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1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638827

RESUMO

Interaction of cannabinoid receptor type 1 (CB1) and GABAergic neuronal activity is involved in drug abuse-related behavior. However, its role in drug-dependent Pavlovian conditioning is not well understood. In this study, we aimed to evaluate the effects of a CB1 agonist, JWH-210, on the development of conditioned place preference (CPP)-induced by methamphetamine (METH). Pretreatment with a synthetic cannabinoid, JWH-210 (CB1 agonist), increased METH-induced CPP score and METH-induced dopamine release in acute striatal slices. Interestingly, CB1 was expressed in glutamate decarboxylase 67 (GAD67) positive cells, and overexpression of CB1 increased GAD67 expression, while CB1 knockdown reduced GAD67 expression in vivo and in vitro. GAD67 is known as an enzyme involved in the synthesis of GABA. CB1 knockdown in the mice striatum increased METH-induced CPP. When GAD67 decreased in the mice striatum, mRNA level of CB1 did not change, suggesting that CB1 can regulate GAD67 expression. GAD67 knockdown in the mouse striatum augmented apomorphine (dopamine receptor D2 agonist)-induced climbing behavior and METH-induced CPP score. Moreover, in the human brain, mRNA level of GAD67 was found to be decreased in drug users. Therefore, we suggest that CB1 potentiates METH-induced CPP through inhibitory GABAergic regulation of dopaminergic neuronal activity.


Assuntos
Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Regulação Enzimológica da Expressão Gênica , Glutamato Descarboxilase/biossíntese , Receptor CB1 de Canabinoide/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Apomorfina/farmacologia , Técnicas de Silenciamento de Genes , Glutamato Descarboxilase/genética , Humanos , Indóis/farmacologia , Masculino , Metanfetamina/farmacologia , Camundongos , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética
2.
Drug Alcohol Depend ; 227: 108930, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358767

RESUMO

BACKGROUND: The present study investigated the effects of the dual orexin receptor antagonist (DORA) almorexant, a sleep-modulating drug, on the sleep-disrupting effects of methamphetamine in adult rhesus monkeys. METHODS: Monkeys were fitted with primate collars to which actigraphy monitors were attached. To determine the effects of methamphetamine on daytime activity and sleep-like parameters, monkeys were given acute injections of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.) in the morning (9:00 h) (n = 4 males). We then determined the ability of almorexant to alter the daytime and/or sleep-like effects of the largest (effective) dose of methamphetamine. Vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30 h, 1.5 h before "lights off") following morning (9:00 h) administration of methamphetamine (0.3 mg/kg, i.m.), or as a pretreatment (8:30 h) before methamphetamine injections (9:00 h) (n = 4 males). The ability of almorexant (10 mg/kg) to improve sleep-like behaviors also was assessed in a group of monkeys quantitatively identified with short-duration sleep (n = 2 males, 2 females). RESULTS: Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys (0.3 mg/kg significantly increased sleep latency and decreased sleep efficiency). Administration of almorexant, both as a pretreatment or as an evening treatment, improved methamphetamine-induced sleep impairment in a dose dependent manner. Morning pretreatment with almorexant also blocked the daytime stimulant effects of methamphetamine. Evening, but not morning, treatment with almorexant in a group of monkeys with baseline short-duration sleep improved sleep measures. CONCLUSIONS: Our findings indicate that orexin receptor systems are involved in methamphetamine-induced hyperarousal and sleep disruption.


Assuntos
Metanfetamina , Acetamidas , Animais , Feminino , Isoquinolinas , Macaca mulatta , Masculino , Metanfetamina/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Sono
3.
Psychopharmacology (Berl) ; 238(10): 2947-2961, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34268586

RESUMO

RATIONALE: Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood. OBJECTIVES: The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress - CMUS) on the liability to mephedrone-induced reward in Wistar rats. METHODS: The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively. RESULTS: Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats' prefrontal cortex and hippocampus. CONCLUSIONS: Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.


