RESUMO
Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.
Assuntos
Estimulantes do Sistema Nervoso Central , Dimesilato de Lisdexanfetamina , Humanos , Adulto , Criança , Adolescente , Masculino , Ratos , Animais , Dimesilato de Lisdexanfetamina/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Dextroanfetamina/toxicidade , Dextroanfetamina/uso terapêutico , Resultado do Tratamento , Ratos Wistar , SêmenRESUMO
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
Early life stressors, such as social isolation (SI), can disrupt brain development contributing to behavioral and neurochemical alterations in adulthood. Purinergic receptors and ectonucleotidases are key regulators of brain development in embryonic and postnatal periods, and they are involved in several psychiatric disorders, including schizophrenia. The extracellular ATP drives purinergic signaling by activating P2X and P2Y receptors and it is hydrolyzed by ectonucleotidases in adenosine, which activates P1 receptors. The purpose of this study was to investigate if SI, a rodent model used to replicate abnormal behavior relevant to schizophrenia, impacts purinergic signaling. Male Wistar rats were reared from weaning in group-housed or SI conditions for 8 weeks. SI rats exhibited impairment in prepulse inhibition and social interaction. SI presented increased ADP levels in cerebrospinal fluid and ADP hydrolysis in the hippocampus and striatum synaptosomes. Purinergic receptor expressions were upregulated in the prefrontal cortex and downregulated in the hippocampus and striatum. A2A receptors were differentially expressed in SI prefrontal cortex and the striatum, suggesting distinct roles in these brain structures. SI also presented decreased ADP, adenosine, and guanosine levels in the cerebrospinal fluid in response to D-amphetamine. Like patients with schizophrenia, uric acid levels were prominently increased in SI rats after D-amphetamine challenge. We suggest that the SI-induced deficits in prepulse inhibition might be related to the SI-induced changes in purinergic signaling. We provide new evidence that purinergic signaling is markedly affected in a rat model relevant to schizophrenia, pointing out the importance of purinergic system in psychiatry conditions.
Assuntos
Receptores Purinérgicos , Transdução de Sinais , Isolamento Social , Difosfato de Adenosina/líquido cefalorraquidiano , Animais , Comportamento Animal , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Masculino , Nucleotidases/metabolismo , Ratos , Ratos Wistar , Receptor A2A de Adenosina/metabolismo , Receptores Purinérgicos P2X/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Reflexo de Sobressalto , Psicologia do Esquizofrênico , Comportamento Social , Isolamento Social/psicologia , DesmameRESUMO
Metabolic and psychiatric disorders present a bidirectional relationship. GLP-1 system, known for its insulinotropic effects, has also been associated with numerous regulatory effects in cognitive and emotional processing. GLP-1 receptors (GLP-1R) agonists present neuroprotective and antidepressant/anxiolytic properties. However, the effects of GLP-1R agonism in bipolar disorder (BD) mania and the related cognitive disturbances remains unknown. Here, we investigated the effects of the GLP-1R agonist liraglutide (LIRA) at monotherapy or combined with lithium (Li) against D-amphetamine (AMPH)-induced mania-like symptoms, brain oxidative and BDNF alterations in mice. Swiss mice received AMPH 2 mg/kg or saline for 14 days. Between days 8-14, they received LIRA 120 or 240 µg/kg, Li 47.5 mg/kg or the combination Li + LIRA, on both doses. After behavioral evaluation the brain areas prefrontal cortex (PFC), hippocampus and amygdala were collected. AMPH induced hyperlocomotion, risk-taking behavior and multiple cognitive deficits which resemble mania. LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments, while Li + LIRA240 rescued all behavioral changes induced by AMPH. LIRA reversed AMPH-induced hippocampal oxidative and neurotrophic changes. Li + LIRA240 augmented Li antioxidant effects and greatly reversed AMPH-induced BDNF changes in PFC and hippocampus. LIRA rescued the weight gain induced by Li in the course of mania model. Therefore, LIRA can reverse some mania-like behavioral alterations and combined with Li augmented the mood stabilizing and neuroprotective properties of Li. This study points to LIRA as a promising adjunctive tool for BD treatment and provides the first rationale for the design of clinical trials investigating its possible antimanic effect.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Dextroanfetamina/toxicidade , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Liraglutida/administração & dosagem , Lítio/administração & dosagem , Mania/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Animais , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Sinergismo Farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Mania/induzido quimicamente , Mania/psicologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , CamundongosRESUMO
The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel), Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats, which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All these impairments were reversed by treatment with Li and/or Cel, in a way dependent on cerebral area and biochemical analysis. Li and Cel coadministration reversed the d-AMPH-induced decrease in catalase activity in cerebral structures. The activity of glutathione peroxidase was decreased in the frontal cortex of animals receiving d-AMPH, and treatment with Li, Cel, or a combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antimaníacos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Celecoxib/uso terapêutico , Compostos de Lítio/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antimaníacos/administração & dosagem , Transtorno Bipolar/induzido quimicamente , Celecoxib/administração & dosagem , Dextroanfetamina/administração & dosagem , Modelos Animais de Doenças , Dopamina/metabolismo , Quimioterapia Combinada , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Compostos de Lítio/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
