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1.
Lakartidningen ; 1182021 09 13.
Artigo em Sueco | MEDLINE | ID: mdl-34515329

RESUMO

Workplace alcohol and drug testing is increasingly used at employment, for regular checks, and in case of accident, incident, or suspicion of drug exposure. The test results provide valuable objective information about drug use in the society. At the Karolinska University Laboratory (Stockholm, Sweden), the number of samples from drug testing in the workplace has quadrupled in the last decade. Almost all urine samples are tested for amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (prescribed substances), cannabis, cocaine and opiates, and some also for alcohol (i.e. the metabolites ethyl glucuronide and ethyl sulfate) and drugs such as tramadol and oxycodone. The proportion of samples that test positive for one or more drugs has increased steadily in recent years to over 5%. Substances commonly detected are, in order of appearance, cannabis, amphetamines (amphetamine and MDMA), benzodiazepines, opiates (mainly codeine and only few due to heroin use), and cocaine. Other common substances are alcohol, tramadol, and oxycodone, but these are only tested for in a limited, and possibly selected, proportion of samples. After an MRO has reviewed the positive laboratory results, about 30% of cases are excluded mainly due to legal prescription as medicine. In 2020, the proportion of positive test results decreased, possibly due to reduced access to illicit drugs during the corona pandemic. In summary, results from drug testing in the workplace indicate that illicit use of drugs shows an increasing trend in Sweden.


Assuntos
Cocaína , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Anfetamina , Humanos , Detecção do Abuso de Substâncias , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Suécia/epidemiologia , Local de Trabalho
2.
BMJ Case Rep ; 14(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413029

RESUMO

Thyroid storm is a rare, life-threatening endocrine emergency with a high mortality rate of up to 30%. We present a unique management challenge of a critically ill patient who developed thyroid storm in the setting of a duodenal perforation from amphetamine-associated non-occlusive mesenteric ischaemia. The diagnosis of 'thyroid storm' was made based on clinical criteria and a Burch-Wartofsky score of 100. During emergent exploratory laparotomy, a 1 cm duodenal perforation with surrounding friable tissue was found and repaired. Intraoperatively, a nasogastric tube was guided distal to the area of perforation to allow for enteric administration of medications, which was critical in the setting of thyroid storm. Therapeutic plasma exchange achieved biochemical control of our patient's thyroid storm but ultimately did not prevent in-hospital mortality.


Assuntos
Úlcera Duodenal , Úlcera Péptica Perfurada , Crise Tireóidea , Anfetamina , Humanos , Isquemia/induzido quimicamente , Crise Tireóidea/complicações , Crise Tireóidea/tratamento farmacológico
3.
J Pharm Biomed Anal ; 205: 114317, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34419812

RESUMO

Amphetamine-type stimulants (ATS) like amphetamine ('speed'), methamphetamine ('crystal meth') and 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy') represent some of the most frequently abused drugs worldwide. Another less frequently abused ATS is 4-fluoroamphetamine (4-FA). The enantiomers of these four compounds exhibit different pharmacokinetic and pharmacodynamic properties. According to the free drug theory, the pharmacological properties of a substance are dependent on its plasma protein binding (PPB). However, data on PPB of stimulant enantiomers in humans are rare or non-existent. Human plasma samples were spiked with racemic mixtures of the stimulants and subjected to ultrafiltration to extract the unbound fraction. Enantioselective liquid chromatography - tandem mass spectrometry (LC-MS/MS) methods were applied using a chiral Phenomenex® Lux3 µm AMP column. Method validation showed satisfactory selectivity, linearity (0.5 250 ng/mL), accuracy and precision. Enantiomers were quantified before and after ultracentrifugation to determine PPB. For all analytes, low to medium plasma protein binding was found. For (R)-amphetamine a slightly but significantly higher PPB was found compared to the (S)-enantiomer (31.7 % vs 29.0 %). (R)-MDMA also showed only slightly but significantly significantly higher PPB than (S)-MDMA, although the mean difference was negligible (21.6 % vs 21.3 %). For the enantiomers of methamphetamine and 4-FA, no significant differences in PPB were found. In summary, there were no or only minor differences in PBB for the enantiomers of all investigated compounds. The different pharmacological properties of the stimulant enantiomers can therefore not be explained by differences in PPB.