Assuntos
Metanfetamina , Caracteres Sexuais , Animais , Condicionamento Clássico , Feminino , Masculino , Metanfetamina/análogos & derivados , Metanfetamina/farmacologia , Ratos , Ratos Wistar , Recompensa
4.
Psychopharmacology (Berl) ; 238(11): 3207-3219, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34313802

RESUMO

RATIONALE: MicroRNAs (miRNAs) regulate neuroplasticity-related proteins and are implicated in methamphetamine (METH) addiction. RhoA is a small Rho GTPase that regulates synaptic plasticity and addictive behaviors. Nevertheless, the functional relationship between RhoA and upstream miRNAs of METH addiction remains unclear. OBJECTIVE: To explore the molecular biology and epigenetic mechanisms of the miR-31-3p/RhoA pathway in METH addiction. METHODS: RhoA protein and its potential upstream regulator, miR-31-3p, were detected. A dual luciferase reporter was employed to determine whether RhoA constituted a specific target of miR-31-3p. Following adeno-associated virus (AAV)-mediated knockdown or overexpression of miR-31-3p or RhoA in the dorsal hippocampus (dHIP), mice were subjected to conditioned place preference (CPP) to investigate the effects of miR-31-3p and RhoA on METH-induced addictive behaviors. RESULTS: RhoA protein was significantly decreased in the dHIP of CPP mice with a concomitant increase in miR-31-3p. RhoA was identified as a direct target of miR-31-3p. Knockdown of miR-31-3p in the dHIP was associated with increased RhoA protein and attenuation of METH-induced CPP. Conversely, overexpression of miR-31-3p was associated with decreased RhoA protein and enhancement of METH effects. Similarly, knockdown of RhoA in the dHIP enhanced METH-induced CPP, whereas RhoA overexpression attenuated the effects of METH. Parallel experiments using sucrose preference revealed that the effects of miR-31-3p/RhoA pathway modulation were specific to METH. CONCLUSIONS: Our findings indicate that the miR-31-3p/RhoA pathway in the dHIP modulates METH-induced CPP in mice. Our results highlight the potential role of epigenetics represented by non-coding RNAs in the treatment of METH addiction.


Assuntos
Metanfetamina , MicroRNAs , Animais , Condicionamento Clássico , Hipocampo , Metanfetamina/farmacologia , Camundongos , MicroRNAs/genética , Proteína rhoA de Ligação ao GTP
5.
J Neurochem ; 158(4): 865-879, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34265079

RESUMO

Methamphetamine (METH) is a potent psychostimulant that exerts many of its physiological and psychomotor effects by increasing extracellular dopamine (DA) concentrations in limbic brain regions. While several studies have focused on how potent, neurotoxic doses of METH augment or attenuate DA transmission, the acute effects of lower and behaviorally activating doses of METH on modulating DA regulation (release and clearance) through DA D2 autoreceptors and transporters remain to be elucidated. In this study, we investigated how systemic administration of escalating, subneurotoxic doses of METH (0.5-5 mg/kg, IP) alter extracellular DA regulation in the nucleus accumbens (NAc), in both anesthetized and awake-behaving rats through the use of in vivo fast-scan cyclic voltammetry. Pharmacological, electrochemical, and behavioral evidence show that lower doses (≤2.0 mg/kg, IP) of METH enhance extracellular phasic DA concentrations and locomotion as well as stereotypies. In contrast, higher doses (≥5.0 mg/kg) further increase both phasic and baseline DA concentrations and stereotypies but decrease horizontal locomotion. Importantly, our results suggest that acute METH-induced enhancement of extracellular DA concentrations dose dependently activates D2 autoreceptors. Therefore, these different METH dose-dependent effects on mesolimbic DA transmission may distinctly impact METH-induced behavioral changes. This study provides valuable insights regarding how low METH doses alter DA transmission and paves the way for future clinical studies on the reinforcing effects of METH.


