhythm that is revealed by administration of stimulant drugs to rodents. Herein we describe the discovery of this circadian rhythm and its underlying oscillator, which is frequently called the methamphetamine-sensitive circadian oscillator, or MASCO. This oscillator is distinct from canonical circadian oscillators because it controls robust activity rhythms independently of the suprachiasmatic nucleus and circadian genes are not essential for its timekeeping. We discuss these fundamental properties of MASCO and integrate studies of strain, sex, and circadian gene mutations on MASCO. The anatomical loci of MASCO are not known, so it has not been possible thus far to discover its novel molecular timekeeping mechanism or its functional significance. However, studies in mutant mice suggest that genetic approaches can be used to identify the neural network involved in the rhythm generation of MASCO. We also discuss parallels between human and rodent studies that support our working hypothesis that a function of MASCO may be to regulate sleep-wake cycles.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Camundongos , Humanos , Animais , Metanfetamina/farmacologia , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Núcleo Supraquiasmático/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ritmo Circadiano/genética
13.
Psychopharmacology (Berl) ; 239(12): 3833-3846, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36269378

RESUMO

RATIONALE: The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches. OBJECTIVES: In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae. METHODS: Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format. RESULTS: METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems. CONCLUSIONS: These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.


Assuntos
Metanfetamina , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Metanfetamina/farmacologia , Larva , Dopamina/farmacologia , Convulsões/induzido quimicamente , Antagonistas de Aminoácidos Excitatórios/farmacologia
14.
Front Endocrinol (Lausanne) ; 13: 999211, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36204112

RESUMO

Methamphetamine (METH) abuse can result in severe neurotoxicity, for which the mechanism is not yet clear. In the present study, we investigated the role of noncoding RNAs in METH-induced dopaminergic neurotoxicity, and analyzed the underlying mechanism using bioinformatic methods. We confirmed by flow cytometry that miR-129-1-3p is involved in promoting dopaminergic apoptosis under METH treatment and its role could be inhibited by a high concentration of circ_0015891. Also, we combined transcriptomic data with bioinformatics to explore the downstream mechanism of miR-129-1-3p regulation of METH-induced apoptosis, highlighted the potentially pivotal figure of response to nutrition. Further bioinformatic analysis of circ_0015891 was conducted as well and showed that circ_0015891 was the sponge of various microRNAs that effect apoptosis by different mechanisms. Collectively, we found a novel circ_0015891/miR-129-1-3p axis that may be a promising therapeutic target for METH-induced dopaminergic neurotoxicity.


Assuntos
Metanfetamina , MicroRNAs , Apoptose/genética , Proliferação de Células , Biologia Computacional , Metanfetamina/farmacologia , MicroRNAs/genética , RNA Circular/genética
15.
Pharmacol Biochem Behav ; 220: 173470, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36206863

RESUMO

BACKGROUND: Polydrug use is well documented in synthetic cathinone users, although the consequences of such use are not well characterized. In pre-clinical research, a pre-exposure to a drug has been reported to attenuate the aversive effects of other drugs which has implications for their abuse potential. The goal of the present study was to investigate the impact of pre-exposure to the synthetic cathinone methylone on the aversive effects of MDPV and MDMA. METHOD: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of five injections) prior to taste avoidance training with 1.8 mg/kg of MDPV or 1 mg/kg of MDMA. RESULTS: MDPV and MDMA induced taste avoidance in males and females (all p's < 0.05). In males, methylone pre-exposure attenuated the avoidance induced by MDPV and MDMA (all p's < 0.05) with the attenuation greater with MDPV. In females, methylone pre-exposure attenuated avoidance induced by MDPV (all p's < 0.05), but it had no effect on those induced by MDMA (all p's > 0.05). CONCLUSIONS: The effects of exposure to methylone on taste avoidance induced by MDPV and MDMA were drug- (MDPV > MDMA) and sex- (MDMA only in males) dependent. The attenuating effects of methylone pre-exposure on MDPV and MDMA were discussed in terms of their shared neurochemical action. These findings suggest that a history of methylone use may reduce the aversive effects of MDPV and MDMA which may have implications for polydrug use involving the synthetic cathinones.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Transtornos Relacionados ao Uso de Substâncias , Animais , Benzodioxóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Metanfetamina/análogos & derivados , Metanfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley
16.
Genes (Basel) ; 13(10)2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-36292701

