RESUMEN
Methamphetamine (MA)-associated psychosis (MAP) is highly debilitating and common among individuals who use the drug, yet the underlying neural mechanism is not clear. This study compared brain functions between patients with MAP and those with schizophrenia during resting state and investigated the effect of brain alteration on the association between MA use and psychosis in patients with MAP. Three groups, including 24 patients with MAP, 17 with schizophrenia in first-episode (SCZ) and 31 healthy controls (HCs), were included after receiving a resting-state functional MRI scan. The severity of psychosis was assessed with Positive and Negative Syndrome Scale (PANSS). Imaging data were analysed using regional homogeneity (ReHo) to measure individual's brain function. Compared with the HC subjects, the MAP and SCZ groups had significantly lower ReHo in the cortical regions including left postcentral cortex, right superior temporal gyrus and right rolandic operculum, while had higher ReHo in the left putamen, with brain dysfunctions being more pronounced in the SCZ group. Among the MAP subjects, a mediating effect of ReHo in the right superior temporal gyrus was found on the association between MA use frequency and PANSS positive score. MAP and schizophrenia had a common trend of brain alteration, with the dysfunction being more pronounced in schizophrenia. This finding implicated that MAP might be a condition with neuropathology approaching schizophrenia. The observed critical role of right superior temporal deficit between MA use and psychosis proposed a potential target for interventions.
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Trastornos Relacionados con Anfetaminas/patología , Metanfetamina/efectos adversos , Psicosis Inducidas por Sustancias/patología , Esquizofrenia/patología , Lóbulo Temporal/fisiología , Adulto , Trastornos Relacionados con Anfetaminas/diagnóstico por imagen , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Gravedad del Paciente , Lóbulo Temporal/diagnóstico por imagenRESUMEN
Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI-induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.
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Antipsicóticos/farmacología , Alucinógenos/toxicidad , Neuronas/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Interacción Social/efectos de los fármacos , Tolueno/toxicidad , Animales , Antipsicóticos/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Masculino , Ratones , Neuronas/metabolismo , Neuronas/patología , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Psicosis Inducidas por Sustancias/metabolismo , Psicosis Inducidas por Sustancias/patología , Reconocimiento en Psicología/fisiología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéuticoRESUMEN
Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser's life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables. 3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.
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Encéfalo/diagnóstico por imagen , Abuso de Marihuana/diagnóstico por imagen , Psicosis Inducidas por Sustancias/diagnóstico por imagen , Adulto , Encéfalo/patología , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Abuso de Marihuana/epidemiología , Abuso de Marihuana/patología , Neuroimagen , Proyectos Piloto , Psicosis Inducidas por Sustancias/epidemiología , Psicosis Inducidas por Sustancias/patologíaRESUMEN
BACKGROUND: Several psychological and neurological pathways are described to explain the emergence and maintenance of psychiatric disorders, and changes in brain volumes and brain activity are observed as correlates of psychiatric disorders. In the present study, we investigated if and to what extent specific voxel-based morphometric brain volume differences could be observed among individuals with methamphetamine-induced psychosis (MAIP) and schizophrenia spectrum disorder (SSD) compared to healthy controls. METHODS: A total of 69 individuals took part in the present study. Of those, 26 were diagnosed with MAIP, 23 with SSD, and 20 were healthy controls. After a thorough psychiatric assessment, participants underwent brain volume measurement. RESULTS: Compared to healthy controls, participants with MAIP had smaller volumes for left caudate and left and right parahippocampal gyrus. Compared to healthy controls, participants with SSD had smaller volumes for the gray and white matter, left amygdala, left hippocampus, left parahippocampal gyrus, left putamen, and the total volume. Compared to individuals with MAIP, individuals with SSD had a lower white matter brain volume. CONCLUSIONS: The pattern of results suggests that individuals with MAIP and SSD showed specific and regional brain atrophies on the left hemisphere, always compared to healthy controls. Given the cross-sectional design, it remains undisclosed if specific and regional brain atrophies were the cause or the consequence of the psychiatric issues.
