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1.
Emergencias (Sant Vicenç dels Horts) ; 31(5): 341-345, oct. 2019. tab
Artículo en Español | IBECS | ID: ibc-184124

RESUMEN

Objetivo. Conocer la epidemiología de las consultas en urgencias por amnesia global transitoria (AGT), ya sea pura, asociada al consumo de tóxicos o en el contexto de una agresión sexual. Método. Estudio retrospectivo de enero a diciembre de 2018. Se revisaron las AGT atendidas en intoxicados (AGTtox), en víctimas de agresiones sexuales (AGTsex) y las amnesias puras (AGTpur), evaluando la presencia de tóxicos. Resultados. Se identificaron 287 AGT: 169 AGTsex (58,9%), 62 AGTpur (21,6%) y 56 AGTtox (19,5%). De ellas, 218 (76%) fueron mujeres y la edad osciló entre 16 y 90 años (60,6% menores de 30 años). Reconocieron consumo de alcohol 201 casos (72,8%), con etanolemia positiva en 105 (49,1%) (media de 0,74 g/l y máxima de 3,9 g/l). Admitieron consumo de cannabis 20 pacientes (7,1%), con analítica positiva en 39 casos (17,3%); cocaína 14 (4,9%), con analítica positiva en 28 (12,4%), y anfetaminas 5 (1,7%), con analítica positiva en 20 (8,8%). Presentaron sínto-mas de intoxicación 58 casos (20,1%). Cuatro pacientes ingresaron en coma. Se realizó una tomografía computariza-da (TC) craneal a 66 pacientes (23%), se hospitalizaron 7 y no hubo ningún fallecimiento. Conclusiones. La prevalencia de AGT es mayor si se incluyen los intoxicados y las agresiones sexuales, modificando la determinación de tóxicos la epidemiología de la AGT en urgencias


Objectives. To study the epidemiology of emergency department visits for transient global amnesia (TGA) by itself or associated with substance abuse or sexual assault. Methods. Retrospective study of cases treated from January to December 2018. Data for all patients with TGA were extracted, and cases were classified as associated with substance abuse (TGASUB), sexual assault (TGASEX), or neither (TGAONLY). Results. A total of 287 TGA cases were found: 169 (58.9%) were TGASEX, 62 (21.6%) TGAONLY, and 56 (19.5%) TGASUB. Two hundred eighteen (76%) were female and 69 (24%) were male. Ages ranged from 16 to 90 years; 174 (60.6%) were under the age of 30 years. Two hundred one patients (72.8%) reported consuming alcohol; and 105 (49.1%) were positive on testing (mean blood alcohol concentration, 0.74 g/L; maximum, 3.9 g/L. Twenty patients (7.1%) reported using cannabis, and 39 (17.3%) had positive test results; 14 reported using cocaine (4.9%) and 28 (12.4%) tested positive; 5 (1.7%) reported using amphetamines and 20 (8.8%) tested positive. Fifty-eight (20.1%) had symptoms of intoxication. Four were admitted in coma. A computed tomography scan was ordered for 66 patients (23%), 7 patients were hospitalized, and none died. Conclusions. The prevalence of TGA is higher if cases of substance abuse and sexual assault are counted. Toxicolgy testing changes the epidemiology of TGA in emergencies


Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Amnesia Global Transitoria/complicaciones , Amnesia Global Transitoria/epidemiología , Trastornos Relacionados con Sustancias/complicaciones , Servicios Médicos de Urgencia/métodos , Delitos Sexuales , Síntomas Toxicológicos/efectos adversos , Estudios Retrospectivos , Coma/complicaciones , Coma/diagnóstico por imagen , Tomografía Computarizada de Emisión , Etanol/toxicidad , Cocaína/toxicidad , Cannabis/toxicidad , Anfetaminas/toxicidad , Análisis de Varianza
2.
Sci Justice ; 59(3): 234-247, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31054814

