RESUMEN
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has been shown to produce serotonergic damage in the brains of primates, including humans, and of rats. Tryptophan, the precursor of serotonin, is primarily degraded through the kynurenine (KYN) pathway, producing among others KYN, the main metabolite of this route. KYN has been reported as an endogenous agonist of the aryl hydrocarbon receptor (AhR), a transcription factor involved in several neurological functions. This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous l-kynurenine or of the AhR positive modulator 3,3'-diindolylmethane (DIM) partially prevented the serotonergic damage induced by the drug. The results demonstrate for the first time that MDMA increases KYN levels and AhR activity, and these changes appear to play a role in limiting the neurotoxicity induced by the drug. This work provides a better understanding of the physiological mechanisms that attenuate the brain damage induced by MDMA and identify modulation of the KYN pathway and of AhR as potential therapeutic strategies to limit the negative effects of MDMA.
Asunto(s)
Hipocampo/efectos de los fármacos , Quinurenina/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Serotoninérgicos/toxicidad , Triptófano Oxigenasa/efectos de los fármacos , Animales , Autorradiografía , Hipocampo/metabolismo , Quinurenina/farmacología , Síndromes de Neurotoxicidad , Ratas , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/metabolismo , Serotonina , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano Oxigenasa/metabolismoRESUMEN
This study evaluated the most common toxic agents affecting domestic cats, the clinical signs of toxicity, and the therapeutic approaches for recovery. A survey on poisoning in cats was conducted among small animal veterinary practitioners from 2017 to 2018. Of the 748 completed questionnaires, 543 (72.6%) were evaluated. Pesticides and household cleaning supplies were the most common causes of poisoning in cats. The toxicant groups included pesticides and household cleaning supplies (organophosphates), human drugs (acetaminophen), plants/plant derivatives (lily), and veterinary drugs (tramadol). The major clinical signs for these four groups of toxicants were (1) acetaminophen poisoning, which caused oxidative erythrocyte damage; (2) muscarinic and nicotinic cholinergic syndrome, which resulted from organophosphate poisoning; (3) acute kidney injury, which resulted from intoxication of lily; and (4) serotonin syndrome, which resulted from tramadol toxicosis. Interventions for treating poisoning in cats were based on the clinical presentation of animals. In the present study, the significant toxins identified to be dangerous for cats were characterized using the obtained data in Brazil as well as the main associated clinical signs and therapy recommended by veterinarians.(AU)
Objetiva-se com este trabalho caracterizar os principais toxicantes para gatos domésticos, bem como os prevalentes sinais clínicos e a terapêutica associada. Uma pesquisa sobre envenenamento em gatos foi realizada entre médicos veterinários no período de 2017 a 2018. Dos 748 questionários preenchidos, 543 (72,6%) foram avaliados. Pesticidas e domissanitários foram os principais causadores de intoxicação em gatos. Entre os grupos tóxicos, destacaram-se, na categoria pesticidas e domissanitários (organofosforados), medicamentos humanos (acetaminofeno), plantas e derivados de planta (lírio) e medicamentos veterinários (tramadol). Os principais sinais clínicos para os quatro grupos de substâncias tóxicas foram: (1) intoxicação por acetaminofeno, que causou dano eritrocitário oxidativo; (2) síndrome colinérgica muscarínica e nicotínica, resultante do envenenamento por organofosforado; (3) lesão renal aguda, causada pela intoxicação por lírio; e (4) síndrome serotoninérgica, resultante da exposição ao tramadol. As intervenções realizadas para o tratamento dos envenenamentos foram justificáveis mediante a apresentação clínica dos animais. Por meio dos dados obtidos, puderam-se caracterizar os principais tóxicos para gatos no Brasil, bem como os principais sinais clínicos associados e a terapêutica preconizada pelos médicos veterinários.(AU)
Asunto(s)
Animales , Gatos , Compuestos Organofosforados/toxicidad , Intoxicación/etiología , Intoxicación/veterinaria , Tramadol/toxicidad , Lilium/toxicidad , Acetaminofén/toxicidad , Serotoninérgicos/toxicidad , Estrés Oxidativo , Antagonistas Muscarínicos/toxicidad , Lesión Renal Aguda/inducido químicamenteRESUMEN
The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Trastornos Parkinsonianos , Serotoninérgicos/toxicidad , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Macaca fascicularis , Masculino , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
BACKGROUND: MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS: Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS: Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION: Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.
