RESUMEN
A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/efectos adversos , Calidad de Vida , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , ADN/farmacología , Resistencia a Antineoplásicos/genética , Línea Celular TumoralRESUMEN
PURPOSE: Emerging evidence suggests that 5' Adenosine Monophosphate-Activated Protein Kinase (AMPK), a key regulator of cellular bioenergetics, is a novel target for the treatment of glioblastoma (GBM), a lethal brain tumor. SBI-0206965, an aminopyrimidine derivative, is a potent AMPK inhibitor being investigated for the treatment of GBM. Here we characterized the systemic and brain pharmacokinetics (PK) and hepatic metabolism of SBI-0206965. METHODS: We performed intracerebral microdialysis to determine brain partitioning of SBI-0206965 in jugular vein cannulated rats. We assessed systemic PK of SBI-0206965 in rats and C57BL/6 mice following oral administration. Employing human, mouse, and rat liver microsomes we characterized the metabolism of SBI-0206965. RESULTS: SBI-0206965 is quickly absorbed, achieving plasma and brain extracellular fluid (ECF) peak levels within 0.25 - 0.65 h. Based on the ratio of Cmax and AUC in brain ECF to plasma (corrected for protein binding), brain partitioning is ~ 0.6-0.9 in rats. However, the compound has a short elimination half-life (1-2 h) and low relative oral bioavailability (~ 0.15). The estimated in-vitro hepatic intrinsic clearance of SBI-0206965 in mouse, rat and human was 325, 76 and 68 mL/min/kg, respectively. SBI-0206965 metabolites included desmethylated products, and the metabolism was strongly inhibited by ketoconazole, a CYP3A inhibitor. CONCLUSION: SBI-0206965 has adequate brain permeability but low relative oral bioavailability which may be due to rapid hepatic metabolism, likely catalyzed by CYP3A enzymes. Our observations will facilitate further development of SBI-0206965, and/or other structurally related molecules, for the treatment of GBM and other brain tumors.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Benzamidas , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Drogas en Investigación , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Pirimidinas , RatasRESUMEN
3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA-treated rats. We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A receptors. The increased activation of 5HT2A receptors promotes the production of prostaglandin E2 (PGE2) and subsequent activation of EP1 receptors in the dentate gyrus. EP1 receptor activation leads to eventual excitotoxicity and loss of PV interneurons resulting in reduced inhibition and lowered seizure threshold resulting in increased seizure susceptibility.
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Giro Dentado/efectos de los fármacos , Hidrazinas/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuronas/efectos de los fármacos , Oxazepinas/farmacología , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Giro Dentado/metabolismo , Dinoprostona/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae.
Asunto(s)
Conmoción Encefálica , Núcleo Dorsal del Rafe , Humanos , Serotonina , Conmoción Encefálica/complicaciones , Neuronas , Perfilación de la Expresión Génica , Neuronas SerotoninérgicasRESUMEN
Various forms of traumatic brain injury (TBI) are a leading cause of disability in the United States, with the generation of neuropsychiatric complications such as depression, anxiety, social dysfunction, and suicidality being common comorbidities. Serotonin (5-HT) signaling is linked to psychiatric disorders; however, the effects of neurotrauma on normal, homeostatic 5-HT signaling within the central nervous system (CNS) have not been well characterized. We hypothesize that TBI alters specific components of 5-HT signaling within the CNS and that the elucidation of specific TBI-induced alterations in 5-HT signaling may identify novel targets for pharmacotherapies that ameliorate the neuropsychiatric complications of TBI. Herein, we provide evidence that closed-head blast-induced mild TBI (mTBI) results in selective alterations in cortical 5-HT2A receptor signaling. We find that mTBI increases in vivo cortical 5-HT2A receptor sensitivity and ex vivo radioligand binding at time points corresponding with mTBI-induced deficits in social behavior. In contrast, in vivo characterizations of 5-HT1A receptor function revealed no effect of mTBI. Notably, we find that repeated pharmacologic activation of 5-HT2A receptors post-injury reverses deficits in social dominance resulting from mTBI. Cumulatively, these studies provide evidence that mTBI drives alterations in cortical 5-HT2A receptor function and that selective targeting of TBI-elicited alterations in 5-HT2A receptor signaling may represent a promising avenue for the development of pharmacotherapies for TBI-induced generation of neuropsychiatric disorders.