RESUMO

Polysubstance use (PSU) generally involves the simultaneous use of an opioid along with a stimulant. In recent years, this problem has escalated into a nationwide epidemic. Understanding the mechanisms and effects underlying the interaction between these drugs is essential for the development of treatments for those suffering from addiction. Currently, the effect of PSU on synapses-critical points of contact between neurons-remains poorly understood. Using an in vitro model of primary neurons, we examined the combined effects of the psychostimulant methamphetamine (METH) and the prescription opioid oxycodone (oxy) on the synaptic proteome using quantitative mass-spectrometry-based proteomics. A further ClueGO analysis and Ingenuity Pathway Analysis (IPA) indicated the dysregulation of several molecular functions, biological processes, and pathways associated with neural plasticity and structural development. We identified one key synaptic protein, Striatin-1, which plays a vital role in many of these processes and functions, to be downregulated following METH+oxy treatment. This downregulation of Striatin-1 was further validated by Western blot. Overall, the present study indicates several damaging effects of the combined use of METH and oxy on neural function and warrants further detailed investigation into mechanisms contributing to synaptic dysfunction.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Metanfetamina/farmacologia , Oxicodona/farmacologia , Proteoma/genética , Analgésicos Opioides , Estimulantes do Sistema Nervoso Central/farmacologia
17.
Addict Biol ; 27(6): e13240, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36301216

RESUMO

Previously, bupropion (BUP), a norepinephrine (NE)/dopamine (DA) transporter blocker and nicotinic acetylcholine receptors (nAChRs) antagonist, was found to intensify methamphetamine (METH) craving behaviours in mice. Intense craving causes relapse in drug dependence. This study characterized local field potential (LFP) patterns in the brain regions associated with METH-conditioned place preference (CPP) enhanced by BUP. Male Swiss albino ICR mice were implanted with LFP electrodes to the ventral tegmental area (VTA), medial prefrontal cortex (mPFC) and the nucleus accumbens core (NAcc). Animals received sessions to learn the association between injection effects (1 mg/kg METH and normal saline) with contextual environments (METH- and saline-paired compartments) during the conditioning phase. A total of 20 mg/kg BUP was given to animals before LFP, and behaviour recording in the CPP apparatus during the post-conditioning phase. The results showed that increased CPP scores and % number of entries to the METH-paired zone, as well as changes in VTA, mPFC and NAcc spectral powers and coherence among these areas, were associated with METH-CPP. Treatment with BUP increased VTA delta and gamma I, decreased mPFC alpha, increased NAcc gamma I and decreased gamma II powers. Coherence analyses revealed that BUP decreased gamma II VTA-mPFC and increased beta and gamma I VTA-NAcc connectivity. Altogether, BUP produced additional effects to that of METH-CPP alone. These findings demonstrated changes in neural circuit activities associated with METH-CPP intensified by BUP. Moreover, modulation of NE/DA systems and/or nAChRs actions in the VTA-cortico-accumbens loop might underlie METH craving and dependence.


Assuntos
Metanfetamina , Área Tegmentar Ventral , Animais , Camundongos , Masculino , Metanfetamina/farmacologia , Bupropiona/farmacologia , Fissura , Núcleo Accumbens , Antagonistas Nicotínicos/farmacologia
18.
Front Immunol ; 13: 952183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059515

RESUMO

HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation. Substance use disorders in PWH, including the use of methamphetamine (meth), can exacerbate HIV neuropathogenesis. We characterized the effects of meth on the transcriptional profile of HIV-infected mature monocytes using RNA-sequencing. We found that meth mediated an upregulation of gene transcripts related to viral infection, cell adhesion, cytoskeletal arrangement, and extracellular matrix remodeling. We also identified downregulation of several gene transcripts involved in pathogen recognition, antigen presentation, and oxidative phosphorylation pathways. These transcriptomic changes suggest that meth increases the infiltration of mature monocytes that have a migratory phenotype into the CNS, contributing to dysregulated inflammatory responses and viral reservoir establishment and persistence, both of which contribute to neuronal damage. Overall, our results highlight potential molecules that may be targeted for therapy to limit the effects of meth on HIV neuropathogenesis.