Assuntos
Comportamento Animal/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/fisiologia , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/psicologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos
6.
Curr Top Med Chem ; 21(11): 964-975, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34061003

RESUMO

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Preparações Farmacêuticas/metabolismo , Álcoois/metabolismo , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Cannabis/metabolismo , Cocaína/metabolismo , Cocaína/farmacologia , Humanos , Ligantes , Metanfetamina/metabolismo , Metanfetamina/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Nicotina/metabolismo , Oxirredução , Isoformas de Proteínas , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo
7.
PLoS One ; 16(6): e0252895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34115777

RESUMO

Illicit drugs are known to affect central nervous system (CNS). Majorly psychostimulants such as cocaine, methamphetamine (METH) and opioids such as morphine are known to induce epigenetic changes of histone modifications and chromatin remodeling which are mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Aberrant changes in histone acetylation-deacetylation process further exacerbate dysregulation of gene expression and protein modification which has been linked with neuronal impairments including memory formation and synaptic plasticity. In CNS, astrocytes play a pivotal role in cellular homeostasis. However, the impact of psychostimulants and opioid mediated epigenetic changes of HAT/HADCs in astrocytes has not yet been fully elucidated. Therefore, we have investigated the effects of the psychostimulants and opioid on the acetylation-regulating enzymes- HAT and HDACs role in astrocytes. In this study, Class I and II HDACs and HATs gene expression, protein changes and global level changes of acetylation of H3 histones at specific lysines were analyzed. In addition, we have explored the neuroprotective "nootropic" drug piracetam were exposed with or without psychostimulants and opioid in the human primary astrocytes. Results revealed that psychostimulants and opioid upregulated HDAC1, HDAC4 and p300 expression, while HDAC5 and GCN5 expression were downregulated. These effects were reversed by piracetam coexposure. Psychostimulants and opioid exposure upregulated global acetylation levels of all H3Ks, except H3K14. These results suggest that psychostimulants and opioids differentially influence HATs and HDACs.


Assuntos
Astrócitos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Histona Acetiltransferases/genética , Histona Desacetilases/genética , Metanfetamina/farmacologia , Morfina/farmacologia , Acetilação/efeitos dos fármacos , Astrócitos/enzimologia , Epigênese Genética/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Humanos , Piracetam/farmacologia , Cultura Primária de Células , Regulação para Cima/efeitos dos fármacos
9.
Proteomics ; 21(15): e2100005, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051048

RESUMO

HIV-1 infection of macrophages is a multistep and multifactorial process that has been shown to be enhanced by exposure to methamphetamine (Meth). In this study, we sought to identify the underlying mechanisms of this effect by quantifying the effect of Meth on the proteome of HIV-1-infected macrophages using sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) approach. The analyses identified several members of the Rab family of proteins as being dysregulated by Meth treatment, which was confirmed by bioinformatic analyses that indicated substantial alteration of vesicular transport pathways. Validation of the SWATH-MS was performed using an MRM based approach, which confirmed that Meth exposure affects expression of the Rab proteins. However, the pattern of expression changes were highly dynamic, and displayed high donor-to-donor variability. Surprisingly a similar phenomenon was observed for Actin. Our results demonstrate that Meth affects vesicular transport pathways, suggesting a possible molecular mechanism underlying its effect on HIV infection hMDM and a potential broader effect of Meth on cellular homeostasis.


Assuntos
Infecções por HIV , HIV-1 , Metanfetamina , Humanos , Macrófagos , Metanfetamina/farmacologia , Proteoma
10.
Neurochem Res ; 46(8): 2008-2018, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33993443

RESUMO

Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant's rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Canabidiol/uso terapêutico , Fármacos do Sistema Nervoso Central/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Metanfetamina/farmacologia , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Região CA1 Hipocampal/metabolismo , Antagonistas de Dopamina/farmacologia , Masculino , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores
11.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946401

RESUMO

The deposition of amyloid-beta (Aß) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer's disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the "Molecule Activity Predictor" feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Proteína HMGB1/metabolismo , Metanfetamina/farmacologia , Doença de Alzheimer/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/uso terapêutico , Humanos , Metanfetamina/uso terapêutico , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803075

RESUMO

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR-CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/metabolismo , Metanfetamina/farmacologia , Neurônios/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores sigma/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos
14.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668155

