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1.
Expert Opin Drug Metab Toxicol ; 17(9): 1125-1138, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34410209

RESUMO

INTRODUCTION: Catha edulis (Vahl) Forssk. ex Endl. (Celestraceae) is used as a recreational drug on daily basis for its euphoric and psychostimulant effects. It is also chewed by individuals who are on medications, raising the possibility of drug-khat interaction. However, limited data are available in the literature, although clinically significant interactions are expected, as khat contains a complex mixture of pharmacologically active constituents. AREAS COVERED: It provides an overview of the phytochemistry, pharmacokinetics, pharmacodynamics, and pharmacogenetics of khat based on the literature mined from PubMed, Google Scholar, and Cochrane databases. It also presents a detailed account of drug-khat interactions with specific examples and their clinical significance. The interactions mainly occur at the pharmacokinetics level and particular attention is paid for the phases of absorption and cytochrome P450 enzyme-mediated metabolism. EXPERT OPINION: Despite the increasing trend of khat chewing with medications among the populace and the potential risk for the occurrence of clinically significant interactions, there is paucity of data in the literature demonstrating the magnitude of the risk. The available data, however, clearly demonstrate that the consequence of drug-khat interaction is dependent on genotype. Genotyping, where feasible, could be used to improve clinical outcome and minimize adverse reactions.


Assuntos
Catha/química , Interações Ervas-Drogas , Extratos Vegetais/farmacologia , Estimulantes do Sistema Nervoso Central/isolamento & purificação , Estimulantes do Sistema Nervoso Central/farmacologia , Genótipo , Humanos , Farmacogenética , Farmacocinética
2.
Nutrients ; 13(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445005

RESUMO

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect (Garcinia cambogia, Coleus forskohlii, Camellia sinensis L., Irvingia gabonensis, and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.


Assuntos
Nível de Alerta/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Eletroencefalografia , Garcinia cambogia , Extratos Vegetais/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Encéfalo/fisiologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/isolamento & purificação , Frutas , Garcinia cambogia/química , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pentobarbital/farmacologia , Extratos Vegetais/isolamento & purificação , Sono/efeitos dos fármacos
3.
J Consult Clin Psychol ; 89(7): 615-625, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34383534

RESUMO

Objective: Although attention deficit hyperactivity disorder (ADHD) is associated with cognitive deficits, there is considerable heterogeneity and only a minority of individuals with the disorder demonstrate a deficit in any cognitive domain. Recent studies indicate that the relationships between ADHD symptoms and cognition are complex with a dissociation between medication responses across these two domains. Method: We examined whether methylphenidate (MPH) differentially impacts on cognition in those with and without pretreatment cognitive deficits in a 4-week randomized controlled crossover of high (0.6 mg/kg/dose) and low (0.3 mg/kg/dose) dose MPH and placebo in 75 medication-naive boys with ADHD. Cognition was assessed using tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Confirmatory factor analysis (CFA) was used to form latent cognitive factors of executive functioning, visual memory, and reaction time, as well as a general cognition factor. Results: Compared to placebo, both high and low MPH doses significantly improved performance on pattern recognition (PR), spatial recognition (SR), and simple reaction time. The low, but not the high, dose improved performance on the Stockings of Cambridge (SOC) and delayed matching-to-sample tasks. Both doses also significantly improved performance on the executive functioning, visual memory, reaction time skills, and general cognitive latent variables. There were however no differences in the effects of MPH on cognition between those with and without a baseline cognitive deficit, for either the observed task values or the latent cognitive factor scores. Conclusions: We conclude that MPH can enhance executive functioning, visual memory, reaction time, and general cognitive function in boys with ADHD. These improvements are not dependent on baseline cognitive performance. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição/efeitos dos fármacos , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Adolescente , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Testes Neuropsicológicos
4.
Curr Sports Med Rep ; 20(7): 338-344, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34234088

RESUMO

ABSTRACT: Creatine is a popular and widely used ergogenic dietary supplement among athletes, for which studies have consistently shown increased lean muscle mass and exercise capacity when used with short-duration, high-intensity exercise. In addition to strength gains, research has shown that creatine supplementation may provide additional benefits including enhanced postexercise recovery, injury prevention, rehabilitation, as well as a number of potential neurologic benefits that may be relevant to sports. Studies show that short- and long-term supplementation is safe and well tolerated in healthy individuals and in a number of patient populations.