RESUMEN
Pyrethroid pesticides are widely used and can cause long-term effects after early exposure. Epidemiological and animal studies reveal associations between pyrethroid exposure and altered cognition following prenatal and/or neonatal exposure. However, little is known about the cellular effects of such exposure. Sprague Dawley rats were gavaged with 0 or 1.0 mg/kg deltamethrin (DLM), a Type II pyrethroid, in corn oil (dose volume 5 mL/kg) once per day from postnatal day (P) 3-20 and assessed shortly after dosing ended or as adults. No effects of DLM exposure were found on striatal dopaminergic markers, nor on AMPA receptor subunits or on NMDA-NR1. However, DLM increased NMDA-NR2A and decreased NMDA-NR2B levels in the hippocampus, in males but not females. Additionally, adult hippocampal CA1 long-term potentiation was increased in DLM-treated males but not females. Potassium stimulated extracellular glutamate release in the hippocampus was not affected using in vivo microdialysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed increased apoptotic cells in the dentate gyrus of male rats, in the absence of changes in cleaved caspase-3 at P21. Proinflammatory cytokines interferon gamma trended up in striatum, interleukin-1ß trended down in nucleus accumbens, IL-13 trended up in hippocampus, and keratinocyte chemoattractant/human growth-regulated oncogene (KC/GRO or CXCL1) was significantly increased in the hippocampus in male DLM-treated rats on P20. The data point to the developing hippocampus as a susceptible region to DLM-induced adverse effects.
RESUMEN
PURPOSE: The DNA alkylating agent temozolomide (TMZ), is the first-line therapeutic for the treatment of glioblastoma (GBM). However, its use is confounded by the occurrence of drug resistance and debilitating adverse effects. Previously, we observed that letrozole (LTZ), an aromatase inhibitor, has potent activity against GBM in pre-clinical models. Here, we evaluated the effect of LTZ on TMZ activity against patient-derived GBM cells. METHODS: Employing patient-derived G76 (TMZ-sensitive), BT142 (TMZ-intermediately sensitive) and G43 and G75 (TMZ-resistant) GBM lines we assessed the influence of LTZ and TMZ on cell viability and neurosphere growth. Combination Index (CI) analysis was performed to gain quantitative insights of this interaction. We then assessed DNA damaging effects by conducting flow-cytometric analysis of Ë H2A.X formation and induction of apoptotic signaling pathways (caspase3/7 activity). The effects of adding estradiol on LTZ-induced cytotoxicity and DNA damage were also evaluated. RESULTS: Co-treatment with LTZ at a non-cytotoxic concentration (40 nM) reduced TMZ IC50 by 8, 37, 240 and 640 folds in G76, BT-142, G43 and G75 cells, respectively. The interaction was deemed to be synergistic based on CI analysis. LTZ co-treatment also significantly increased DNA damaging effects of TMZ. Addition of estradiol abrogated these LTZ effects. CONCLUSIONS: LTZ increases DNA damage and synergistically enhances TMZ activity in TMZ sensitive and TMZ-resistant GBM lines. These effects are abrogated by the addition of exogenous estradiol underscoring that the observed effects of LTZ may be mediated by estrogen deprivation. Our study provides a strong rationale for investigating the clinical potential of combining LTZ and TMZ for GBM therapy.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Inhibidores de la Aromatasa/farmacología , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos , Estradiol/farmacología , Glioblastoma/metabolismo , Humanos , Letrozol/farmacología , Letrozol/uso terapéutico , Temozolomida/farmacología , Temozolomida/uso terapéuticoRESUMEN
Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Estimulantes del Sistema Nervioso Central/efectos adversos , Hipertermia Inducida , Discapacidades para el Aprendizaje/inducido químicamente , Metanfetamina/efectos adversos , Estimulación Acústica/métodos , Adrenalectomía/métodos , Animales , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Corticosterona/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Discapacidades para el Aprendizaje/sangre , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacosRESUMEN
