RESUMO
INTRODUCTION: There have been substantial increases in the use of Schedule II stimulants in the United States. Schedule II stimulants are the gold standard treatment for attention-deficit hyperactivity disorder (ADHD), but also carry the risk of addiction. Since the neurocognitive deficits seen in ADHD resemble those of chronic cannabis use, and the rise in stimulant use is incompletely understood, this study sought to determine if recreational cannabis (RC) legalization increased distribution rates of Schedule II stimulants. METHODS: The distribution of amphetamine, lisdexamfetamine, and methylphenidate were extracted from the ARCOS database of the Drug Enforcement Administration. The three-year population-corrected slopes of distribution before and after RC sales were evaluated. RESULTS: Total stimulant distribution rates were significantly higher in states with RC sales after (p=0.049), but not before (p=0.221), program implementation compared to states without RC. Significant effects of time (p<0.001) and RC sales status (p=0.045) were observed, while time x RC sales status interaction effects were not significant (p=0.406). DISCUSSION: RC legalization did not contribute to a more pronounced rise in Schedule II stimulant distribution in states. Future studies could explore the impact of illicit cannabis use on stimulant rates and the impact of cannabis sales on distribution rates of non-stimulant ADHD pharmacotherapies and ADHD diagnoses.
Assuntos
Estimulantes do Sistema Nervoso Central , Humanos , Estados Unidos/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Cannabis , Metilfenidato/uso terapêutico , Anfetamina , Legislação de MedicamentosRESUMO
Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.
Assuntos
Anfetamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Angiotensina II , Benzimidazóis , Compostos de Bifenilo , Corpo Estriado , Dopamina , Animais , Anfetamina/farmacologia , Masculino , Dopamina/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Benzimidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ratos Wistar , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Interação Social/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.
Assuntos
Antioxidantes , Doxiciclina , Hipocampo , Mania , Neurônios , Animais , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Antioxidantes/farmacologia , Mania/induzido quimicamente , Mania/tratamento farmacológico , Doxiciclina/farmacologia , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Anfetamina/farmacologia , Anfetamina/toxicidade , Modelos Animais de Doenças , Estimulantes do Sistema Nervoso Central/toxicidade , Monoaminas Biogênicas/metabolismo , Dextroanfetamina/farmacologia , Dextroanfetamina/toxicidade , Antimaníacos/farmacologia , Fármacos Neuroprotetores/farmacologiaRESUMO
RATIONALE: Relapse into substance use is often triggered by exposure to drug-related environmental cues. The magnitude of drug seeking depends on the duration of abstinence, a phenomenon known as the incubation of drug craving. Clinical and preclinical research shows that the insular cortex is involved in substance use disorders and cue-induced drug seeking. However, the role of the insula on memory retrieval and motivational integration for cue-elicited drug seeking remains to be determined. OBJECTIVES: We investigated the role of the anterior insular cortex (aIC) and its glutamatergic projection to amygdala nuclei (aIC-AMY) on the expression of conditioned place preference (CPP) during early and late abstinence. METHODS: Male adult C57BL/6J mice underwent amphetamine-induced CPP, and their preference was tested following 1 or 14 days of abstinence. aIC and aIC-AMY functional role in CPP expression was assessed at both abstinence periods by employing optogenetic silencing and behavioral pharmacology. RESULTS: Compared to a single day, an exacerbated preference for the amphetamine-paired context was observed after 14 days of abstinence. Photoinhibition of either aIC or aIC-AMY projection reduced CPP expression following late but not early abstinence. Similarly, the antagonism of aIC NMDA receptors reduced CPP expression after 14 days of abstinence but not 1 day. CONCLUSIONS: These results suggest that aIC and its glutamatergic output to amygdala nuclei constitute critical neurobiological substrates mediating enhanced motivational cue reactivity during the incubation of amphetamine craving rather than contextual memory recall. Moreover, cortical NMDA receptor signaling may become sensitized during abstinence, ultimately modulating disproportioned drug seeking.
Assuntos
Córtex Insular , Memória , Camundongos , Animais , Masculino , Camundongos Endogâmicos C57BL , Memória/fisiologia , Tonsila do Cerebelo , Anfetamina/farmacologiaRESUMO
The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1ß, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.