Assuntos
Infecções por HIV , Metanfetamina , Humanos , Macrófagos/metabolismo , Metanfetamina/farmacologia , Monócitos , Qualidade de Vida
19.
Brain Struct Funct ; 227(8): 2681-2699, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36112231

RESUMO

Drug memory is associated with drug-taking experience and environmental cues, which mainly contribute to addiction. Recent studies report that glycogenolysis-derived lactate from astrocyte transport to neurons is necessary for long-term potentiation and memory formation instead of its function as an energy substrate. However, the role of astrocyte-neuron lactate transfer in neuronal plasticity and methamphetamine (METH)-induced addiction memory consolidation and retrieval, especially the underlying mechanisms, are not clear. C57BL/6 J mice trained for METH-induced conditioned place preference (CPP) were stereotaxically injected with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) into the dorsal hippocampus (dHPC) 15 min before training. The CPP score was recorded, and neuronal synaptic plasticity was detected with Golgi staining. The neuronal Ca2+ levels were examined using AAV-GCaMP6 injection. Moreover, monocarboxylate transporters (MCT1, MCT2, MCT4) were inhibited with oligodeoxynucleotides in the dHPC to further prove the METH appetitive memory changes. The data showed that inhibiting lactate transport by microinjection with DAB or monocarboxylate transporter oligodeoxynucleotides in the dHPC completely destroyed METH-induced CPP, reduced Npas4 and other plasticity-associated gene expression and decreased neuronal Ca2+ levels and neuronal arborization and spine density, all of which were fully rescued by L-lactate coadministration except for MCT2-ODN administration. Furthermore, the downstream signaling molecule NADH could mimic lactate's effects and trigger METH CPP by influencing the redox state of neurons and regulating NMDA receptor activity. Collectively, these findings indicate that astrocyte-neuron lactate transfer is crucial for METH-induced memory consolidation and retrieval.


Assuntos
Consolidação da Memória , Metanfetamina , Camundongos , Animais , Metanfetamina/farmacologia , Astrócitos/metabolismo , NAD/metabolismo , NAD/farmacologia , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Hipocampo/metabolismo , Oligodesoxirribonucleotídeos/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
20.
Behav Brain Res ; 435: 114064, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-35987306

RESUMO

Repeated methamphetamine exposure impairs reversal learning in laboratory animals and downregulates dopamine D2 receptor expression. In the present study, we tested the possibility that repeated exposure to the dopamine D2 antagonist, eticlopride, would increase D2 receptor expression, improve behavioral flexibility and restore behavioral flexibility that was disrupted by exposure to methamphetamine in rats. Male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, 14 days). Three days after the last treatment, whole brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry in one group and reversal learning performance was measured in another group. Reversal learning was also measured in other groups prior to and after methamphetamine exposure (0.0 or 2.0 mg/kg, 4 injections, 2 h apart, 1 day) followed by repeated eticlopride (0.0 or 0.3 mg/kg, 14 days) treatment. Eticlopride treatment increased D2 receptor expression and improved reversal learning performance. Methamphetamine impaired reversal learning performance and eticlopride treatment reversed the deficit. These results suggest that repeated administration of eticlopride can restore behavioral flexibility and that upregulation of D2 receptors might be an effective adjunct to treatment of methamphetamine misuse.


Assuntos
Metanfetamina , Animais , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Metanfetamina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Salicilamidas/farmacologia
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