Assuntos
Atletas , Creatina/farmacologia , Suplementos Nutricionais , Substâncias para Melhoria do Desempenho/farmacologia , Anaerobiose/efeitos dos fármacos , Desempenho Atlético , Composição Corporal/efeitos dos fármacos , Concussão Encefálica/prevenção & controle , Concussão Encefálica/terapia , Cafeína/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Carboidratos da Dieta/farmacologia , Exercício Físico , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Força Muscular/efeitos dos fármacos , Treinamento de Força , Valeratos/farmacologia
5.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207724

RESUMO

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.


Assuntos
Antidepressivos , Estimulantes do Sistema Nervoso Central , Hipocampo/metabolismo , Peptídeos , Hormônio Liberador de Tireotropina/antagonistas & inibidores , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/patologia , Masculino , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Hormônio Liberador de Tireotropina/metabolismo
6.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198510

RESUMO

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M-1 and enthalpy change values up to -4 kJ·M-1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cafeína/farmacologia , Compostos Heterocíclicos/química , Pentoxifilina/farmacologia , Antibacterianos/química , Bactérias/crescimento & desenvolvimento , Cafeína/química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Interações Medicamentosas , Testes de Sensibilidade Microbiana , Pentoxifilina/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
7.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199192

RESUMO

The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine's effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine's mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1ß, IP-10, MIP-1α, MIP-1ß and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals' secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Simulação por Computador/estatística & dados numéricos , Melaninas/metabolismo , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Bases de Dados Genéticas , Regulação da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia
8.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
9.
J Int Soc Sports Nutr ; 18(1): 49, 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34147116

RESUMO

PURPOSE: Previous investigations have found positive effects of acute ingestion of capsules containing 4-to-9 mg of caffeine per kg of body mass on several aspects of judo performance. However, no previous investigation has tested the effectiveness of caffeinated chewing gum as the form of caffeine administration for judoists. The main goal of this study was to assess the effect of acute ingestion of a caffeinated chewing gum on the results of the special judo fitness test (SJFT). METHODS: Nine male elite judo athletes of the Polish national team (23.7 ± 4.4 years, body mass: 73.5 ± 7.4 kg) participated in a randomized, crossover, placebo-controlled and double-blind experiment. Participants were moderate caffeine consumers (3.1 mg/kg/day). Each athlete performed three identical experimental sessions after: (a) ingestion of two non-caffeinated chewing gums (P + P); (b) a caffeinated chewing gum and a placebo chewing gum (C + P; ~2.7 mg/kg); (c) two caffeinated chewing gums (C + C; ~5.4 mg/kg). Each gum was ingested 15 min before performing two Special Judo Fitness Test (SJFT) which were separated by 4 min of combat activity. RESULTS: The total number of throws was not different between P + P, C + P, and C + C (59.66 ± 4.15, 62.22 ± 4.32, 60.22 ± 4.08 throws, respectively; p = 0.41). A two-way repeated measures ANOVA indicated no significant substance × time interaction effect as well as no main effect of caffeine for SJFT performance, SJFT index, blood lactate concentration, heart rate or rating of perceived exertion. CONCLUSIONS: The results of the current study indicate that the use of caffeinated chewing gum in a dose up to 5.4 mg/kg of caffeine did not increase performance during repeated SJFTs.


Assuntos
Atletas , Desempenho Atlético , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Goma de Mascar , Artes Marciais/fisiologia , Desempenho Atlético/fisiologia , Desempenho Atlético/estatística & dados numéricos , Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Frequência Cardíaca , Humanos , Ácido Láctico/sangue , Masculino , Artes Marciais/estatística & dados numéricos , Aptidão Física , Placebos/administração & dosagem , Adulto Jovem
10.
Int J Sport Nutr Exerc Metab ; 31(4): 321-328, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010807