Asunto(s)
Ambiente , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neurotoxinas/toxicidad , Serotoninérgicos/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Síndromes de Neurotoxicidad/veterinaria , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
BACKGROUND: Diffusion tensor imaging has received major interest to highlight markers of neurodegeneration in Parkinson's disease. Whether the alteration of diffusion parameters mostly depicts dopaminergic lesions or can also reveal serotonergic denervation remains a question. OBJECTIVES: The aim of this study was to determine the best diffusion tensor imaging markers of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylene-dioxy-methamphetamine (MDMA; also known as ecstasy) lesions in the nonhuman primate. METHODS: We acquired measures of mean diffusivity and fractional anisotropy longitudinally (before and after MPTP and MDMA) and correlated them with severity of parkinsonism, PET imaging, and postmortem fiber quantification. RESULTS: MPTP-induced lesions were associated with increases of mean diffusivity within both the caudate nucleus and the anterior cingulate cortex, whereas MDMA-induced lesions caused an increase of fractional anisotropy within the caudate nucleus. These variations of diffusion tensor imaging correlated with the motor score. CONCLUSION: Taken together, these results demonstrate that diffusion measures within specific brain regions can mark severity of dopaminergic and serotonergic induced lesions in a neurotoxic nonhuman primate model of Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.
Asunto(s)
Encéfalo/metabolismo , Imagen de Difusión Tensora , Dopamina/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Serotonina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Macaca fascicularis , Masculino , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Serotoninérgicos/toxicidad , Estadísticas no Paramétricas , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: Preclinical data have suggested involvement of the endocannabinoid (eCB) system in MDMA-induced memory impairment. Clinical research has shown that blockade of the 5-HT2 receptor nulls memory impairment during MDMA intoxication. Interestingly, studies have demonstrated that the eCB and the 5-HT system interact. It was hypothesized that MDMA would cause an increase in eCB concentrations together with a decrease in memory performance, and that combining MDMA with a 5-HT2 receptor blocker ketanserin would lead to a counteraction of the MDMA effects on eCB concentrations and memory. METHODS: Twenty healthy recreational polydrug users entered a double-blind placebo-controlled within-subject study. Participants received a pre-treatment (ketanserin 40 mg, placebo) followed 30 min later by a treatment (MDMA 75 mg, placebo). Verbal memory was tested by means of a 30-word learning test. Endocannabinoid concentrations (anandamide (2-AG); N-arachidonylethanolamine (AEA)) were assessed in blood at baseline, before (90 min post-treatment) and after cognitive tests (150 min post-treatment). RESULTS: Findings showed that MDMA impaired memory 90 min post-treatment in the word learning task. This effect was a replication of previous studies using the same dose of MDMA (75 mg) and the same learning paradigm. Contrary to our hypothesis, MDMA did not affect eCB concentrations, nor did ketanserin block MDMA-induced memory impairment. Ketanserin caused an increase in AEA concentrations, 180 min after administration. CONCLUSION: Current findings suggest that peripherally measured endocannabinoids are not associated with the verbal memory deficit during MDMA intoxication. TRIAL REGISTRATION NUMBER: NTR3691.