Assuntos
Estimulantes do Sistema Nervoso Central , Drogas Ilícitas , Anfetamina , Cromatografia Líquida , Humanos , Ligação Proteica , Estereoisomerismo , Espectrometria de Massas em Tandem
4.
Transl Psychiatry ; 11(1): 427, 2021 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-34392304

RESUMO

Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.


Assuntos
Adiposidade , Anfetamina , Tecido Adiposo , Anfetamina/farmacologia , Animais , Encéfalo , Dieta Hiperlipídica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade
5.
Eur J Neurosci ; 54(3): 4934-4952, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34216157

RESUMO

Activation of cannabinoid 1 receptors (CB1 R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB1 R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB1 R activation, yet the involvement of CB1 R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB1 R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB1 R in MSN on a CB1 R knockout (KO) background (CB1 R(MSN) mice). The absence of cannabimimetic responses measured in CB1 R KO mice was not rescued in CB1 R(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB1 R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB1 R KO mice were fully rescued in CB1 R(MSN) mice. Impaired motor coordination in CB1 R KO mice measured on the Rotarod was partially rescued in CB1 R(MSN) mice. Thus, CB1 R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB1 R expression and their causal link in the control of specific behaviors.


Assuntos
Anfetamina , Canabinoides , Corpo Estriado , Receptor CB1 de Canabinoide , Anfetamina/farmacologia , Animais , Camundongos , Camundongos Knockout , Neurônios , Receptor CB1 de Canabinoide/genética
6.
Sci Total Environ ; 797: 149058, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34303256

RESUMO

The occurrence and levels of amphetamine like substances (ALSs) in various environments, as a group of illicit psychoactive substances, have attracted great attention due to their potential ecological risks. In this study, three ALSs (i.e., ephedrine (EPH), amphetamine (AMP) and methamphetamine (METH)) in the raw domestic wastewater (RDW) and surface river water (SRW) collected from the rural area in South China were analyzed. METH was identified as the prevalent and dominant ALS in the RDW, which was detected in approximately 99.0% of the samples with a mean concentration of 0.7 µg·L-1, followed by AMP and EPH. Consistent trend was also found in the SRW collected from the same region. METH concentrations in the SRW were significantly and positively correlated with those in the RDW (p < 0.05), indicating that the discharge of RDW could be the important source of METH in the nearby rivers. The mean mass load of METH in the study rural area was about 65.8 mg·day-1·1000 inhabitants-1. Source apportionment showed that the abuse consumption was the main source of METH at most of sampling towns in the investigated rural area, and the mean mass load of METH at these towns (24.5 mg·day-1·1000 inhabitants-1) might reflect the abuse level of METH in this region. The disposal and illegal synthesis of METH could be important point sources, which led to the elevated METH level in the RDW. Risk assessment demonstrated that ALSs posed a minimal or medium risk to aquatic organisms. Our results provided valuable insights into the mass loads, source characteristics and ecological risks of ALSs in the rural area.


Assuntos
Anfetamina , Poluentes Químicos da Água , China , Monitoramento Ambiental , Rios , Poluentes Químicos da Água/análise
7.
Psychopharmacology (Berl) ; 238(9): 2601-2615, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34104987

RESUMO

BACKGROUND: Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. AIMS: This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. METHODS: We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. RESULTS: Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. CONCLUSIONS: These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Anfetamina/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento de Escolha , Comportamento Impulsivo , Ratos , Tempo de Reação
8.
Am J Psychiatry ; 178(8): 744-751, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34086483