RESUMEN

The emergence of new psychoactive substances (NPS) has raised many issues in the context of law enforcement and public drug policies. In this scenario, interdisciplinary studies are crucial to the decision-making process in the field of criminal science. Unfortunately, information about how NPS affect people's health is lacking even though knowledge about the toxic potential of these substances is essential: the more information about these drugs, the greater the possibility of avoiding damage within the scope of a harm reduction policy. Traditional analytical methods may be inaccessible in the field of forensic science because they are relatively expensive and time-consuming. In this sense, less costly and faster in silico methodologies can be useful strategies. In this work, we submitted computer-calculated toxicity values of various amphetamines and cathinones to an unsupervised multivariate analysis, namely Principal Component Analysis (PCA), and to the supervised techniques Soft Independent Modeling of Class Analogy and Partial Least Square-Discriminant Analysis (SIMCA and PLS-DA) to evaluate how these two NPS groups behave. We studied how theoretical and experimental values are correlated by PLS regression. Although experimental data was available for a small amount of molecules, correlation values reproduced literature values. The in silico method efficiently provided information about the drugs. On the basis of our findings, the technical information presented here can be used in decision-making regarding harm reduction policies and help to fulfill the objectives of criminal science.


Asunto(s)
Alcaloides/toxicidad , Anfetaminas/toxicidad , Simulación por Computador , Psicotrópicos/toxicidad , Pruebas de Toxicidad/métodos , Animales , Análisis Discriminante , Toxicología Forense , Reducción del Daño , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Análisis de los Mínimos Cuadrados , Dosificación Letal Mediana , Ratones , Estructura Molecular , Análisis Multivariante , Análisis de Componente Principal , Ratas , Análisis de Regresión
3.
J Biochem Mol Toxicol ; 33(5): e22302, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30790395

RESUMEN

OBJECTIVE: Tourette syndrome (TS) is a chronic neuropsychiatric disorder. Its clinical manifestations are involuntary and recurrent muscle twitch, resulting in motor twitch and occurrence twitch. Traditional Chinese medicine has obvious advantages in treating TS. The aim of this study was to investigate the effects and mechanism of gastrodin on 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced TS in rats. METHODS: TS model was induced by DOI. Behaviors in TS rats were detected. The striatum, serum inflammatory factors interleukin-6, interleukin-1ß, and tumor necrosis factor-a were detected by enzyme-linked immunosorbent assay. Western blot technique was used to detect the expressions of TLR/NF-κB and TLR/MAPK signaling pathways in the striatum. RESULTS: Gastrodin can significantly improve behavioral changes of TS rats induced by DOI, reduce inflammatory factors in serum and striatum in TS rats, and inhibit activation of TLR/NF-κB and TLR/MAPK signaling in striatum in TS rats. CONCLUSION: Gastrodin can significantly relieve the TS induced by DOI in rats. Its mechanism is related to the inhibition of striatal TLR/NF-κB and TLR/MAPK signaling activation.


Asunto(s)
Anfetaminas/toxicidad , Conducta Animal/efectos de los fármacos , Alcoholes Bencílicos/farmacología , Glucósidos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Síndrome de Tourette/tratamiento farmacológico , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratas , Ratas Sprague-Dawley , Síndrome de Tourette/inducido químicamente , Síndrome de Tourette/metabolismo , Síndrome de Tourette/patología
5.
Artículo en Inglés | MEDLINE | ID: mdl-29601895