Asunto(s)
Endocannabinoides/sangre , Trastornos de la Memoria/sangre , Trastornos de la Memoria/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Aprendizaje Verbal/efectos de los fármacos , Adulto , Ácidos Araquidónicos/sangre , Ácidos Araquidónicos/farmacología , Método Doble Ciego , Endocannabinoides/farmacología , Femenino , Humanos , Ketanserina/farmacología , Ketanserina/uso terapéutico , Masculino , Trastornos de la Memoria/prevención & control , Alcamidas Poliinsaturadas/sangre , Alcamidas Poliinsaturadas/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Serotoninérgicos/toxicidad , Aprendizaje Verbal/fisiología , Adulto JovenRESUMEN
BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer's disease (AD). Accumulation of toxic amyloid-ß (Aß) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aß pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aß pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aß pathology in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD. METHODS: We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. RESULTS: Amyloid-ß-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aß42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aß40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aß42 and Aß40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. CONCLUSIONS: Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aß42 and Aß40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aß pathology.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/efectos de los fármacos , Citalopram/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Serotonina/metabolismo , 5,7-Dihidroxitriptamina/toxicidad , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Bencilaminas/farmacocinética , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Indoles/metabolismo , Inyecciones Intraventriculares , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética , Serotoninérgicos/toxicidad , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Tritio/farmacocinéticaRESUMEN
3,4-methylenedioxymethamphetamine (MDMA) leads to apoptosis in the hippocampus with consequent induction of learning and memory impairment. In this study, we have investigated the effects of treadmill exercise on memory in relation to apoptosis and oxidative stress in the hippocampi of MDMA-treated rats. Male Wistar rats received multiple intraperitoneal (IP) injections of MDMA (10 mg/kg) and exercised for one month on a treadmill (simultaneously or asynchronously with MDMA). We assessed memory function with the Morris water maze (MWM) test. Lipid peroxidation (LPO) and expression of caspase 3, Bax, and Bcl-2 were examined by the thiobarbituric acid assay (TBA) and western blot, respectively. Our results showed that asynchronous treadmill exercise could significantly improve MDMA-induced memory impairment in the MWM test. Caspase 3 expression decreased in the exercise group compared to the MDMA group. Although MDMA treatment caused an increase in the Bax/Bcl-2 ratio, the treadmill exercise reduced this ratio. Simultaneous exercise caused a reduction in lipid peroxidation in the hippocampus. This data suggests that treadmill exercise can be a useful strategy for treating memory impairment in persons with neurodegenerative disease and stimulant drug users. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Apoptosis/fisiología , Hipocampo/patología , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Condicionamiento Físico Animal/fisiología , Serotoninérgicos/toxicidad , Animales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Toxicity of 3,4-methylenedioxymethamphetamine (MDMA) towards biogenic amine neurons is well documented and in primate brain predominantly affects serotonin (5-HT) neurons. MDMA induces damage of 5-HT axons and nerve fibres and intracytoplasmic inclusions. Whilst its pathobiology involves mitochondrially-mediated oxidative stress, we hypothesised MDMA possessed the capacity to activate autophagy, a proteostatic mechanism for degradation of cellular debris. We established a culture of ventral pons from embryonic murine brain enriched in 5-HT neurons to explore mechanisms of MDMA neurotoxicity and recruitment of autophagy, and evaluated possible neuroprotective actions of the clinically approved agent rilmenidine. MDMA (100 µM-1 mM) reduced cell viability, like rapamycin (RM) and hydrogen peroxide (H2O2), in a concentration- and time-dependent manner. Immunocytochemistry revealed dieback of 5-HT arbour: MDMA-induced injury was slower than for RM and H2O2, neuritic blebbing occurred at 48 and 72 h and Hoechst labelling revealed nuclear fragmentation with 100 µM MDMA. MDMA effected concentration-dependent inhibition of [3H]5-HT uptake with 500 µM MDMA totally blocking transport. Western immunoblotting for microtubule associated protein light chain 3 (LC3) revealed autophagosome formation after treatment with MDMA. Confocal analyses and immunocytochemistry for 5-HT, Hoechst and LC3 confirmed MDMA induced autophagy with abundant LC3-positive puncta within 5-HT neurons. Rilmenidine (1 µM) protected against MDMA-induced injury and image analysis showed full preservation of 5-HT arbours. MDMA had no effect on GABA neurons, indicating specificity of action at 5-HT neurons. MDMA-induced neurotoxicity involves autophagy induction in 5-HT neurons, and rilmenidine via beneficial actions against toxic intracellular events represents a potential treatment for its pathobiology in sustained usage.