Mammary gland development is controlled by a dynamic interplay between endocrine hormones and locally produced factors. Biogenic monoamines (serotonin, dopamine, norepinephrine, and others) are an important class of bioregulatory molecules that have not been shown to participate in mammary development. Here we show that mammary glands stimulated by prolactin (PRL) express genes essential for serotonin biosynthesis (tryptophan hydroxylase [TPH] and aromatic amine decarboxylase). TPH mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. TPH was induced by PRL in mammosphere cultures and by milk stasis in nursing dams, suggesting that the gene is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein gene expression and caused shrinkage of mammary alveoli. Conversely, TPH1 gene disruption or antiserotonergic drugs resulted in enhanced secretory features and alveolar dilation. Thus, autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.
Asunto(s)
Comunicación Autocrina/fisiología , Glándulas Mamarias Humanas/crecimiento & desarrollo , Comunicación Paracrina/fisiología , Prolactina/metabolismo , Serotonina/fisiología , Animales , Animales Recién Nacidos , Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Comunicación Autocrina/efectos de los fármacos , Caseínas/genética , Caseínas/metabolismo , Células Cultivadas , Clonación Molecular , Diálisis , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Fenclonina/farmacología , Regulación del Desarrollo de la Expresión Génica , Histología , Humanos , Ácido Hidroxiindolacético/metabolismo , Inmunohistoquímica , Hibridación in Situ , Lactalbúmina/genética , Lactalbúmina/metabolismo , Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/efectos de los fármacos , Metisergida/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Leche/metabolismo , Proteínas de la Leche/genética , Proteínas de la Leche/metabolismo , Mucinas/genética , Mucinas/metabolismo , Técnicas de Cultivo de Órganos , Comunicación Paracrina/efectos de los fármacos , Embarazo , Prolactina/deficiencia , Prolactina/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Antagonistas de la Serotonina/farmacología , Factores de Tiempo , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismoRESUMEN
Pyrethroids are synthetic insecticides that act acutely on voltage gated sodium channels to prolong channel opening and depolarization. Epidemiological studies find that exposure to pyrethroids are associated with neurological and developmental abnormalities in children. The long-term effects of type II pyrethroids, such as deltamethrin (DLM), on development have received little attention. We exposed Sprague-Dawley rats to DLM by gavage at doses of 0, 0.25, 0.5, and 1.0 mg/kg/day from postnatal day (P) 3-20 in a split-litter design. Following behavioral testing as adults, monoamine levels, release, and mRNA were assessed via high performance liquid chromatography, microdialysis, and qPCR, respectively. Long-term potentiation (LTP) was assessed at P25-35. Developmental DLM exposure resulted in deficits in allocentric and egocentric learning and memory, increased startle reactivity, reduced conditioned contextual freezing, and attenuated MK-801 induced hyperactivity compared with controls. Startle and egocentric learning were preferentially affected in males. Deltamethrin-treated rats exhibited increased CA1 hippocampal LTP, decreased extracellular dopamine release by microdialysis, reduced dopamine D1 receptor mRNA expression in neostriatum, and decreased norepinephrine levels in the hippocampus. The data indicate that neonatal DLM exposure has adverse long-term effects on learning, memory, startle, glutamatergic function, LTP, and norepinephrine.