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Estimulantes del Sistema Nervioso Central/efectos adversos , Sustancia Gris/patología , Sistema Límbico/patología , Metanfetamina/efectos adversos , Psicosis Inducidas por Sustancias/patología , Putamen/patología , Esquizofrenia/patología , Sustancia Blanca/patología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Atrofia/patología , Femenino , Sustancia Gris/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Sistema Límbico/diagnóstico por imagen , Masculino , Giro Parahipocampal/diagnóstico por imagen , Giro Parahipocampal/patología , Psicosis Inducidas por Sustancias/diagnóstico por imagen , Psicosis Inducidas por Sustancias/etiología , Putamen/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
Although epidemiological data suggest that repeated use of cannabis during adolescence may increase the risk for psychosis, its precise molecular mechanisms remain undetermined. In this study, we examined whether brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling plays a role in the risk for psychosis after exposure of cannabinoid (CB) receptor agonist during adolescence. Repeated administration of the CB receptor agonist WIN55,212-2 (2â¯mg/kg/day) during adolescence (P35 - P45) significantly increased methamphetamine (METH: 1â¯mg/kg)-induced hyperlocomotion in adulthood (P70 - P74) compared with vehicle-treated mice. Western blot analysis showed that BDNF-TrkB signaling in the nucleus accumbens (NAc) of WIN55,212-2-treated mice were significantly higher than that of vehicle-treated mice. Interestingly, an increase in the METH-induced locomotion in WIN55,212-2-treated mice was significantly attenuated by subsequent repeated administration of the TrkB antagonist ANA-12 (0.5â¯mg/kg/day from P70 to P83). Furthermore, increased BDNF-TrkB signaling in the NAc from WIN55,212-2-treated mice was also significantly attenuated after subsequent repeated administration of ANA-12. These findings suggest that increased BDNF-TrkB signaling in the NAc plays an important role in the increase in METH-induced locomotion in adulthood after repeated WIN55,212-2 administration during adolescence. Therefore, TrkB antagonists would be potential prophylactic and therapeutic drugs for psychosis in adult with cannabis use during adolescence.
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Benzoxazinas/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Agonistas de Receptores de Cannabinoides/farmacología , Abuso de Marihuana/metabolismo , Glicoproteínas de Membrana/metabolismo , Morfolinas/farmacología , Naftalenos/farmacología , Núcleo Accumbens/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Psicosis Inducidas por Sustancias/patología , Animales , Azepinas/farmacología , Conducta Animal/efectos de los fármacos , Benzamidas/farmacología , Benzoxazinas/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Cannabinoides/farmacología , Cannabis/química , Estimulantes del Sistema Nervioso Central/farmacología , Giro Dentado/metabolismo , Locomoción/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Metanfetamina/farmacología , Ratones , Ratones Endogámicos C57BL , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Corteza Prefrontal/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , RiesgoAsunto(s)
Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Psicosis Inducidas por Sustancias/diagnóstico , Psicosis Inducidas por Sustancias/patología , Sustitución de Medicamentos , Inhibidores de Integrasa VIH/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , PiridonasRESUMEN
Accumulating evidence suggests that neuroinflammation is one of the important etiologic factors of abusive and neuropsychiatric disorders. Platelet-activating factor (PAF) is potent proinflammatory lipid mediat1or and plays a pivotal role in neuroinflammatory disorders through the specific PAF receptor (PAF-R). Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia. Here, we investigated the role of PAF-R in the abnormal behaviors induced by PCP in mice. Repeated treatment with PCP resulted in a significant increase in PAF-R gene expression in the prefrontal cortex (PFC) and in the hippocampus. This increase was more pronounced in the PFC than hippocampus. Treatment with PCP resulted in a significant increase in nuclear translocation of the nuclear factor kappa beta (NF-κB) p65 and DNA binding activity, indicating that the proinflammatory molecule NF-κB was increased through up-regulation of PAF-R. Consistently, NF-κB activation was significantly protected by the PAF-R antagonist, ginkgolide B (Gink B), in PAF-R knockout mice and by the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, PCP-induced abnormal behaviors (i.e., reduced sociability, depression, cognitive impairment, and behavioral sensitization) were significantly attenuated by Gink B, in PAF-R knockout mice, and by PDTC. Importantly, PDTC did not significantly alter the attenuations observed in Gink B-treated mice or PAF-R knockout mice, indicating that NF-κB is a critical target for neuropsychotoxic modulation of PAF-R. Therefore, the results suggest that PAF-R mediates PCP-induced neuropsychotoxicity via a NF-κB-dependent mechanism, and that up-regulation of PAF-R may be associated with schizophrenia-like behavior in animal models.