RESUMEN

The detrimental effects of amphetamines on developmental stages of NPCs are limited to rodent brain and it is not known if these effects occur in nonhuman primates which are the focus of the current investigation. Young adult rhesus macaques either experienced MDMA only, a combination of amphetamines (MDMA, MDA and methamphetamine) or no amphetamines (controls) and hippocampal tissue was processed for immunohistochemical analysis.Quantitative stereological analysis showed that intermittent exposure to MDMA or the three amphetamines over 9.6 months causes >80% decrease in the number of Ki-67 cells (actively dividing NPCs) and >50% decrease in the number of NeuroD1 cells (NPCs that have attained a neuronal phenotype). Co-labeling analysis revealed distinct, actively dividing hippocampal NPCs in the subgranular zone of the dentate gyrus that were in transition from stem-like radial glia-like cells (type-1) to immature transiently amplifying neuroblasts (type-2a, type-2b, and type-3).MDMA-alone and the combination reduced the number of dividing type-1 and type-3 NPCs and cells that were not NPCs. These data indicate that amphetamines interfere with the division and migration of NPCs. Notably, the reduction in the number of NPCs and immature neurons were not associated with changes in cell death (via apoptosis) or granule cell neuron numbers, indicating that amphetamines selectively affected the generation and maturation of newly born granule cell neurons. In sum, our findings suggest that alterations in the cellular composition in the dentate gyrus during chronic exposure to amphetamines can effect neuroplasticity in the hippocampus and influence functional properties of hippocampal neurons.


Asunto(s)
Anfetaminas/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Macaca mulatta , Masculino , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología
6.
J Psychoactive Drugs ; 49(4): 279-288, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28535130

RESUMEN

Emerging trends in market dynamics and the use of new psychoactive substances are both a public health concern and a complex regulatory issue. One novel area of investigation is the availability of homemade opioids, amphetamines and dissociatives, and the potential fueling of interest in clandestine home manufacture of drugs via the Internet. We illustrate here how online communal folk pharmacology of homemade drugs on drug website forums may actually inform home manufacture practices or contribute to the reduction of harms associated with this practice. Discrepancies between online information around purification and making homemade drugs safer, and the synthesis of the same substances in a proper laboratory environment, exist. Moderation and shutdown of synthesis queries and discussions online are grounded in drug websites adhering to harm-reduction principles by facilitating discussions around purification of homemade drugs only. Drug discussion forums should consider reevaluating their policies on chemistry discussions in aiming to reach people who cannot or will not refrain from cooking their own drugs with credible information that may contribute to reductions in the harms associated with this practice.


Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos Opioides/toxicidad , /toxicidad , Anfetaminas/síntesis química , Anfetaminas/toxicidad , Reducción del Daño , Humanos , Internet , Sistemas en Línea
7.
Arch Toxicol ; 91(11): 3663-3676, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28527032

RESUMEN

Autophagy has an essential role in neuronal homeostasis and its dysregulation has been recently linked to neurotoxic effects of a growing list of psychoactive drugs, including amphetamines. However, the role of autophagy in ß-keto amphetamine (ß-KA) designer drugs-induced neurotoxicity has hitherto not been investigated. In the present study, we show that two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), elicit morphological changes consistent with autophagy and neurodegeneration, including formation of autophagic vacuoles and neurite retraction in dopaminergic SH-SY5Y cells. Methylone and MDPV prompted the formation of acidic vesicular organelles (AVOs) and lead to increased expression of the autophagy-associated protein LC3-II in a concentration- and time-dependent manner. Electron microscopy confirmed the presence of autophagosomes with typical double membranes and autolysosomes in cells exposed to both ß-KA. The autophagic flux was further confirmed using bafilomycin A1, a known inhibitor of the late phase of autophagy. Moreover, we showed that autophagy markers were activated before the triggering of cell death and caspase 3 activation, suggesting that ß-KA-induced autophagy precedes apoptotic cell death. To address the role of oxidative stress in autophagy induction, we also investigated the effects of antioxidant treatment with N-acetyl-L-cysteine (NAC) on autophagy and apoptotic markers altered by these drugs. NAC significantly attenuated methylone- and MDPV-induced cell death by completely inhibiting the generation of reactive oxygen and nitrogen species, and hampering both apoptotic and autophagic activity, suggesting that oxidative stress plays an important role in mediating autophagy and apoptosis elicited by these drugs.