OBJECTIVE: The purpose of this study was to determine the prevalence of medical and nonmedical use of prescription attention deficit hyperactive disorder (ADHD) stimulant medication among medical students. MATERIALS AND METHODS: An IRB approved 19-question web survey was sent out to all students from a Puerto Rico (PR) medical school to assess use of ADHD medication. Out of the 250 stu-dents consulted there was a response of 152 surveys. Data was cross-referenced and compared with data from other studies. RESULTS/DISCUSSION: From the results gathered, the study's sample had a higher prevalence of use than the 15% reported in previous studies, reaching 47.4%. Among students who had used these drugs, 89.4% indicated using it without a prescription. 86.8% of all respondents used some form of stimulant or substance in order to cope with the academic workload of medical school, includ-ing coffee, energy drinks, cigarettes, and alcohol. The majority of students (60.5%) considered study techniques workshops and exercise programs to succeed academically. CONCLUSION: This study suggests a higher prevalence of ADHD medication use amongst the PR medical student sample compared to findings reported of US medical students, as well as a high prevalence related to nonmedical use as a means for medical students to cope with their training. The nonmedical use of stimulants in the medical school setting remains of utmost public health and clinical concern. The results of this study could help develop proper workshops and non-pharmacological techniques to help medical students cope with their workload.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Dextroanfetamina/administração & dosagem , Metilfenidato/administração & dosagem , Estudantes de Medicina/estatística & dados numéricos , Adaptação Psicológica , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Feminino , Humanos , Masculino , Prevalência , Porto Rico , Estudantes de Medicina/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
Studies have suggested the involvement of inflammatory processes in the physiopathology of bipolar disorder. Preclinical evidences have shown that histone deacetylase inhibitors may act as mood-stabilizing agents and protect the brain in models of mania and depression. The aim of the present study was to evaluate the effects of sodium butyrate (SB) and valproate (VPA) on behavioral changes, histone deacetylase activity, and the levels of cytokines in an animal model of mania induced by dextroamphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for a period of 14 days, and then, between the 8th and 14th days, the rats were treated with SB, VPA, or Sal. The activity of histone deacetylase and the levels of cytokines (interleukin (IL) IL-4, IL-6, and IL-10 and tumor necrosis factor-alpha (TNF-α)) were evaluated in the frontal cortex and striatum of the rats. The administration of d-AMPH increased the activity of histone deacetylase in the frontal cortex. Administration of SB or VPA decreased the levels of histone deacetylase activity in the frontal cortex and striatum of rats. SB per se increased the levels of cytokines in both of the brain structures evaluated. AMPH increased the levels of cytokines in both of the brain structures evaluated, and VPA reversed this alteration. The effects of SB on d-AMPH-induced cytokine alterations were dependent on the brain structure and the cytokine evaluated. Despite VPA and SB having a similar mechanism of action, both being histone deacetylase inhibitors, they showed different effects on the levels of cytokines. The present study reinforces the need for more research into histone deacetylase inhibitors being used as a possible target for new medications in the treatment of bipolar disorder.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Dextroanfetamina , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Stimulant medications are used in the treatment of attention deficit hyperactivity disorder and serious cardiac complications can occur when these medications are abused. We present a 15-year-old adolescent girl who was found to have a Takotsubo cardiomyopathy after acute amphetamine/dextroamphetamine ingestion.
Assuntos
Estimulantes do Sistema Nervoso Central/intoxicação , Dextroanfetamina/intoxicação , Imagem Cinética por Ressonância Magnética/métodos , Cardiomiopatia de Takotsubo/induzido quimicamente , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Adolescente , Eletrocardiografia/métodos , Feminino , Humanos , Prognóstico , Recuperação de Função Fisiológica , Medição de Risco , Tentativa de Suicídio , Cardiomiopatia de Takotsubo/terapia , Resultado do TratamentoRESUMO
The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3'-O-(4-benzoyl)benzoyl-adenosine 5'-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1ß; tumor necrosis factor alpha, TNF-α; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R(-/-)) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1ß, TNF-α, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder.
Assuntos
Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Dextroanfetamina/toxicidade , Modelos Animais de Doenças , Receptores Purinérgicos P2X7/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Agonistas Purinérgicos/farmacologia , Antagonistas Purinérgicos/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.