Asunto(s)
Autofagia/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Fármacos Neuroprotectores/farmacología , Oxazoles/farmacología , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Autofagia/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Rilmenidina , Neuronas Serotoninérgicas/fisiología , Serotoninérgicos/toxicidadRESUMEN
Repeated exposure to aversive events leads to the development of tolerance to stress, which involves the serotonergic pathway originated in the Median Raphe Nucleus (MnRN) to the Dorsal Hippocampus (DH). However, it is not clear whether these lesion-induced deficits can be attenuated by treatment with antidepressants. Therefore, the aim of this work was to investigate the effects of chronic treatment with Imipramine (IMI) in rats with lesions in the MnRN and exposed to restraint stress. Male Wistar rats with or without neurochemical lesions of the MnRN serotonergic neurons with the neurotoxin 5,7-DHT were submitted to acute (2h) or chronic restraint (2h/day/seven consecutive days) and treated with saline (1 ml/kg) or imipramine (15 mg/kg) via intraperitoneal twice a day during the same period. In acutely restrained rats, stress occurred on the last day of treatment. Test in the elevated plus maze (EPM) was performed 24h later. After EPM test, animals were sacrificed and had their brains removed. Dorsal hippocampus and striatum were dissected and the levels of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) measured by HPLC analysis. Our results showed that in control rats exposure to acute restraint stress decreased exploration of the open and enclose arms of the EPM, an effect that was attenuated by imipramine. In rats with 5,7-DHT lesions, acute restraint did not change the exploration of the EPM, independently of the treatment. On the other hand, when chronically restrained, saline treated rat with 5,7-DHT lesion showed a reduced exploration of the open arms of the EPM. This effect was attenuated by simultaneous treatment with imipramine. HPLC analysis showed significantly decreases on 5-HT and 5-HIAA levels in the hippocampus, but not in the striatum. These later results confirm that 5,7-DHT lesions of the MnRN had significant impact on the serotonergic projections to the dorsal hippocampus which seems to be essential for the development of tolerance to repeated stress in the absence of any pharmacological treatment.
Asunto(s)
Imipramina/farmacología , Imipramina/uso terapéutico , Núcleos del Rafe/efectos de los fármacos , Neuronas Serotoninérgicas/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , 5,6-Dihidroxitriptamina/toxicidad , Análisis de Varianza , Animales , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Monoaminas Biogénicas/metabolismo , Tolerancia a Medicamentos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Núcleos del Rafe/lesiones , Núcleos del Rafe/metabolismo , Ratas , Ratas Wistar , Serotoninérgicos/toxicidadAsunto(s)
Anestésicos Intravenosos/toxicidad , Fentanilo/toxicidad , Convulsiones/inducido químicamente , Serotoninérgicos/toxicidad , Serotonina/toxicidad , Amitriptilina/toxicidad , Antidepresivos Tricíclicos/toxicidad , Citalopram/toxicidad , Interacciones Farmacológicas , Servicio de Urgencia en Hospital , Femenino , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Extracción Dental/efectos adversos , Adulto JovenRESUMEN
The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) and investigated the protection of RSV against the acute and long-term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Fármacos Neuroprotectores/farmacología , Proteínas de Unión al ARN/metabolismo , Estilbenos/farmacología , Animales , Bencilaminas , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Corticosterona/sangre , Trastorno Depresivo/diagnóstico por imagen , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor , Masculino , Tomografía de Emisión de Positrones , Radiofármacos , Distribución Aleatoria , Ratas Sprague-Dawley , Resveratrol , Serotoninérgicos/toxicidadAsunto(s)
Fallo Hepático Agudo/inducido químicamente , Hígado/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neumatosis Cistoide Intestinal/inducido químicamente , Vena Porta/patología , Serotoninérgicos/toxicidad , Tomografía Computarizada por Rayos X , Adulto , Femenino , Corazón/efectos de los fármacos , Humanos , Ileus/inducido químicamente , Riñón/efectos de los fármacos , Ácido Láctico/sangre , Hígado/diagnóstico por imagen , Hígado/patología , Fallo Hepático Agudo/diagnóstico por imagen , Neumatosis Cistoide Intestinal/diagnóstico por imagen , Neumatosis Cistoide Intestinal/patología , Vena Porta/diagnóstico por imagen , Vena Porta/efectos de los fármacos , Rabdomiólisis/inducido químicamenteRESUMEN
Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.