RESUMO

Although traumatic brain injury (TBI) causes hospitalizations and mortality worldwide, there are no approved neuroprotective treatments, partly due to a poor understanding of the molecular mechanisms underlying TBI neuropathology and neuroprotection. We previously reported that the administration of low-dose methamphetamine (MA) induced significant functional/cognitive improvements following severe TBI in rats. We further demonstrated that MA mediates neuroprotection in part, via dopamine-dependent activation of the PI3K-AKT pathway. Here, we further investigated the proteomic changes within the rat cortex and hippocampus following mild TBI (TM), severe TBI (TS), or severe TBI plus MA treatment (TSm) compared to sham operated controls. We identified 402 and 801 altered proteins (APs) with high confidence in cortical and hippocampal tissues, respectively. The overall profile of APs observed in TSm rats more closely resembled those seen in TM rather than TS rats. Pathway analysis suggested beneficial roles for acute signaling through IL-6, TGFß, and IL-1ß. Moreover, changes in fibrinogen levels observed in TSm rats suggested a potential role for these proteins in reducing/preventing TBI-induced coagulopathies. These data facilitate further investigations to identify specific pathways and proteins that may serve as key targets for the development of neuroprotective therapies.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Dopaminérgicos/farmacologia , Espectrometria de Massas/métodos , Metanfetamina/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteoma/metabolismo , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Masculino , Proteoma/análise , Ratos , Ratos Wistar , Transdução de Sinais
15.
Exp Eye Res ; 206: 108540, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33736986

RESUMO

Central retinal artery occlusion, retinopathy, and retinal neovascularization have been reported in methamphetamine (METH) abusers. In the current study, we investigated whether METH induces retinal neovascularization in a mouse model, and if so, whether the neovascularization is associated with increased hypoxia, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF). Mice were administrated METH by intraperitoneal injection over a 26-day period, or injected with saline as a vehicle control. The number of retinal arterioles and venules were counted using in vivo live imaging following infusion with fluorescein isothiocyanate-dextran. Excised retinas were stained with griffonia simplicifolia lectin I and flat mounted for a measurement of vascularity (length of vessels per tissue area) with AngioTool. Retinal hypoxia was examined by formation of pimonidazole adducts with an anti-pimonidazole antibody, and HIF-1α and VEGFa protein levels in the retina were detected by immunoblot. METH administration increased vascularity (including the number of arterioles) measured on Day 26. Retinal VEGFa protein level was not changed in METH-treated mice on Day 5, but was increased on Day 12 and Day 26. Hypoxia (pimonidazole adduct formation) was increased in retinas of METH-treated mice on Day 12 and Day 26, as were HIF-1α protein expression levels. These results indicate that METH administration induces hypoxia, HIF-1α, VEGFa, and angiogenesis in the retina.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/tratamento farmacológico , Metanfetamina/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Hipóxia/metabolismo , Hipóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Simpatomiméticos/farmacologia
16.
mBio ; 12(2)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33688011

RESUMO

"METH mouth" is a common consequence of chronic methamphetamine (METH) use, resulting in tooth decay and painful oral tissue inflammation that can progress to complete tooth loss. METH reduces the amount of saliva in the mouth, promoting bacterial growth, tooth decay, and oral tissue damage. This oral condition is worsened by METH users' compulsive behavior, including high rates of consumption of sugary drinks, recurrent tooth grinding, and a lack of frequent oral hygiene. Streptococcus mutans is a Gram-positive bacterium found in the oral cavity and associated with caries in humans. Hence, we developed a murine model of METH administration, sugar intake, and S. mutans infection to mimic METH mouth in humans and to investigate the impact of this drug on tooth colonization. We demonstrated that the combination of METH and sucrose stimulates S. mutans tooth adhesion, growth, and biofilm formation in vivo METH and sucrose increased the expression of S. mutans glycosyltransferases and lactic acid production. Moreover, METH contributes to the low environmental pH and S. mutans sucrose metabolism, providing a plausible mechanism for bacterium-mediated tooth decay. Daily oral rinse treatment with chlorhexidine significantly reduces tooth colonization in METH- and sucrose-treated mice. Furthermore, human saliva inhibits S. mutans colonization and biofilm formation after exposure to either sucrose or the combination of METH and sucrose. These findings suggest that METH might increase the risk of microbial dental disease in users, information that may help in the development of effective public health strategies to deal with this scourge in our society.IMPORTANCE "METH mouth" is characterized by severe tooth decay and gum disease, which often causes teeth to break or fall out. METH users are also prone to colonization by cariogenic bacteria such as Streptococcus mutans In addition, this oral condition is aggravated by METH users' compulsive behavior, including the consumption of beverages with high sugar content, recurrent tooth grinding, and a lack of frequent oral hygiene. We investigated the effects of METH and sugar consumption on S. mutans biofilm formation and tooth colonization. Using a murine model of METH administration, sucrose ingestion, and oral infection, we found that the combination of METH and sucrose increases S. mutans adhesion and biofilm formation on the teeth of C57BL/6 mice. However, daily chlorhexidine-based oral rinse treatment reduces S. mutans tooth colonization. Similarly, METH has been associated with dry mouth or hyposalivation in users. Hence, we assessed the impact of human saliva on biofilm formation and demonstrated that surface preconditioning with saliva substantially reduces S. mutans biofilm formation. Our results are significant because to our knowledge, this is the first basic science study focused on elucidating the fundamentals of METH mouth using a rodent model of prolonged drug injection and S. mutans oral infection. Our findings may have important translational implications for the development of treatments for the management of METH mouth and more effective preventive public health strategies that can be applied to provide effective dental care for METH users in prisons, drug treatment centers, and health clinics.