Asunto(s)
Autofagia/efectos de los fármacos , Benzodioxoles/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , Metanfetamina/análogos & derivados , Pirrolidinas/toxicidad , Acetilcisteína/farmacología , Anfetaminas/toxicidad , Apoptosis/efectos de los fármacos , Benzodioxoles/administración & dosificación , Línea Celular , Estimulantes del Sistema Nervioso Central/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Relación Dosis-Respuesta a Droga , Humanos , Metanfetamina/administración & dosificación , Metanfetamina/toxicidad , Proteínas Asociadas a Microtúbulos/metabolismo , Síndromes de Neurotoxicidad/etiología , Estrés Oxidativo/efectos de los fármacos , Pirrolidinas/administración & dosificación
8.
Metab Brain Dis ; 32(2): 519-528, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27987060

RESUMEN

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.


Asunto(s)
Anfetaminas/toxicidad , Antimaníacos/uso terapéutico , Depresores del Apetito/toxicidad , Conducta Animal/efectos de los fármacos , Ácidos Grasos Omega-3/uso terapéutico , Hipercinesia/psicología , Estrés Oxidativo/efectos de los fármacos , Animales , Química Encefálica/efectos de los fármacos , Hipercinesia/inducido químicamente , Hipercinesia/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Carbonato de Litio/uso terapéutico , Masculino , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Ácido Valproico/uso terapéutico
9.
Neuropharmacology ; 113(Pt A): 502-510, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27816502

RESUMEN

The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30-50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.


Asunto(s)
Anfetaminas/toxicidad , Conducta Exploratoria/fisiología , Alucinógenos/toxicidad , Movimientos de la Cabeza/fisiología , Corteza Motora/fisiología , Neostriado/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Ondas Encefálicas/efectos de los fármacos , Ondas Encefálicas/fisiología , Conducta Exploratoria/efectos de los fármacos , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Ratones , Corteza Motora/efectos de los fármacos , Neostriado/efectos de los fármacos
10.
J Psychoactive Drugs ; 48(5): 351-354, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27636207

RESUMEN

We present a case of "ecstasy" ingestion revealing 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dimethoxyamphetamine (3,4-DMA) and absence of cytochrome P450 (CYP)-2D6 MDMA metabolites. CASE REPORT: A 19-year-old presented following a seizure. Initial vital signs were normal. Laboratories were normal with the exception of sodium 127 mEq/L and urine drugs of abuse screen positive for amphetamines. Twelve hours later, serum sodium was 114 mEq/L and a second seizure occurred. After receiving hypertonic saline (3%), the patient had improvement in mental status and admitted to taking "ecstasy" at a rave prior to her initial presentation. Liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS) of serum and urine revealed MDMA, 3,4-DMA, and the CYP-2B6 MDMA metabolites 3,4-methylendioxyamphetamine (MDA) and 4-hydroxy-3-methoxyamphetamine (HMA). The CYP2D6 metabolites of MDMA, 3,4-dihydromethamphetamine (HHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), were detected at very low levels. CONCLUSION: This case highlights the polypharmacy which may exist among users of psychoactive illicit substances and demonstrates that concurrent use of MDMA and 3,4-DMA may predispose patients to severe toxicity. Toxicologists and other healthcare providers should be aware of this potential toxicity.


Asunto(s)
Anfetaminas/toxicidad , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Convulsiones/inducido químicamente , 3,4-Metilenodioxianfetamina/metabolismo , Anfetaminas/administración & dosificación , Anfetaminas/farmacocinética , Cromatografía Liquida/métodos , Dopamina/análogos & derivados , Dopamina/metabolismo , Interacciones de Drogas , Femenino , Alucinógenos/administración & dosificación , Alucinógenos/farmacocinética , Humanos , Espectrometría de Masas/métodos , Metanfetamina/análogos & derivados , Metanfetamina/metabolismo , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , N-Metil-3,4-metilenodioxianfetamina/farmacocinética , Detección de Abuso de Sustancias/métodos , Adulto Joven
11.
Basic Clin Pharmacol Toxicol ; 119(2): 133-40, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27004621