RESUMO

OBJECTIVE: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development. METHODS: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations. RESULTS: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence. CONCLUSIONS: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Adolescente , Anfetamina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Feminino , Neuroimagem Funcional , Humanos , Entrevista Psicológica , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Metilfenidato/uso terapêutico , Vias Neurais , Resultado do Tratamento
9.
Analyst ; 146(10): 3336-3345, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33999061

RESUMO

The abuse of methamphetamine (MA) is to date detected and subsequently verified through the monitoring of MA and its metabolites within biological specimens. Current approaches require complex sample purification strategies alongside significant analysis time. Given the high prevalence of MA within the global drug market, there remains a need for rapid, portable and alternative screening approaches appropriate for direct detection within biological matrices for employment across the forensic and clinical environments. This contribution illustrates the use of an electrochemiluminescence (ECL) strategy for the screening of MA, amphetamine (AMP) and para hydroxy-methamphetamine (pOH-MA) for such applications. The sensing system showed ideal analytical performance with linear ranges at forensically relevant concentrations of 0.1 µM to 0.5 mM for MA, 10 µM to 1 mM AMP and 10 µM to 5 mM for pOH-MA, and superb detection limits of 74.6 nM, 6 µM and 82. µM for MA, AMP and pOH-MA respectively. Furthermore, the sensor was successful in the detection of MA, AMP and pOH-AMP within human pooled serum, artificial urine and saliva, without any prior purification strategies. Here a portable ECL sensor is detailed for the successful employment of the direct screening of these amphetamine type substances and their corresponding metabolites at clinically and forensically relevant concentrations within a range of biological matrices. This approach successfully represents a strong proof-of-concept, for a novel, simple and rapid screening method with significant potential for high-throughput screening of biological samples for drug metabolites, widening the avenues where ECL sensors could be employed.


Assuntos
Metanfetamina , Anfetamina , Humanos , Medições Luminescentes , Saliva , Detecção do Abuso de Substâncias
10.
Exp Neurol ; 342: 113754, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34000249

RESUMO

The alkaloid ephedrine derived from Ephedra vulgaris is at the origin of psychostimulant-drugs as amphetamine. These drugs have been principally utilized for medical treatments in the past, while their utilization has been largely reduced from the 1970s when the high risk of addiction and abuse has been recognized. The first reported treatments were as anti-asthmatics and to contrast narcolepsy until their recreational stimulant and anorexic effects were reported. Benzedrine and Pervitin use were of great importance during the Second World War due to their abundant utilization among military troops. Nowadays the use of selective amphetamine-like drugs is limited to ADHD treatment.


Assuntos
Doença da Altitude/história , Anfetamina/história , Transtorno do Deficit de Atenção com Hiperatividade/história , Estimulantes do Sistema Nervoso Central/história , Fadiga/história , Doença da Altitude/tratamento farmacológico , Anfetamina/administração & dosagem , Animais , Conflitos Armados/história , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Fadiga/tratamento farmacológico , História do Século XIX , História do Século XX , História do Século XXI , Humanos
11.
Clin Biochem ; 93: 99-103, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33844982