Assuntos
Açúcares da Dieta/administração & dosagem , Metanfetamina/farmacologia , Boca/efeitos dos fármacos , Boca/patologia , Streptococcus mutans/metabolismo , Animais , Aderência Bacteriana/efeitos dos fármacos , Biofilmes , Cárie Dentária , Modelos Animais de Doenças , Feminino , Infecções por Bactérias Gram-Positivas/microbiologia , Masculino , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Boca/microbiologia , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/crescimento & desenvolvimento , Dente/efeitos dos fármacos , Dente/microbiologia
17.
J Neuroinflammation ; 18(1): 63, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648543

RESUMO

BACKGROUND: Synthetic cathinones are a category of psychostimulants belonging to the growing number of designer drugs also known as "Novel Psychoactive Substances" (NPS). In recent years, NPS have gained popularity in the recreational drug market due to their amphetamine-like stimulant effects, low cost, ease of availability, and lack of detection by conventional toxicology screening. All these factors have led to an increase in NPS substance abuse among the young adults, followed by spike of overdose-related fatalities and adverse effects, severe neurotoxicity, and cerebral vascular complications. Much remains unknown about how synthetic cathinones negatively affect the CNS and the status of the blood-brain barrier (BBB). METHODS: We used in vitro models of the BBB and primary human brain microvascular endothelial cells (hBMVEC) to investigate the effects of the synthetic cathinone, 4-methyl methcathinone (mephedrone), on BBB properties. RESULTS: We showed that mephedrone exposure resulted in the loss of barrier properties and endothelial dysfunction of primary hBMVEC. Increased permeability and decreased transendothelial electrical resistance of the endothelial barrier were attributed to changes in key proteins involved in the tight junction formation. Elevated expression of matrix metalloproteinases, angiogenic growth factors, and inflammatory cytokines can be explained by TLR-4-dependent activation of NF-κB signaling. CONCLUSIONS: In this first characterization of the effects of a synthetic cathinone on human brain endothelial cells, it appears clear that mephedrone-induced damage of the BBB is not limited by the disruption of the barrier properties but also include endothelial activation and inflammation. This may especially be important in comorbid situations of mephedrone abuse and HIV-1 infections. In this context, mephedrone could negatively affect HIV-1 neuroinvasion and NeuroAIDS progression.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Drogas Desenhadas/farmacologia , Células Endoteliais/efeitos dos fármacos , Metanfetamina/análogos & derivados , Psicotrópicos/farmacologia , Células Cultivadas , Humanos , Metanfetamina/farmacologia
18.
J Neurochem ; 158(2): 429-443, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33655498