Asunto(s)
Cognición/efectos de los fármacos , Insecticidas/toxicidad , Nitrilos/toxicidad , Piretrinas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Aprendizaje/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Rats treated with (+/-)-3,4-methylenedioxymethamphetamine (MDMA) or (+)-methamphetamine (MA) neonatally exhibit long-lasting learning impairments (i.e., after treatment on postnatal days (P)11-15 or P11-20). Although both drugs are substituted amphetamines, they each produce a unique profile of cognitive deficits (i.e., spatial vs. path integration learning and severity of deficits) which may be the result of differential early neurochemical changes. We previously showed that MA and MDMA increase corticosterone (CORT) and MDMA reduces levels of serotonin (5-HT) 24 h after treatment on P11, however, learning deficits are seen after 5 or 10 days of drug treatment, not just 1 day. Accordingly, in the present experiment, rats were treated with MA or MDMA starting on P11 for 5 or 10 days (P11-15 or P11-20) and tissues collected on P16, P21, or P30. Five-day MA administration dramatically increased CORT on P16, whereas MDMA did not. Both drugs decreased hippocampal 5-HT on P16 and P21, although MDMA produced larger reductions. Ten-day treatment with either drug increased dopamine utilization in the neostriatum on P21, whereas 5-day treatment had no effect. No CORT or brain 5-HT or dopamine changes were found with either drug on P30. Although the monoamine changes are transient, they may alter developing neural circuits sufficiently to permanently disrupt later learning and memory abilities.
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Inhibidores de Captación Adrenérgica/farmacología , Monoaminas Biogénicas/metabolismo , Corticosterona/sangre , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 x 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 x 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1-4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.
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Alucinógenos/farmacología , Aprendizaje/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Animales , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Natación/psicología , Factores de TiempoRESUMEN
BACKGROUND: Methamphetamine (MA) use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+)-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+)-MA (4 doses at 2 h intervals) on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session) 4 times at 2 h intervals]. RESULTS: MA increased corticosterone from 1-72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h. CONCLUSION: Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Glucemia/metabolismo , Corticosterona/sangre , Creatina/sangre , Creatinina/sangre , Metanfetamina/farmacología , Natación/fisiología , Glándulas Suprarrenales/anatomía & histología , Análisis de Varianza , Animales , Temperatura Corporal/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Masculino , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/metabolismo , Timo/anatomía & histologíaRESUMEN
RATIONALE: Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems but few associated cognitive effects. OBJECTIVES: Since questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. MATERIALS AND METHODS: Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 x 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161-166, 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 x 1.67 mg/kg once every 15 min) matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. RESULTS: On markers of neurotoxicity, MA showed decreased dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. CONCLUSIONS: MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/toxicidad , Aprendizaje/efectos de los fármacos , Metanfetamina/farmacología , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/psicología , Reconocimiento en Psicología/efectos de los fármacos , Animales , Monoaminas Biogénicas/metabolismo , Temperatura Corporal/efectos de los fármacos , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Conducta Estereotipada/efectos de los fármacos , Natación/psicologíaRESUMEN
PURPOSE: Gemcitabine is a pyrimidine nucleoside analogue anticancer agent that has shown promising anti-tumor activity in several experimental models of brain tumor. However, the pharmacokinetic behavior of gemcitabine in the central nervous system, especially in brain tumors is currently not well understood. In this study we evaluated the gemcitabine brain extracellular fluid (ECF) in normal rats and in ECF obtained from tumor- and tumor-free regions of glioma-bearing rats, to better understand the availability of the drug to brain and brain tumors. METHODS: The brain ECF pharmacokinetics of gemcitabine were investigated employing intracerebral microdialysis following intravenous administration of 10, 25 and 100 mg/kg doses in male Sprague-Dawley rats. In the second phase of the study, gemcitabine (25 mg/kg) was intravenously administered in rats implanted with C6 gliomas and ECF samples were simultaneously obtained from the tumor and tumor-free regions of