RESUMO

BACKGROUND: Immunoassays provide a rapid tool for the screening of drugs-of-abuse (DOA). However, results are presumptive and confirmatory testing is warranted. To reduce associated cost and delay, laboratories should employ assays with high positive and negative predictive values (PPVs and NPVs). Here, we compared the results of urine drug screens on cobas 6000 (cobas) and ARCHITECTi2000 (ARCHITECT) platforms for six drugs against LC-MS/MS to assess the analytical performance of these assays. METHODS: Eighty nine residual urine specimens, which tested positive for amphetamine, THC-COOH, benzoylecgonine, EDDP, opiates and/or oxycodone during routine drug testing, were stored frozen until later confirmation by LC-MS/MS. Immunoassays were performed on cobas and ARCHITECT using a split sample. A third aliquot from these samples was tested by LC-MS/MS to assess the percentage of false positive, false negative, true positive and true negative results and calculate the PPVs and NPVs for each immunoassay. RESULTS: The PPVs of THC-COOH and EDDP assays were 100% on both platforms. Suboptimal PPVs were achieved for oxycodone (cobas, 57.1% vs ARCHITECT, 66.7%), amphetamine (77.8 vs. 100%), opiates (80.0 vs. 84.6%) and benzoylecgonine (88.9 vs. 84.2%) assays. The NPV was 100% for cobas and ARCHITECT oxycodone assays. Lower NPVs were achieved for THC-COOH (cobas, 28.6% vs ARCHITECT, 25.0%), EDDP (72.7% for both assays), benzoylecgonine (74.4% vs 73.8%), amphetamine (83.3% vs 82.8%) and opiates (100% vs 85.3%). CONCLUSION: Overall, cobas and ARCHITECT urine drug screens have comparable analytical performance. Confirmatory testing is warranted for positive test results especially for oxycodone, amphetamine, opiates and cocaine. Negative drug screen results must be interpreted with caution especially for THC-COOH, EDDP, benzoylecgonine, amphetamine and opiates.


Assuntos
Anfetamina/urina , Cocaína/análogos & derivados , Dronabinol/análogos & derivados , Alcaloides Opiáceos/urina , Oxicodona/urina , Pirrolidinas/urina , Detecção do Abuso de Substâncias/métodos , Cromatografia Líquida de Alta Pressão , Cocaína/urina , Erros de Diagnóstico , Dronabinol/urina , Humanos , Imunoensaio/métodos , Valor Preditivo dos Testes , Espectrometria de Massas em Tandem
12.
Behav Neurosci ; 135(1): 32-38, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33734732

RESUMO

Prepulse inhibition (PPI) refers to the modulation of the startle response by the presentation of a weaker stimulus prior to the onset of the startle stimulus. This response is consolidated along the maturation process of the mesocortical system, where the dopamine neurotransmitter plays an important role. In fact, it has been reported that agonist and antagonist dopaminergic drugs are able to change PPI expression. This study was aimed to analyze the relationship between the adult medial prefrontal cortex (mPfc) and dopaminergic involvement in PPI throughout the life span. Specifically, the present experiment analyzed the effect of the administration of dopaminergic agonist amphetamine on PPI in two different age periods in Wistar rats: postnatal day (PND) 28 and PND 70. In this last period, we also explored the relationship between PPI response and amphetamine effects after mPfc lesion. The results showed that PPI was expressed in all groups and periods; however, amphetamine only modulated this effect during adulthood. We also found that the mPfc is essential to modulate PPI after amphetamine consumption. Besides, our results suggest a role for dopamine and mPfc as important modulators of PPI in adulthood. Nevertheless, this neurotransmitter could not be involved in the expression of PPI because the administration of a dopaminergic agonist was ineffective in PND-28 period. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Anfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Estimulação Acústica , Animais , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Masculino , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia
13.
PLoS One ; 16(3): e0247707, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33647040

RESUMO

Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.


Assuntos
Anfetamina/toxicidade , Benzilaminas/farmacologia , Ciclamos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Locomoção , Receptores CXCR4/antagonistas & inibidores , Animais , Fármacos Anti-HIV/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Masculino , Ratos , Ratos Long-Evans
15.
Eur J Neurosci ; 53(8): 2450-2468, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33759265