RESUMO

The long-standing caffeine habituation paradigm was never investigated in strength endurance and jumping exercise performance through a straightforward methodology. The authors examined if habitual caffeine consumption would influence the caffeine ergogenic effects on strength endurance and jumping performance as well as perceptual responses. Thirty-six strength-trained individuals were mathematically allocated into tertiles according to their habitual caffeine consumption: low (20 ± 11 mg/day), moderate (88 ± 33 mg/day), and high consumers (281 ± 167 mg/day). Then, in a double-blind, crossover, counterbalanced fashion, they performed a countermovement vertical jump test and a strength endurance test either after caffeine (6 mg/kg) and placebo supplementation or after no supplementation (control). Perceptual responses such as ratings of perceived exertion and pain were measured at the termination of the exercises. Acute caffeine supplementation improved countermovement vertical jump performance (p = .001) and total repetitions (p = .004), regardless of caffeine habituation. Accordingly, analysis of absolute change from the control session showed that caffeine promoted a significantly greater improvement in both countermovement vertical jump performance (p = .004) and total repetitions (p = .0001) compared with placebo. Caffeine did not affect the rating of perceived exertion and pain in any exercise tests, irrespective of tertiles (for all comparisons, p > .05 for both measures). Caffeine side effects were similar in low, moderate, and high caffeine consumers. These results show that habitual caffeine consumption does not influence the potential of caffeine as an ergogenic aid in strength endurance and jumping exercise performance, thus challenging recommendations to withdraw from the habitual caffeine consumption before supplementing with caffeine.


Assuntos
Desempenho Atlético/fisiologia , Cafeína/administração & dosagem , Suplementos Nutricionais , Substâncias para Melhoria do Desempenho/farmacologia , Resistência Física/efeitos dos fármacos , Treinamento de Força , Adulto , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Medição da Dor/métodos , Placebos/administração & dosagem , Placebos/farmacologia , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Antagonistas de Receptores Purinérgicos P1/farmacologia , Fenômenos Fisiológicos da Nutrição Esportiva , Adulto Jovem
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
13.
Psychopharmacology (Berl) ; 238(8): 2191-2200, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33963883

RESUMO

BACKGROUND: Zebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints. METHODS: Here, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish. RESULTS: Repeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility. CONCLUSION: Chronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Dextroanfetamina/farmacologia , Locomoção/efeitos dos fármacos , Nicotina/farmacologia , Fatores Etários , Animais , Cognição/fisiologia , Feminino , Locomoção/fisiologia , Masculino , Peixe-Zebra
14.
Cogn Neuropsychol ; 38(2): 138-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33840374

RESUMO

The deficit in "interference control" found in children with Attention Deficit Hyperactivity Disorder (ADHD) could be due to two distinct processes, which are not disentangled in most studies: a larger susceptibility to activating prepotent response impulses and a deficit in suppressing them. Here, we investigated the effect of 1/ADHD and 2/ methylphenidate (MPH), on these two components of interference control. We compared interference control between untreated children with ADHD, children with ADHD under MPH, and typically developing children performing a Simon task. The main findings were that 1/ children with ADHD were more susceptible to reacting impulsively and less efficient at suppressing impulsive actions, and 2/ MPH improved the selective inhibition of impulsive actions but did not modify the strength of response impulse. This work provides an example of how pharmacological interventions and selective responses to them can be used to investigate and further our understanding of cognitive processing.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento Impulsivo/efeitos dos fármacos , Inibição Psicológica , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Adolescente , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Inibidores da Captação de Dopamina/farmacologia , Inibidores da Captação de Dopamina/uso terapêutico , Feminino , Humanos , Masculino
15.
ACS Chem Neurosci ; 12(7): 1170-1177, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33689284

RESUMO

Synthetic cathinones are a class of new psychoactive substances that induce psychostimulant effects and pose risk for hospitalizations, overdose, and death. At the present time, derivatives of the synthetic cathinone, methylone, are being confiscated in nonmedical (i.e., recreational) drug markets worldwide. In particular, eutylone is a newly emerging methylone analog that possesses ethyl groups at the α-carbon and amine positions. Little information is available about the pharmacological effects of eutylone, but based on its structure, we surmised that the compound interacts with monoamine transporters in the brain. To test this hypothesis, we compared the effects of eutylone and its structural isomers, dibutylone and pentylone, using in vitro transporter assays in rat brain synaptosomes and in vivo locomotor activity assessments in mice. All drugs displayed dose-related inhibition of [3H]neurotransmitter uptake at dopamine transporters (DAT) and norepinephrine transporters (NET), but effects at DAT were 10-fold more potent (IC50 = 120 nM). Eutylone and pentylone inhibited uptake at serotonin transporters (SERT), while dibutylone did not. Additionally, eutylone and pentylone displayed weak partial releasing actions at SERT which achieved 50% of maximal response. All drugs stimulated dose-related locomotion in mice, and eutylone was most potent and efficacious in this regard (ED50 = 2 mg/kg, sc). Our results demonstrate that eutylone is a hybrid transporter compound with uptake inhibition properties at DAT and NET but substrate activity at SERT. The effects of eutylone are similar to those produced by pentylone, which suggests that eutylone will exhibit abuse liability and pose risks for psychostimulant side-effects in human users.