the brain. Serial blood samples were obtained for evaluating the plasma pharmacokinetics of gemcitabine. Non-compartmental approach was employed for the analyses of the brain ECF and plasma pharmacokinetics of gemcitabine. RESULTS: Following intravenous administration, gemcitabine rapidly distributed into rat brain. At doses equivalent to 10, 25 and 100 mg/kg, the brain ECF gemcitabine AUC (area under the plasma concentration--time curve measured over the last sampling time point) values were 2.46 +/- 0.7, 3.20 +/- 1.1, and 9.06 +/- 3.0 microg h/ml, respectively. The brain ECF concentrations of gemcitabine declined in parallel with plasma concentrations. At the three doses evaluated, the relative brain distribution coefficient (AUC brainECF/AUC plasma) of gemcitabine ranged from 0.07 to 0.09 suggesting limited gemcitabine availability to brain tissues. Studies on C6 glioma-bearing rats revealed that following an intravenous dose of 25 mg/kg, the AUC values in the tumor-free and tumor-brain regions were 4.52 +/- 2.4, and 9.82 +/- 3.3 microg h/ml, respectively. Thus, the AUC of gemcitabine in the tumor ECF was on average 2.2-fold greater than the corresponding value in the tumor-free ECF of the brain. Plasma pharmacokinetics of gemcitabine remained unaltered in tumor-bearing animals, when compared to plasma pharmacokinetics in healthy animals. CONCLUSIONS: Our findings suggest that the overall brain exposure to gemcitabine is likely to be low as evident from the relative brain distribution coefficient of <0.1. However, the exposure is likely to be considerably higher in the brain tumor relative to tumor-free regions of the brain. The higher drug levels in brain tumor compared to the non-tumor region may facilitate selectively higher cytotoxicity against brain tumor cells.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Desoxicitidina/análogos & derivados , Líquido Extracelular/metabolismo , Análisis de Varianza , Animales , Área Bajo la Curva , Disponibilidad Biológica , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Glioma/metabolismo , Inyecciones Intravenosas , Masculino , Microdiálisis , Trasplante de Neoplasias , Ratas , Ratas Sprague-Dawley , GemcitabinaRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.
Asunto(s)
Acetilcolina/metabolismo , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Microdiálisis , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotonina/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Glucosa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismoRESUMEN
Among young adults, 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular drug of abuse, and anecdotal evidence indicates that repeated use of MDMA may result in impairments in sexual function and decreased sex drive in human users. There has been little investigation of the effects of MDMA on sexual function in rodents. In the present study, the authors determined that in male rats (Rattus novegicus) tested in a sexually naïve or a sexually experienced state, administration of a serotonin (5-HT)-depleting regimen of MDMA did not produce a change in mount, intromission, and ejaculation latency or in mount and intromission frequency compared with such latency and frequency in vehicle-treated control rats. In contrast to vehicle-treated rats, MDMA-treated rats did not form a conditioned place preference (CPP) to sex. Failure of MDMA-treated rats to form CPP to sex may be due to MDMA-induced impairments in circuits mediating sexual reward.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotoninérgicos/farmacología , Conducta Sexual Animal/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Serotonina/metabolismoRESUMEN
BACKGROUND: +/-3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that causes cognitive deficits in humans. A rat model for learning and memory deficits has not been established, although some cognitive deficits have been reported. METHODS: Male Sprague-Dawley rats were treated with MDMA (15 mg/kg x 4 doses) or saline (SAL) (n = 20/treatment group) and tested in different learning paradigms: 1) path integration in the Cincinnati water maze (CWM), 2) spatial learning in the Morris water maze (MWM), and 3) novel object recognition (NOR). One week after drug administration, testing began in the CWM, then four phases of MWM, and finally NOR. Following behavioral testing, monoamine levels were assessed. RESULTS: +/-3,4-Methylenedioxymethamphetamine-treated rats committed more CWM errors than did SAL-treated rats. +/-3,4-Methylenedioxymethamphetamine-treated animals were further from the former platform position during each 30-second MWM probe trial but showed no differences during learning trials with the platform present. There were no group differences in NOR. +/-3,4-Methylenedioxymethamphetamine depleted serotonin in all brain regions and dopamine in the striatum. CONCLUSIONS: +/-3,4-Methylenedioxymethamphetamine produced MWM reference memory deficits even after complex learning in the CWM, where deficits in path integration learning occurred. Assessment of path integration may provide a sensitive index of MDMA-induced learning deficits.