Asunto(s)
Antipsicóticos/farmacología , Ginkgólidos/farmacología , Lactonas/farmacología , FN-kappa B/metabolismo , Fenciclidina/toxicidad , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Psicosis Inducidas por Sustancias/metabolismo , Psicosis Inducidas por Sustancias/patología , Psicosis Inducidas por Sustancias/psicología , Pirrolidinas/farmacología , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Tiocarbamatos/farmacologíaRESUMEN
Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
Asunto(s)
Cannabinoides/efectos adversos , Abuso de Marihuana/patología , Abuso de Marihuana/fisiopatología , Neuroimagen , Psicosis Inducidas por Sustancias/patología , Psicosis Inducidas por Sustancias/fisiopatología , Humanos , Abuso de Marihuana/diagnóstico por imagen , Psicosis Inducidas por Sustancias/diagnóstico por imagenRESUMEN
With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as 'substance-induced psychosis' (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p < 0.05) in voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways. The greatest differences in white matter integrity were present in the corpus callosum, corona radiata, bilateral superior longitudinal fasciculi and bilateral inferior longitudinal fasciculi. Additionally, the CAP group had voxels of significantly higher radial diffusivity in a subset of the previously mentioned pathways. These results are the first description of white matter integrity abnormalities in a SIP sample and indicate that differences in these pathways may be a shared factor in the expression of different forms of psychosis.
Asunto(s)
Trastornos Relacionados con Cocaína/complicaciones , Trastornos Relacionados con Cocaína/patología , Psicosis Inducidas por Sustancias/complicaciones , Sustancia Blanca/patología , Adulto , Mapeo Encefálico/métodos , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Psicosis Inducidas por Sustancias/patología , Sustancia Blanca/diagnóstico por imagenRESUMEN
The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer disease, Parkinson disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, anecdotal data and the high level of interest in this treatment must not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure. This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure and is combined with an illustration of the neuropathologic findings in a fatal case of cannabis-induced psychosis. The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if subsets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis.
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Encéfalo/efectos de los fármacos , Cannabinoides/efectos adversos , Cannabinoides/uso terapéutico , Cannabis/efectos adversos , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Encéfalo/fisiopatología , Resultado Fatal , Humanos , Masculino , Abuso de Marihuana/patología , Abuso de Marihuana/fisiopatología , Persona de Mediana Edad , Psicosis Inducidas por Sustancias/patología , Psicosis Inducidas por Sustancias/fisiopatologíaRESUMEN
Reversible corpus callosum splenial (CCS) lesions are rare findings and usually detected incidentally. We presented a case of 15-year-old boy with a diagnoses of nephrotic syndrome. He was referred for neuropsychiatric symptoms following dose reduction on steroid treatment. Brain magnetic resonance imaging (MRI) revealed a focal lesion in the CCS, hyperintense on T2 and FLAIR and hypointense on T1 images with diffusion restriction on apparent diffusion coefficient map. Follow-up MRI 3 weeks later showed complete resolution of the lesion. It was probably result of focal intramyelinic edema due to excytotoxic mechanisms and/or arginine-vasopressin release.
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Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/patología , Síndrome Nefrótico/tratamiento farmacológico , Psicosis Inducidas por Sustancias/patología , Adolescente , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/patología , Psicosis Inducidas por Sustancias/etiología , Resultado del TratamientoRESUMEN
For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Drogas Ilícitas/efectos adversos , Ketamina/efectos adversos , Psicosis Inducidas por Sustancias , Receptores de N-Metil-D-Aspartato , Trastornos Relacionados con Sustancias , Humanos , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/metabolismo , Psicosis Inducidas por Sustancias/genética , Psicosis Inducidas por Sustancias/metabolismo , Psicosis Inducidas por Sustancias/patología , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores de N-Metil-D-Aspartato/genética , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/patologíaRESUMEN
When drug-induced psychoses were first identified in the mid-20th century, schizophrenia was considered a discrete disease with a likely genetic cause. Consequently, drug-induced psychoses were not considered central to understanding schizophrenia as they were thought to be phenocopies rather than examples of the illness secondary to a particular known cause. However, now that we know that schizophrenia is a clinical syndrome with multiple component causes, then it is clear that the drug-induced psychoses have much to teach us. This article shows how the major neuropharmacological theories of schizophrenia have their origins in studies of the effects of drugs of abuse. Research into the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP and ketamine the glutamatergic hypothesis, while most recently the effects of cannabis have provoked interest in the role of endocannabinoids in schizophrenia. None of these models account for the complete picture of schizophrenia; rather the various drug models mimic different aspects of the illness. Determining the different molecular effects of those drugs whose pharmacological effects do and do not mimic the various aspects of schizophrenia has much to teach us concerning the pathogenesis of the illness.