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Anfetamina , Sepse , Ratos , Animais , Ratos Wistar , Anfetamina/farmacologia , Punções , Modelos Animais de DoençasRESUMO
BACKGROUND: Perception of drug adulteration has increased in Mexico, but there is little research on adulterants and toxicity. The aim of this study was to identify drug composition in an electronic music outdoor festival nearby Mexico City. METHODS: The participants completed a questionnaire with demographic data, harm reduction strategies, drug-use patterns, history, and the drug they expected to find. We took a small sample of each substance and prepared it for drug checking. A two-section drug testing station was placed within the grounds of the festival. Interaction with participants occurred at the front part. Drug checking was conducted at the rear part. The service was free of charge, voluntary and confidential. Forty persons aged 22 to 48 years participated (mode = 28), of which 92.5% were male, most (82.5%) were single. Through the Substance Analysis Program of "ReverdeSer Collective," we conducted the testing with the attendants that provided 51 drug samples, following ethical and biosafety protocols. We used colorimetry, Fourier Transform Infrared Spectroscopy, and fentanyl immunoassay strips for sample analysis. RESULTS: Substances of choice among attendants were psychostimulants (MDMA and other amphetamine-like drugs) and hallucinogens. Most samples contained what the users expected plus adulterants. Main adulterants were methylene-dioxy-ethyl-amphetamine, methylene-dioxy-propyl-amphetamine, hydroxyamphetamine, and the selective serotonin reuptake inhibitor venlafaxine. Fentanyl was present in 2 out of 4 cocaine samples and in 14 of the 22 confirmed MDMA samples. CONCLUSIONS: Some of the adulterants found pose serious health risks, especially fentanyl, amphetamine-like substances, and venlafaxine. Therefore, it is urgent to monitor these adulterants at electronic music festivals and to implement prevention, treatment, and harm reduction public policies. Naloxone distribution and drug-assisted therapies should be part of government programs in Mexico.
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Drogas Ilícitas , N-Metil-3,4-Metilenodioxianfetamina , Humanos , Masculino , Feminino , Drogas Ilícitas/análise , Fentanila/análise , Férias e Feriados , México , Cloridrato de Venlafaxina , AnfetaminaRESUMO
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.
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Transtornos Relacionados ao Uso de Anfetaminas , Analgésicos Opioides , Ratos , Masculino , Animais , Fatores de Crescimento Neural/farmacologia , Anfetamina , Encéfalo , Naloxona/farmacologia , Núcleo AccumbensRESUMO
This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North American region, focusing on the increasing adulteration of METH with fentanyl.
Assuntos
3,4-Metilenodioxianfetamina , Estimulantes do Sistema Nervoso Central , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Humanos , Anfetamina/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversosRESUMO
Patterns of drug ingestion may have a dissimilar impact on the brain, and therefore also the development of drug addiction. One pattern is binge intoxication that refers to the ingestion of a high amount of drug on a single occasion followed by an abstinence period of variable duration. In this study, our goal was to contrast the effect of continuous low amounts with intermittent higher amounts of Arachidonyl-chloro-ethylamide (ACEA), a CB1R agonist, on amphetamine seeking and ingestion, and describe the effects on the expression of CB1R and CRFR1 in the central nucleus of the amygdala (CeA) and in the nucleus accumbens shell (NAcS). Adult male Wistar rats were treated with a daily administration of vehicle or 20 µg of ACEA, or four days of vehicle followed by 100 µg of ACEA on the fifth day, for a total of 30 days. Upon completion of this treatment, the CB1R and CRFR1 expression in the CeA and NAcS was evaluated by immunofluorescence. Additional groups of rats were evaluated for their anxiety levels (elevated plus maze, EPM), amphetamine (AMPH) self-administration (ASA) and breakpoint (A-BP), as well as AMPH-induced conditioned place preference (A-CPP). Results indicated that ACEA induced changes in the CB1R and CRFR1 expression in both the NAcS and CeA. An increase in anxiety-like behavior, ASA, A-BP and A-CPP was also observed. Since the intermittent administration of 100 µg of ACEA induced the most evident changes in most of the parameters studied, we concluded that binge-like ingestion of drugs induces changes in the brain that may make the subject more vulnerable to developing drug addiction.
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Anfetamina , Núcleo Accumbens , Ratos , Masculino , Animais , Núcleo Accumbens/metabolismo , Anfetamina/farmacologia , Ratos Wistar , Tonsila do Cerebelo , Condicionamento ClássicoRESUMO
Algunas situaciones ponen en riesgo a Cuba en cuanto al uso de drogas, entre ellas el aumento del turismo, las relaciones con países que poseen altas tasas de consumo, la ubicación geográfica en corredores de narcotraficantes y la alta prevalencia de drogas porteras. Al respecto, el Sistema Nacional de Salud debe estar preparado para la prevención del problema y la atención a los afectados, de manera que resulta necesario mantener una información actualizada sobre los factores de riesgo y los principales productos utilizados por los consumidores. En la presente revisión bibliográfica sobre el tema se busca llamar la atención de los trabajadores de la salud en tal sentido, se ofrecen datos sobre la magnitud del problema y se abordan elementos de sus antecedentes, así como de la clasificación de las drogas, los factores de riesgo asociados a su consumo y las bases jurídicas para su control en Cuba.
Some situations put Cuba at risk for drug use, such as an increase in tourism, relations with countries that have high rates of substance abuse, the geographic location in drug trafficking corridors, and the high prevalence of "opening doors" drugs. In this regard, the National Health System must be prepared to prevent the problem and care for those affected, so it is necessary to maintain updated information on risk factors and main products used by consumers. In the present literature review on the subject, it is sought to draw the attention of health workers to this point, data on the magnitude of the problem and elements of its background are offered, as well as drug classification, the risk factors associated with its use and the legal bases for its control in Cuba.