RESUMO

Disruptive or excessive repetitive motor patterns (stereotypies) are cardinal symptoms in numerous neuropsychiatric disorders. Stereotypies are also evoked by psychomotor stimulants such as amphetamine. The acquisition of motor sequences is paralleled by changes in activity patterns in the striatum, and stereotypies have been linked to abnormal plasticity in these reinforcement-related circuits. Here, we designed experiments in mice to identify transcriptomic changes that underlie striatal plasticity occurring alongside the development of drug-induced stereotypic behavior. We identified three schedules of amphetamine treatment inducing different degrees of stereotypy and used bulk RNAseq to compare striatal gene expression changes among groups of mice treated with the different drug-dose schedules and vehicle-treated, cage-mate controls. Mice were identified as naïve, sensitized, or tolerant to drug-induced stereotypy. All drug-treated groups exhibited expression changes in genes that encode members of the extracellular signal-regulated kinase (ERK) cascades known to regulate psychomotor stimulant responses. In the sensitized group with the most prolonged stereotypy, we found dysregulation of 20 genes that were not changed in other groups. Gene set enrichment analysis indicated highly significant overlap with genes regulated by neuregulin 1 (Nrg1). Nrg1 is known to be a schizophrenia and autism susceptibility gene that encodes a ligand for Erb-B receptors, which are involved in neuronal migration, myelination, and cell survival, including that of dopamine-containing neurons. Stimulant abuse is a risk factor for schizophrenia onset, and these two disorders share behavioral stereotypy phenotypes. Our results raise the possibility that drug-induced sensitization of the Nrg1 signaling pathway might underlie these links.


Assuntos
Preparações Farmacêuticas , Transcriptoma , Anfetamina , Animais , Corpo Estriado , Camundongos , Comportamento Estereotipado
16.
Obesity (Silver Spring) ; 29(4): 721-730, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33660412

RESUMO

OBJECTIVE: Binge-eating disorder (BED) disrupts dopamine neuron function, in part by altering dopamine transporter (DAT) activity. This study characterized the effects of high-fat bingeing on presynaptic dopamine terminals and tested the hypothesis that acute low-dose amphetamine would restore DAT function. METHODS: C57BL/6 mice were given limited access (LimA) to a high-fat diet (2 h/d, 3 d/wk) or standard chow (control). After 6 weeks, ex vivo fast-scan cyclic voltammetry was used to characterize dopamine-terminal adaptations in the nucleus accumbens. Prior to undergoing fast-scan cyclic voltammetry, some mice from each group were given amphetamine (0.5 mg/kg intraperitoneally). RESULTS: Escalation of high fat intake, termed bingeing, occurred in the LimA group and coincided with increased phasic dopamine release, reduced dopamine uptake rates, and increased dopamine receptor 2 (D2 ) autoreceptor function. Acute amphetamine selectively reversed dopamine uptake changes in the LimA group and restored the potency of amphetamine to inhibit uptake. CONCLUSIONS: High-fat bingeing enhanced dopaminergic signaling in the nucleus accumbens by promoting phasic dopamine release and reducing clearance. This study's data show that amphetamine was efficacious in restoring impaired DAT function caused by high-fat bingeing but did not reduce dopamine release to normal. These presynaptic changes should be considered if amphetamine-like dopamine releasers are used as treatments for BED.


Assuntos
Anfetamina/uso terapêutico , Transtorno da Compulsão Alimentar/sangue , Dieta Hiperlipídica/efeitos adversos , Dopamina/metabolismo , Núcleo Accumbens/fisiopatologia , Anfetamina/farmacologia , Animais , Masculino , Camundongos
17.
Eur J Pharmacol ; 899: 174039, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737011

RESUMO

The orexigenic peptide ghrelin increases the release of dopamine in the nucleus accumbens (NAc) shell via central ghrelin receptors, especially those located in the ventral tegmental area (VTA). The activity of the VTA dopamine neurons projecting to NAc shell, involves somatodendritic dopamine release within the VTA. However, the effects of ghrelin on the concomitant dopamine release in the VTA and NAc shell is unknown. It is further unknown whether addictive drugs, such as alcohol and amphetamine, enhance the dopamine levels in both these areas via ghrelin receptor dependent mechanisms. Thus, the effects of a ghrelin receptor antagonist, JMV2959, on the ability of i) central ghrelin ii) systemic alcohol or iii) systemic amphetamine to increase the dopamine release in the VTA and in the NAc shell in rats by using in vivo microdialysis was explored. We showed that systemic administration of JMV2959 blocks the ability of central ghrelin to increases dopamine release in the VTA and the NAc shell, and reduces the alcohol- and amphetamine-induced dopamine release in both these areas. Locomotor activity studies was then conducted in an attempt to correlate the ghrelin-induced dopamine release in the VTA to a behavioural outcome. These revealed that local infusion of a dopamine D1 receptor antagonist into the VTA blocks the ability of central ghrelin to cause a locomotor stimulation in mice. Collectively, this study adds to the growing body of evidence indicating that ghrelin signalling modulates the ability of ghrelin, and addictive drugs, to activate the mesoaccumbal dopamine pathway.