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Modelos Biológicos , Psicosis Inducidas por Sustancias/patología , Esquizofrenia/patología , Endocannabinoides/metabolismo , Glutamatos/metabolismo , Humanos , Serotonina/metabolismoAsunto(s)
Ciprofloxacina/efectos adversos , Psicosis Inducidas por Sustancias/diagnóstico , Trastornos de la Visión/inducido químicamente , Bronquiectasia/tratamiento farmacológico , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Psicosis Inducidas por Sustancias/patología , Enfermedad Pulmonar Obstructiva Crónica/diagnósticoRESUMEN
Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures. In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced. Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity. Especially direct THC effects (or via endocannabinoids) may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss in a small pilot study. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors. We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD.
Asunto(s)
Encéfalo/patología , Cannabidiol/uso terapéutico , Abuso de Marihuana/complicaciones , Fármacos Neuroprotectores/uso terapéutico , Psicosis Inducidas por Sustancias/etiología , Humanos , Abuso de Marihuana/patología , Psicosis Inducidas por Sustancias/patologíaRESUMEN
Growing evidence implicates that abnormal stem cell proliferation and neurodegenerative mechanisms may be involved in the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we studied the underlying pathomechanisms of psychosis. We are employing a translational approach combining in vivo data with supplementary data from an adult neuronal stem cell-derived cell culture model by generating a large number of analytes in our specimens following a multiplexing strategy. In the animal model the NMDA receptor was chronically antagonized by MK-801 at ultralow doses. As a result of this, we were able to demonstrate a roughly twofold increased density of PCNA positive cells in the germinal zone of the dentate gyrus indicating enhanced neuroproliferative activity. In vitro stem cell experiments additionally pointed to this direction showing an increase both in proliferation and neuronal differentiation after MK-801 treatment. These alterations were partially prevented by coapplication of the dopamine receptor antagonist haloperidol. In addition, apoptotic activity assessed by immunohistochemical demonstration of cleaved caspase-3 stainings was unaffected by MK-801 treatment. These observations were largely supported by microarray gene expression analysis, which permits high-throughput multiplexed assessment of expression data from a comprehensive set of genes and showed parallels with data from human post mortem studies. In conclusion, our data support the notion, that abnormal proliferation due to anti-apoptotic mechanisms may represent a factor in the pathogenesis of psychosis. Thus, research on the exact interplay between glutamatergic neurotransmission and neuronal proliferation deserves more attention. This dual in vivo and in vitro strategy described here may prove as a suitable model for addressing complex neuropsychiatric diseases especially when taking advantage of the potential of multiplex technologies not only in diagnostics but also in basic research.
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Apoptosis , Proliferación Celular , Neuronas/fisiología , Psicosis Inducidas por Sustancias/patología , Esquizofrenia/patología , Animales , Antígenos Nucleares/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Psicosis Inducidas por Sustancias/metabolismo , Ratas , Ratas Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/inducido químicamente , Esquizofrenia/metabolismoRESUMEN
The use of methamphetamine (METH) is a growing public health problem, because its abuse is associated with long-term biochemical and structural effects on the human brain. Neurodegeneration is often observed in humans, because of mechanical injuries (e.g., traumatic brain injury [TBI]) and ischemic damage (strokes). In this review, we discuss recent findings documenting the fact that the psychostimulant drug METH can cause neuronal damage in several brain regions. The accumulated evidence from our laboratories and those of other investigators indicates that acute administration of METH leads to activation of calpain and caspase proteolytic systems. These systems are also involved in causing neuronal damage secondary to traumatic and ischemic brain injuries. Protease activation is accompanied by proteolysis of endogenous neuronal structural proteins (alphaII-spectrin protein and microtubule-associated protein-tau), evidenced by the appearance of their breakdown products after these injuries. When taken together, these observations suggest that METH exposure, like TBI, can cause substantial damage to the brain by causing both apoptotic and necrotic cell death in the brains of METH addicts who use large doses of the drug during their lifetimes. Finally, because METH abuse is accompanied by functional and structural changes in the brain similar to those in TBI, METH addicts might experience greater benefit if their treatment involved greater emphasis on rehabilitation in conjunction with potential neuroprotective pharmacological agents such as calpain and caspase inhibitors similar to those used in TBI.