Asunto(s)
Dopamina/metabolismo , Intoxicación por MPTP/fisiopatología , Trastornos Mentales/etiología , Serotonina/metabolismo , Compuestos de Anilina , Animales , Antiparkinsonianos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Mapeo Encefálico , Chlorocebus aethiops , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Femenino , Levodopa/uso terapéutico , Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Masculino , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Nortropanos , Cintigrafía , Serotoninérgicos/toxicidad , SulfurosRESUMEN
RATIONALE: Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors. OBJECTIVES: Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome. METHODS: Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome. RESULTS: Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine. CONCLUSIONS: Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5-hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms).
Asunto(s)
Ambiente , Calor/efectos adversos , Actividad Motora/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Síndrome de la Serotonina/inducido químicamente , Animales , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Síndrome de la Serotonina/metabolismoRESUMEN
Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has been hampered by the contradictory findings, across studies, of increased sensitivity to punishment in terms of subsequent response choice but decreased sensitivity to punishment-induced response suppression following gross depletion of central 5-HT. To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common marmoset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effectiveness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensitivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning and decreased response suppression. Computational modeling of behavior on the discrimination task showed that the lesions reduced reinforcement sensitivity. A novel, unitary account of the findings in terms of the causal role of 5-HT in the anticipation of both negative and positive motivational outcomes is proposed and discussed in relation to current theories of 5-HT function and our understanding of mood and anxiety disorders.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Motivación/fisiología , Corteza Prefrontal/metabolismo , Castigo , Recompensa , Serotonina/deficiencia , 5,7-Dihidroxitriptamina/toxicidad , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Callithrix , Discriminación en Psicología , Femenino , Masculino , Estimulación Luminosa , Corteza Prefrontal/efectos de los fármacos , Probabilidad , Reconocimiento en Psicología , Retención en Psicología/fisiología , Serotoninérgicos/toxicidadRESUMEN
The present study was designed to investigate the effects of long-term exposure (4 weeks) to the widely used narcotic drug and putative neurotoxicant 3,4-methylenedioxymetamphetamine (MDMA; "ecstasy") on neuronal transmitter transport and progression of experimental periodontitis in male Wistar rats. The rats were exposed to MDMA (10mg/kg/day i.p.) or saline five days a week for four consecutive weeks. Exposure to MDMA induced a significant reduction in the synaptosomal reuptake of serotonin, while the uptake of dopamine was significantly increased 24h after the last injection of MDMA. In contrast, the synaptosomal uptake of noradrenaline and the vesicular uptake through the vesicular monoamine transporter 2 were not affected. In the experiments of periodontitis development, ligature-induced periodontitis was induced three days prior to MDMA administration. Compared to controls, MDMA-treated rats developed significantly more periodontitis. In conclusion, our results show that long-term exposure to MDMA affects the serotonergic and dopaminergic transport systems in the rat brain and increased the susceptibility to the psychosomatic ailment periodontitis following disturbances of brain immune-regulatory systems. These results are interesting with respect to recent research showing that changes in neurotransmitter signalling may alter the reactivity of brain-controlled immunoregulatory systems controlling pathogenic microorganisms colonizing mucosal surfaces.