Assuntos
Estimulantes do Sistema Nervoso Central , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Camundongos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina , Sinaptossomos
16.
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
17.
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
18.
Pharmacol Biochem Behav ; 204: 173158, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33675838

RESUMO

BACKGROUND: It is commonly believed that drugs, including stimulants, are used recreationally because of their ability to induce pleasurable subjective effects. However, recreational drug use sometimes occurs in the absence of positive subjective effects, suggesting that other factors contribute. Here, we examine the extent to which the direct subjective effects of amphetamine, a commonly misused stimulant, predict subsequent choice of the drug vs placebo. METHODS: Healthy adults (N = 112) participated in a five-session amphetamine choice study. On the first four sessions, participants sampled either 20 mg d-amphetamine or placebo in color-coded capsules two times each. On the fifth session, they chose which color (d-amphetamine or placebo) they preferred. We examined the choice of drug vs placebo in relation to demographic characteristics, baseline mood states, personality and subjective and cardiovascular responses to acute administration of the drug. RESULTS: Eighty-one participants chose amphetamine (Choosers) while 31 chose placebo (Non-choosers). Overall, amphetamine produced typical stimulant-like effects on subjective questionnaires, and it elevated heart rate and blood pressure vs placebo. Choosers reported greater positive mood, elation and stimulant-like effects following amphetamine compared to Non-choosers. The Choosers also exhibited a greater increase in systolic blood pressure, but not heart rate. The groups did not differ on demographic characteristics, mood states before drug administration or personality. CONCLUSIONS: These findings support the idea that pleasurable subjective responses to amphetamine, including positive mood, elation, and stimulant-like effects influence behavioral choice of the drug.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Dextroanfetamina/administração & dosagem , Adulto , Afeto/efeitos dos fármacos , Nível de Alerta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Personalidade/efeitos dos fármacos , Uso Recreativo de Drogas , Adulto Jovem
19.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540617

RESUMO

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metanfetamina/farmacologia , Transtornos Relacionados com Narcóticos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Relacionados com Narcóticos/psicologia , Fosforilação , Córtex Pré-Frontal/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Receptor de Glutamato Metabotrópico 5/química , Reforço Psicológico , Recompensa
20.
Neurosci Lett ; 749: 135733, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33592304

RESUMO

The emission of ultrasonic vocalizations (USVs) is thought to communicate the behavioral and emotional states elicited in rodents by social and non-social stimuli. On this basis, studies of psychopharmacology in rats are increasingly utilizing USVs as a behavioral marker to evaluate the effects of drugs on the emotional state. Conversely, very limited information is available as to whether psychoactive drugs influence USV emissions in mice. To provide new insights in this respect, we evaluated the emission of USVs in C57BL/6J mice subjected to repeated treatment with the dopaminergic psychostimulant of abuse amphetamine. Mice were first allowed to perform social contacts in dyads, and 2 days later they received amphetamine (1-4 mg/kg, i.p.) in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, mice were re-exposed to the test cage to evaluate whether the presentation of drug-paired environmental cues elicited calling behavior, and thereafter received an amphetamine challenge. An additional group of animals received the dopamine receptor agonist apomorphine (1-4 mg/kg, i.p.), to further clarify the role of dopamine transmission in calling behavior of mice. C57BL/6J mice emitted USVs during social contacts, but did not significantly vocalize after amphetamine administration, in response to amphetamine-paired environmental cues, and after apomorphine administration. These results indicate that C57BL/6J mice may respond differently to social and pharmacological stimuli in terms of USV emissions, and may lay the foundation for future studies aimed at clarifying whether USVs may be a useful behavioral marker in studies of psychopharmacology in mice.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ultrassom , Vocalização Animal/efeitos dos fármacos , Animais , Apomorfina/farmacologia , Sinais (Psicologia) , Agonistas de Dopamina/farmacologia , Camundongos Endogâmicos C57BL , Psicotrópicos/farmacologia
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