Asunto(s)
Lesiones Encefálicas/patología , Estimulantes del Sistema Nervioso Central/toxicidad , Metanfetamina/toxicidad , Psicosis Inducidas por Sustancias/patología , Animales , Lesiones Encefálicas/genética , Lesiones Encefálicas/psicología , Muerte Celular/efectos de los fármacos , Humanos , Neuronas/patología , Proteómica , Psicosis Inducidas por Sustancias/genética , Psicosis Inducidas por Sustancias/psicologíaRESUMEN
Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors. Among the environmental factors, cannabis use has been associated with increased risk for patients with schizophrenia, but the effect of cannabis on their brain structure is unclear. We examined gray matter alterations in first episode schizophrenia patients (FES) with cannabis use (FES+C; n=15) compared to FES without cannabis use (FES-C; n=24) and 42 healthy controls who did not use cannabis. We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions. We observed a decrease in gray matter density in the right posterior cingulate cortex (PCC) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure, in particular regions rich in CB1 receptors. These findings need to be confirmed by larger, prospective studies.
Asunto(s)
Encéfalo/efectos de los fármacos , Cannabinoides/toxicidad , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Abuso de Marihuana/complicaciones , Cómputos Matemáticos , Psicosis Inducidas por Sustancias/patología , Trastornos Psicóticos/patología , Esquizofrenia/inducido químicamente , Adolescente , Adulto , Encéfalo/patología , Dominancia Cerebral/fisiología , Femenino , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/patología , Humanos , Masculino , Abuso de Marihuana/patología , Receptor Cannabinoide CB1/efectos de los fármacos , Esquizofrenia/patologíaRESUMEN
Delayed hypoxic leukoencephalopathy is an underrecognized syndrome of delayed demyelination, which is important to consider when delayed onset of neuropsychiatric symptoms follows a hypoxic event. The authors describe clinical and diagnostic features of three such cases, review the pathophysiology of delayed hypoxic leukoencephalopathy, and discuss features which may help distinguish it from toxic leukoencephalopathy.
Asunto(s)
Encéfalo/patología , Hipoxia Encefálica/diagnóstico , Hipoxia Encefálica/patología , Adulto , Analgésicos Opioides/envenenamiento , Benzodiazepinas/envenenamiento , Cocaína/envenenamiento , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/psicología , Sobredosis de Droga , Femenino , Fentanilo/envenenamiento , Fibromialgia/tratamiento farmacológico , Fibromialgia/psicología , Trastornos Neurológicos de la Marcha/inducido químicamente , Trastornos Neurológicos de la Marcha/patología , Humanos , Hipoxia Encefálica/inducido químicamente , Imagen por Resonancia Magnética , Metadona/envenenamiento , Persona de Mediana Edad , Neuronas Motoras/fisiología , Antagonistas de Narcóticos/envenenamiento , Pruebas Neuropsicológicas , Psicosis Inducidas por Sustancias/patología , Psicosis Inducidas por Sustancias/psicología , Intento de SuicidioRESUMEN
We evaluated the effects of caffeic acid phenethyl ester (CAPE) on antioxidant enzyme levels and histopathologic changes in dizocilpine (MK-801) induced schizophrenic rat testis. A total of 30 adult male Wistar-Albino rats were divided into three groups. Group-I was used as control. Rats in the Group-II were intraperitoneally injected with MK-801, whereas those in Group-III were intraperitoneally injected with CAPE in addition to MK-801. The testes were collected for biochemical and histopathological examinations. Antioxidant enzyme activities, malondialdehyde, protein carbonyl and nitric oxide levels in testicular tissues were analyzed with spectrophotometric methods. Induction of schizophrenia resulted in a significant oxidative stress by increasing the levels of antioxidant enzymes. Tissue malondialdehyde and protein carbonyl levels were also increased. Treatment with CAPE led to significant decrease in oxidative injury. Administration of CAPE reduced the detrimental histopathologic changes caused by MK-801. The results showed that experimentally induced schizophrenia caused oxidative stress in testes of rats and treatment with CAPE reduced these harmful effects.