RESUMEN

Fenethylline is a theophylline derivative of amphetamine having stimulant effects similar to those of other amphetamine-type derivatives. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression, but it has also been used as a drug of abuse under the common name of 'captagon'. Unlike other drugs of abuse, the clandestine synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. A review of all the existing knowledge of fenethylline is reported, concerning its chemistry, synthesis, pharmacology and toxicology, legislation, its prevalence and use as drug of abuse, as well as its analysis in biological or seized samples. Published or reported captagon-related cases and seizures are also presented. All the reviewed information was gathered through a detailed search of PubMed and the Internet. The primary drug market for fenethylline (as captagon) has traditionally been countries located on the Arabian Peninsula but also North Africa since 2013. In Arab countries, millions of captagon tablets are seized every year which represents one-third of global amphetamines seizures within a year. Furthermore, three of four patients treated for drug problems in Saudi Arabia are addicted to amphetamines, almost exclusively in the form of captagon. Significant information on fenethylline is provided for pharmacologists, toxicologists and forensic pathologists. Fenethylline, although old, has recently been introduced to the drug market, especially in Arab countries. Continuous community alertness is needed to tackle this current growing phenomenon.


Asunto(s)
Anfetaminas/toxicidad , Estimulantes del Sistema Nervioso Central/toxicidad , Trastornos Relacionados con Sustancias/epidemiología , Teofilina/análogos & derivados , Anfetaminas/química , Estimulantes del Sistema Nervioso Central/química , Humanos , Medio Oriente/epidemiología , Convulsiones/inducido químicamente , Convulsiones/patología , Teofilina/química , Teofilina/toxicidad
12.
Artículo en Inglés | MEDLINE | ID: mdl-26612552

RESUMEN

BACKGROUND: 4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular "legal highs". Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined. METHODS: The addictive potential and locomotor potentiation by 4-methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze. RESULTS: A conditioning dose of 10 mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30 mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30 mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats. CONCLUSIONS: The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4-methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period.


Asunto(s)
Anfetaminas/farmacología , Ansiedad/inducido químicamente , Fármacos del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , Actividad Motora/efectos de los fármacos , Propiofenonas/farmacología , Anfetaminas/toxicidad , Animales , Fármacos del Sistema Nervioso Central/toxicidad , Relación Dosis-Respuesta a Droga , Masculino , Metanfetamina/toxicidad , Propiofenonas/toxicidad , Ratas Sprague-Dawley , Recompensa , Conducta Espacial/efectos de los fármacos , Síndrome de Abstinencia a Sustancias
13.
Psychopharmacology (Berl) ; 233(5): 795-807, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26613735

RESUMEN

RATIONALE: Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. OBJECTIVE: The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. METHODS: Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. RESULTS: The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. CONCLUSIONS: AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.


Asunto(s)
Anfetaminas/toxicidad , Estimulantes del Sistema Nervioso Central/toxicidad , Trastornos del Conocimiento/inducido químicamente , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Reacción de Prevención , Conducta Animal/efectos de los fármacos , Bencimidazoles/farmacología , Trastornos del Conocimiento/fisiopatología , Hipocampo/efectos de los fármacos , Inyecciones Intraventriculares , Losartán/farmacología , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos , Tetrazoles/farmacología
14.
Neurotox Res ; 29(3): 394-407, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26501352