Assuntos
Anfetamina/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Grelina/farmacologia , Glicina/análogos & derivados , Antagonistas de Hormônios/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de Grelina/antagonistas & inibidores , Triazóis/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Glicina/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Núcleo Accumbens/metabolismo , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Grelina/metabolismo , Recompensa , Área Tegmentar Ventral/metabolismo
18.
Clin Rheumatol ; 40(7): 3007-3014, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33786691

RESUMO

Musculoskeletal diseases (MSDs) are common in the general population, frequently associated with pain, functional limitation, and reduction in quality of life. Similarly, drug/substance use disorders are common in the general population. Recently, opioid drug use disorder has gained a lot of attention as a public health problem. To our knowledge, limited data exist regarding the non-opioid drug/substance use disorders in musculoskeletal diseases. This study's objective was to examine the frequency and rates of common drug/substance use disorder hospitalizations in five MSDs, namely gout, osteoarthritis, fibromyalgia, rheumatoid arthritis, and low back pain. This was achieved by using the diagnostic codes for cocaine, hallucinogen, amphetamine, or ASH use disorder hospitalization in five MSDs in the US National Inpatient Sample from 1998 to 2014. Cocaine, hallucinogen, amphetamine, or ASH use disorder hospitalizations per 1 million NIS total hospitalizations for five MSDs in 2013-2014 were as follows, respectively: gout, 10.2, 0.1, 2.8, and 1.5; osteoarthritis, 21.4, 0.4, 5.9, and 7.7; fibromyalgia, 5.5, 0.1, 2.0, and 2.3; rheumatoid arthritis, 8.7, 0.4, 4.5, and 7.7, and low back pain, 16.2, 0.5, 7.3, and 7.5. The frequency and the rate of each drug use disorder hospitalization increased in each of the five MSDs from 1998 to 2014. Key Points • Cocaine or hallucinogen use disorder hospitalization rates increased several-fold in people with MSDs from 1998 to 2014. • Amphetamine and anxiolytic, sedative, or hypnotic (ASH) use disorder hospitalization rates increased 9- to 23-fold vs. 4- to 7-fold, respectively, in people with common MSDs in the USA from 1998 to 2014.


Assuntos
Ansiolíticos , Cocaína , Alucinógenos , Anfetamina , Hospitalização , Humanos , Hipnóticos e Sedativos , Qualidade de Vida
19.
Pharmacol Biochem Behav ; 204: 173157, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33647274

RESUMO

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (µ), kappa- (κ), and delta- (δ) opioid receptors and functions as a µ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.


Assuntos
Dopamina/metabolismo , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Etanol/farmacologia , Humanos , Masculino , Microdiálise/métodos , Naltrexona/farmacologia , Núcleo Accumbens/metabolismo , Oxicodona/farmacologia , Ratos , Ratos Wistar , Receptores Opioides mu/metabolismo , Autoadministração/métodos
20.
Psychopharmacology (Berl) ; 238(4): 927-947, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33606060

RESUMO

Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words "social isolation" and "adolescence" and "drug" or "cocaine" or "amphetamine" or "nicotine", resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.


Assuntos
Anfetamina/farmacologia , Cocaína/farmacologia , Nicotina/farmacologia , Animais , Locomoção/efeitos dos fármacos , Camundongos , Ratos , Autoadministração , Isolamento Social , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
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