RESUMO
The astrocytic glutamate transporter GLT-1 performs glutamate uptake thereby mediating NMDAr responses in neurons. Ceftriaxone (CEF) upregulates astrocytic GLT-1 expression/activity, which could counteract excessive glutamate levels and aggressive behavior induced by anabolic synthetic steroids such as nandrolone decanoate (ND). Here, adult male CF-1 mice were allocated to oil (VEH), ND, CEF, and ND/CEF groups. Mice were subcutaneously (s.c.) injected with ND (15 mg/kg) or VEH for 19 days, and received intraperitoneal (i.p.) injections of CEF (200 mg/kg) or saline for 5 days. The ND/CEF group received ND for 19 days plus coadministration of CEF in the last 5 days. On the 19th day, the aggressive phenotypes were evaluated through the resident-intruder test. After 24 h, cerebrospinal fluid was collected to measure glutamate levels, and the pre-frontal cortex was used to assess GLT-1, pGluN2BTyr1472, and pGluN2ATyr1246 by Western blot. Synaptosomes from the left brain hemisphere was used to evaluate mitochondrial function including complex II-succinate dehydrogenase (SDH), Ca2+ handling, membrane potential (ΔÑ°m), and H2O2 production. ND decreased the latency for the first attack and increased the number of attacks by the resident mice against the intruder, mechanistically associated with an increase in glutamate levels and pGluN2BTyr1472 but not pGluN2ATyr1244, and GLT-1 downregulation. The abnormalities in mitochondrial Ca2+ influx, SDH, ΔÑ°m, and H2O2 implies in deficient energy support to the synaptic machinery. The ND/CEF group displayed a decreased aggressive behavior, normalization of glutamate and pGluN2BTyr1472levels, and mitochondrial function at synaptic terminals. In conclusion, the pharmacological modulation of GLT-1 highlights its relevance as an astrocytic target against highly impulsive and aggressive phenotypes.
Assuntos
Agressão/efeitos dos fármacos , Astrócitos/fisiologia , Transportador de Glucose Tipo 1/fisiologia , Psicoses Induzidas por Substâncias/psicologia , Congêneres da Testosterona/efeitos adversos , Agressão/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nandrolona/efeitos adversos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Psicoses Induzidas por Substâncias/metabolismo , Psicoses Induzidas por Substâncias/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Regulação para Cima/efeitos dos fármacosRESUMO
Methylphenidate-induced psychosis has been scarcely studied due to bioethical and neurobiological issues regarding its research. Although some authors have hypothesized that there might be a vulnerability for the development of a major psychiatric disorder in the long term, there is no agreement about the predictive value of this type of psychosis in children and adolescents, and its origin is also uncertain. It has been suggested that higher dopamine levels in some cerebral regions and a family history of mental disorders might increase the risk of psychosis secondary to psychostimulants. We present the case of a nine-year-old child diagnosed with attention deficit disorder and oppositional defiant disorder, who exhibited visual and auditory hallucinations and delirious ideas about harm during methylphenidate treatment. The patients symptoms regressed after drug removal. We discuss the key issues related to the origin, causality, management, and prognosis of psychostimulant-induced psychosis.
La psicosis inducida por metilfenidato ha sido escasamente estudiada debido a los problemas bioéticos y neurobiológicos relacionados con su investigación. Si bien evidenciaría una vulnerabilidad a largo plazo para el desarrollo de un trastorno psiquiátrico mayor, no hay consenso sobre su valor predictivo en la población infanto-juvenil, mientras que su origen es incierto. Se ha sugerido que los mayores niveles de dopamina en ciertas zonas cerebrales y el antecedente familiar de algunos trastornos mentales, aumentaría el riesgo de presentar psicosis secundaria a psicoestimulantes. Presentamos el caso de un niño de nueve años de edad, con diagnóstico de trastorno por déficit de atención comórbido a una oposición desafiante, que durante el tratamiento con metilfenidato presentó alucinaciones visuales y auditivas e ideas deliriosas de daño que cedieron con la suspensión del fármaco. Se discuten los principales aspectos relacionados con el origen, la causalidad, el manejo y el pronóstico de la psicosis inducida por psicoestimulantes.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Metilfenidato/efeitos adversos , Psicoses Induzidas por Substâncias/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Criança , Humanos , Masculino , Metilfenidato/administração & dosagem , Psicoses Induzidas por Substâncias/diagnóstico , Psicoses Induzidas por Substâncias/fisiopatologiaRESUMO
La fenciclidina (PCP) produce psicosis muy similares a la esquizofrenia. Mientras las psicosis inducidas por anfetamina presentan sólo síntomas positivos como delirio y alucinaciones, las psicosis inducidas por PCP presentan tanto síntomas positivos como negativos (aplanamiento afectivo, retardo psicomotor, empobrecimiento del discurso). De este modo las psicosis anfetamínicas se ajustan a un modelo schneideriano y las psicosis por PCP a un modelo bleuleriano de esquizofrenia. La PCP se une selectivamente a un sitio de unión específico, el receptor a aminoácidos excitatorios N-metil-D-aspaertato (NMDA). Estos hallazgos sugieren que una disfunción de la neurotransmisión mediada por el receptor NMDA puede contribuir a la etiopatogenia de la esquizofrenia
Assuntos
Humanos , Fenciclidina/farmacocinética , Esquizofrenia/induzido quimicamente , Anfetamina/efeitos adversos , Abuso de Fenciclidina/fisiopatologia , Fenciclidina/efeitos adversos , Psicoses Induzidas por Substâncias/fisiopatologia , Transtornos Psicóticos/fisiopatologiaRESUMO
A first episode of psychosis occurred in a young woman of West Indian parentage and one of identical twins following a brief period of high consumption of a drink made from Colubrina plant extract (mabi bark). The course of the psychosis is described and possible underlying mechanisms and the relationship to amphetamine psychosis are discussed.