Asunto(s)
Química Encefálica/efectos de los fármacos , Encéfalo/inmunología , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neurotransmisores/metabolismo , Periodontitis/patología , Serotoninérgicos/toxicidad , Pérdida de Hueso Alveolar/inducido químicamente , Pérdida de Hueso Alveolar/patología , Animales , Encéfalo/efectos de los fármacos , Progresión de la Enfermedad , Masculino , Ratas , Ratas Wistar , Aumento de Peso/efectos de los fármacosRESUMEN
The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two foods, with the spatial position (left-right) of the cues above two levers pseudorandomized across trials. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received either excitotoxic OFC lesions made by NMDA (N-methyl-d-aspartic acid), serotonin-specific OFC lesions made by 5,7-DHT (5,7-dihydroxytryptamine), or sham lesions. In sham-lesioned rats, devaluation of one food (by feeding to satiety) significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. Both types of OFC lesions disrupted the devaluation effect. In contrast, extinction learning was not affected by serotonin-specific lesions and was only mildly retarded in rats with excitotoxic lesions. Thus, serotonin within OFC is necessary for appropriately adjusting behavior toward cues that predict reward but not for reducing responses in the absence of reward. Our results are the first to demonstrate that serotonin in OFC is necessary for reinforcer devaluation, but not extinction.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/toxicidad , Extinción Psicológica/fisiología , Corteza Prefrontal/lesiones , Refuerzo en Psicología , Serotoninérgicos/toxicidad , 5,7-Dihidroxitriptamina/toxicidad , Análisis de Varianza , Animales , Condicionamiento Operante/fisiología , Extinción Psicológica/efectos de los fármacos , Masculino , N-Metilaspartato/toxicidad , Corteza Prefrontal/fisiología , Ratas , Ratas Long-Evans , Estadísticas no ParamétricasRESUMEN
We previously showed that developmental 3,4-methylenedioxymethamphetamine (MDMA) treatment induces long-term spatial and egocentric learning and memory deficits and serotonin (5-HT) reductions. During brain development, 5-HT is a neurotrophic factor influencing neurogenesis, synaptogenesis, migration, and target field organization. MDMA (10 mg/kg × 4/d at 2 h intervals) given on post-natal day (PD) 11-20 in rats (a period of limbic system development that approximates human third trimester brain development) induces 50% reductions in 5-HT during treatment and 20% reductions when assessed as adults. To determine whether the 5-HT reduction is responsible for the cognitive deficits, we used citalopram (Cit) pretreatment to inhibit the effects of MDMA on 5-HT reuptake in a companion study. Cit attenuated MDMA-induced 5-HT reductions by 50% (Schaefer et al., 2012). Here we tested whether Cit (5 or 7.5 mg/kg × 2/d) pretreatment attenuates the cognitive effects of MDMA. Within each litter, different offspring were treated on PD11-20 with saline (Sal) + MDMA, Cit + MDMA, Cit + Sal or Sal + Sal. Neither spatial nor egocentric learning/memory was improved by Cit pretreatment. Unexpectedly, Cit + Sal (at both doses) produced spatial and egocentric learning deficits as severe as those caused by Sal + MDMA. These are the first data showing cognitive deficits resulting from developmental exposure to a selective serotonin reuptake inhibitor. These data indicate the need for further research on the long-term safety of antidepressants during pregnancy.
Asunto(s)
Citalopram/toxicidad , Trastornos del Conocimiento/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Femenino , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Natación/psicologíaRESUMEN
Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5HT) in the CNS. 5HT is well known to improve mood; however, only when the levels of its release are in an appropriate range. Excessive 5HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of this study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5HT-promoting drugs: (i) (±)-3,4-methylenedioxymethamphetamine (MDMA); (ii) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; (iii) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography (EEG), tremor, and brain/plasma 5HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5HT efflux in brain dialysate and the increased concentration of unbound 5HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5HT concentration in the plasma.