Asunto(s)
Conducta Animal/efectos de los fármacos , Alucinógenos/farmacología , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/farmacología , Conducta Espacial/efectos de los fármacos , Análisis de Varianza , Animales , Cognición/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Cloruro de Sodio/administración & dosificación , Factores de TiempoRESUMEN
RATIONALE: The neurochemical effects produced by acute administration of 3,4-methylenedioxymethamphetamine (MDMA) on the monoaminergic systems in the brain are well documented; however, there has been little consideration of the potential effects of MDMA on other neurotransmitter systems. OBJECTIVE: The present study was designed to investigate the acute effect of MDMA on cholinergic neurons by measuring acetylcholine (ACh) release in the medial prefrontal cortex (PFC) and dorsal hippocampus, terminal regions of cholinergic projection neurons originating in the basal forebrain. METHODS: In vivo microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) were used to assess the effects of MDMA on the extracellular concentration of ACh in the PFC and dorsal hippocampus of the rat. RESULTS: The systemic administration of MDMA (3-20 mg/kg, i.p.) resulted in an increased extracellular concentration of ACh in the PFC and dorsal hippocampus. Reverse dialysis of MDMA (100 microM) into the PFC and hippocampus also increased ACh release in these brain regions. Treatment with parachlorophenylalanine and alpha-methyl-para-tyrosine, inhibitors of serotonin (5-HT) and dopamine (DA) synthesis, respectively, significantly attenuated the release of ACh stimulated by MDMA in the PFC, but not in the dorsal hippocampus. CONCLUSIONS: MDMA exerts a stimulatory effect on the release of ACh in the PFC and dorsal hippocampus in vivo, possibly by mechanisms localized within these brain regions. In addition, these results suggest that the MDMA-induced release of ACh in the PFC involves both serotonergic and dopaminergic mechanisms.
Asunto(s)
Acetilcolina/metabolismo , Alucinógenos/farmacología , Hipocampo/metabolismo , N-Metil-3,4-metilenodioxianfetamina/farmacología , Corteza Prefrontal/metabolismo , Anfetamina/farmacología , Animales , Cromatografía Líquida de Alta Presión , Inhibidores de Captación de Dopamina/farmacología , Electroquímica , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Alucinógenos/administración & dosificación , Hipocampo/efectos de los fármacos , Masculino , Microdiálisis , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To review the evidence for the use of modafinil in the treatment of attention deficit/hyperactivity disorder (ADHD). DATA SOURCES: A MEDLINE search (January 1990-May 2006) was conducted using MeSH terms ADHD and modafinil. The search was limited to English-language articles on clinical trials in humans. The Cochrane Database was also searched. STUDY SELECTION AND DATA EXTRACTION: The literature search yielded 4 randomized clinical trials. DATA SYNTHESIS: The use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures used to assess the status of patients diagnosed with ADHD. Several aspects of cognitive function in ADHD patients also appear to improve following modafinil treatment. Modafinil shows a favorable adverse effect profile. Insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. However, it has not been demonstrated that the beneficial effects of modafinil are maintained with chronic administration. CONCLUSIONS: Modafinil may be a viable option for some patients in the treatment of ADHD, perhaps those for whom standard ADHD therapies have not been successful or tolerated. There remains a need for additional large, long-term studies using flexible titration methods to optimize the dose of modafinil to establish safety and efficacy, as well as head-to-head comparisons between modafinil and both long- and short-acting stimulants to determine the role of modafinil in the treatment of ADHD.