RESUMEN

New psychoactive "designer drugs" are synthetic compounds developed to provide similar effects to illicit drugs of abuse, but not subjected to legal control. The rapidly changing legal status of novel psychoactive drugs triggers the development of new compounds, analogs of well-known amphetamine or mescaline. New designer drugs used as substitutes in ecstasy pills are the least investigated and can cause life-threatening effects on users. The aim of our research was to examine the effects of acute administration of 4-methoxyamphetamine (PMA, 5 and 10 mg/kg), 4-methoxy-N-methylamphetamine (PMMA, 5 and 10 mg/kg), and mephedrone (MEPH, 5, 10 and 20 mg/kg) on extracellular and tissue level of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in rat brain, by microdialysis method in freely moving animals and HPLC. Similarly to 3,4-methylenedioxymethamphetamine (MDMA, 5 and 10 mg/kg) PMA, PMMA and MEPH enhanced the release of DA and 5-HT in rat striatum, nucleus accumbens, and frontal cortex. DA tissue content was increased by MEPH and PMMA in striatum, by MEPH, PMA, and PMMA in nucleus accumbens, and by PMA in frontal cortex. Instead, cortical DA level was decreased by MEPH and PMMA. MEPH did not influence 5-HT tissue level in striatum and nucleus accumbens, but decreased its level in frontal cortex. PMMA increased 5-HT content in striatum, while PMA enhanced it in nucleus accumbens and frontal cortex. Observed changes in brain monoamines and their metabolites by new psychoactive drugs suggest that these drugs may be capable of development of dependence. Further experiments are needed to fully investigate the neurotoxic and abuse potential of those drugs.


Asunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Anfetaminas/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Metanfetamina/análogos & derivados , Psicotrópicos/toxicidad , Serotonina/metabolismo , 3,4-Metilenodioxianfetamina/toxicidad , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Metanfetamina/toxicidad , Ratas
15.
Life Sci ; 132: 6-12, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25936963

RESUMEN

AIMS: We investigated whether trans-fat supplemented over two generations of rats could alter neuronal membranes and influence mania-like behaviors, as well as the effects of lithium (Li). MAIN METHODS: Two generations of female rats were supplemented with soybean oil (SO-C, rich in n-6 fatty acids - FA) or hydrogenated vegetable fat (HVF, rich in trans-fatty acids - TFA). Male rats born from the 1st and 2nd generations were maintained in the same supplementation until adulthood, when they were exposed to an amphetamine (AMPH)-induced model of mania and co-treated with Li or not. KEY FINDINGS: AMPH increased locomotion of both generations and this influence was higher in the HVF than in the SO-C group. Conversely, AMPH increased long-term memory in SO-C group of the 2nd generation. HVF supplementation allowed hippocampal TFA incorporation in rats of both generations (0.1 and 0.2%, respectively). Oxidative parameters indicated higher levels of protein carbonyl (PC) in the HVF group with no changes in catalase (CAT) activity in the 1st generation. In the 2nd generation, AMPH increased PC levels of both experimental groups, whereas CAT activity was lower per se in the HVF group only. The co-treatment with Li leveled out all behavioral parameters, PC levels and CAT activity indicating a significant neuroprotective role. SIGNIFICANCE: These findings suggest that chronic HVF consumption allows a rising incorporation of TFA in the brain, which may be reflected on the neuropsychiatric conditions related to mania, whereas the effects of Li are not modified in the course of this harmful dietary habit.


Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Suplementos Dietéticos/efectos adversos , Litio/uso terapéutico , Ácidos Grasos Trans/efectos adversos , Anfetaminas/toxicidad , Análisis de Varianza , Animales , Trastorno Bipolar/inducido químicamente , Catalasa/metabolismo , Femenino , Hipocampo/química , Locomoción/efectos de los fármacos , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Ratas , Ratas Wistar , Aceite de Soja/administración & dosificación , Ácidos Grasos Trans/administración & dosificación , Ácidos Grasos Trans/análisis
16.
Arch Toxicol ; 89(10): 1695-725, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25743372

RESUMEN

Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.


Asunto(s)
Trastornos Relacionados con Anfetaminas/complicaciones , Mitocondrias/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Anfetaminas/administración & dosificación , Anfetaminas/farmacocinética , Anfetaminas/toxicidad , Animales , Barrera Hematoencefálica/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/toxicidad , Transporte de Electrón/efectos de los fármacos , Humanos , Síndromes de Neurotoxicidad/fisiopatología
17.
Int J Dev Neurosci ; 41: 44-62, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25482046

RESUMEN

Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS.