RESUMO

The major barrier to eradicating Human immunodeficiency virus-1 (HIV) infection is the generation of tissue-associated quiescent long-lasting viral reservoirs refractory to therapy. Upon interruption of anti-retroviral therapy (ART), HIV replication can be reactivated. Within the brain, microglia/macrophages and a small population of astrocytes are infected with HIV. However, the role of astrocytes as a potential viral reservoir is becoming more recognized because of the improved detection and quantification of HIV viral reservoirs. In this report, we examined the infectivity of human primary astrocytes in vivo and in vitro, and their capacity to maintain HIV infection, become latently infected, be reactivated, and transfer new HIV virions into neighboring cells. Analysis of human brain tissue sections obtained from HIV-infected individuals under effective and prolonged ART indicates that a small population of astrocytes has integrated HIV-DNA. In vitro experiments using HIV-infected human primary astrocyte cultures confirmed a low percentage of astrocytes had integrated HIV-DNA, with poor to undetectable replication. Even in the absence of ART, long-term culture results in latency that could be transiently reactivated with histone deacetylase inhibitor, tumor necrosis factor-alpha (TNF-α), or methamphetamine. Reactivation resulted in poor viral production but efficient cell-to-cell viral transfer into cells that support high viral replication. Together, our data provide a new understanding of astrocytes' role as viral reservoirs within the central nervous system (CNS).


Assuntos
Astrócitos/virologia , Encéfalo/virologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV , Replicação Viral/efeitos dos fármacos , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Pré-Escolar , DNA Viral/genética , Feminino , Infecções por HIV/transmissão , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Metanfetamina/farmacologia , Pessoa de Meia-Idade , Cultura Primária de Células , Fator de Necrose Tumoral alfa/farmacologia
19.
Eur J Pharmacol ; 900: 174066, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33789156

RESUMO

Methamphetamine (MA) abuse is associated with the development of pulmonary arterial hypertension (PAH) and subsequent right ventricular failure. A recent clinical study demonstrated that female sex is a major risk factor for MA-induced PAH. The mechanisms associated with increased prevalence and severity of MA-induced PAH in females are still unclear. We hypothesized that MA may promote changes in gene expression in the right ventricle contributing to the development and/or worsening of PAH in females. Male and female C57BL/6 mice were treated with either MA or vehicle. Right and left ventricular systolic pressures (RVSP and LVSP, respectively) were assessed and tissue samples were collected for gene expression and histology. LVSP and RVSP were not affected by MA in either males or females. Right ventricular hypertrophy was significantly increased by MA in females but it was not affected by MA in males. In the female mice, MA-induced right ventricular hypertrophy was associated with increased expression of brain natriuretic peptide gene and members of the TGF-ß receptor signaling pathway such as TGF-ß receptor-1, smad3 and smad7. In male mice, there were no changes in right ventricular gene expression. Our results suggest that MA caused right ventricular hypertrophy in female mice, but not in males and that this was associated with an increase in hypertrophic genes. The right ventricular hypertrophy was not dependent on increased RVSP suggesting a direct effect of MA on the right ventricle. If this translates to PAH patients, it might explain the poor outcome observed in MA-associated female PAH patients.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Hipertrofia Ventricular Direita/genética , Metanfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipertensão Arterial Pulmonar/genética , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
20.
J Psychiatr Res ; 137: 260-265, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33725638

RESUMO

Cannabis and ecstasy are illicit substances, and currently, there are no approved treatments for methamphetamine (METH) use disorder. Some studies have proposed that cannabidiol (CBD) decreases the motivation for METH seeking, but reports indicate that the therapeutic benefits are only for heroin. Here, we studied the interaction between CBD and METH during the sensitization phase on the rewarding effect of METH, using the conditioned place preference (CPP) paradigm to measure possible alterations in sensitivity. Our data showed that i. p. injection of METH created METH-induced CPP at two of the highest applied doses (1 and 2 mg/kg), and injection of METH during the sensitization period caused an establishment of METH-induced CPP at lower doses (0.25 and 0.5 mg/kg). Data also revealed that i. c.v. administration of CBD during the sensitization phase, shifted the establishment of METH-induced CPP toward a lower dose (0.5 mg/kg). Concurrent administration of CBD (10 µg/5 µl, i. c.v.) and METH (0.25 mg/kg, i. p.) during sensitization phase established METH-induced CPP with sub-threshold doses of METH (0.125, 0.25, and 0.5 mg/kg). Our results suggest the involvement of CBD and prior exposure to METH in creating sensitization to METH CPP.


Assuntos
Canabidiol , Estimulantes do Sistema Nervoso Central , Metanfetamina , Animais , Canabidiol/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico , Masculino , Metanfetamina/farmacologia , Ratos , Recompensa
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