Asunto(s)
Trastornos Relacionados con Anfetaminas/complicaciones , Anfetaminas/toxicidad , Estimulantes del Sistema Nervioso Central/toxicidad , Sistema Nervioso/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Adolescente , Humanos
18.
Behav Brain Res ; 279: 87-99, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25449844

RESUMEN

The prevalence of drug use during pregnancy has increased in recent years and the amount of drug-exposed babies has therefore increased. In order to assess the risk associated with this there has been an increase in the amount of preclinical studies investigating the effects of prenatal and postnatal drug exposure on the offspring. There are many challenges associated with investigating the developmental and behavioural effects of drugs of abuse in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to illustrate the variation in the design of preclinical studies investigating the effects of the amphetamine-type stimulants taken during pregnancy and/or lactation in animal models. Methamphetamine, methylendioxymethamphetamine and amphetamine were included in this review. The protocols used for exploring the effects of these drugs when taking during pregnancy and/or lactation were investigated and summarised into maternal experimental variables and offspring experimental variables. Maternal experimental variables include animals used, mating procedures and drug treatment and offspring experimental variables include litter standardisation, cross fostering, weaning and behaviours and parameters assessed. The findings in this paper suggest that there is a large diversity and little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. For this reason, the importance of steering the preclinical studies in a direction that is most clinically relevant will be an important future recommendation. This will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible.


Asunto(s)
Anfetaminas/administración & dosificación , Anfetaminas/toxicidad , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/toxicidad , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal , Proyectos de Investigación , Anfetamina/administración & dosificación , Anfetamina/toxicidad , Animales , Animales Recién Nacidos , Femenino , Lactancia , Metanfetamina/administración & dosificación , Metanfetamina/toxicidad , Ratones , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Embarazo , Ratas , Ratas Sprague-Dawley , Ratas Wistar
19.
Molecules ; 19(9): 14979-86, 2014 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-25237752

RESUMEN

Hallucinations are a common non-motor symptom of Parkinson's disease and various forms of dementias. Yokukansan and Yokukansankachimpihange have attracted attention due to their effectiveness in the treatment of hallucinations of dementia. To clarify which component in these formulas contribute to the effects, at first, we focused on their differences in compositions to examine the pharmacological effects on the selective 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head-twitch response (HTR) in mice that has been used as animal hallucination model. Results indicated that water extract of Byaku-jutsu (Atractylodes japonica) showed a stronger inhibitory effect on DOI-induced HTR than that of So-jutsu (A. lancea) corresponding to their major constituents of atractylenolide III and ß-eudesmol, and suggested that the major constituents should be active constituents contributing to the antihallucination effects of Byaku- and So-jutsu. Besides, the part B-C ring (butenolide) in atractylenolide III was found to be similar to the structure of serotonin and suggested that the B-C ring may partially play role in antagonistic activity against serotonin receptors. Thus, a novel, rational design of butenolide-related compounds may as potential lead compounds for new drug development. Analysis of the chemical components of Byaku- and So-jutsu and further study on their structure-activity relationships are currently in progress.


Asunto(s)
Anfetaminas/toxicidad , Atractylodes , Alucinaciones/inducido químicamente , Animales , Masculino , Ratones , Ratones Endogámicos ICR
20.
ACS Chem Neurosci ; 5(10): 920-42, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25137629

RESUMEN

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.


Asunto(s)
Aprendizaje por Asociación/efectos de los fármacos , Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Psicotrópicos/farmacología , Piridazinas/farmacología , Receptor Muscarínico M4/metabolismo , Tiofenos/farmacología , Anfetaminas/toxicidad , Animales , Aprendizaje por Asociación/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Línea Celular , Estimulantes del Sistema Nervioso Central/toxicidad , Colinérgicos/síntesis química , Colinérgicos/farmacocinética , Colinérgicos/farmacología , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Psicotrópicos/síntesis química , Psicotrópicos/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Tiofenos/síntesis química , Tiofenos/farmacocinética
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