RESUMEN
BACKGROUND: Fetal ethanol (EtOH) exposure can damage the developing central nervous system and lead to cognitive and behavioral deficits, known as fetal alcohol spectrum disorders (FASD). EtOH exposure to mouse pups during early neonatal development was used as a model of EtOH exposure that overlaps the human third-trimester "brain growth spurt"-a model that has been widely used to study FASD in rats. METHODS: C57BL/6 male and female mice were exposed to EtOH (4 g/kg/d) on postnatal days (PD) 4 to 10 by oral intubation. Intubated and nontreated controls were also included. Behavioral testing of the offspring, including open field, elevated plus maze, and Morris water maze, was performed on PD 20 to 45. RESULTS: EtOH exposure during PD 4 to 10 resulted in hyperactivity and deficits in learning and memory in young mice with no apparent sex differences. CONCLUSIONS: Based on these data, this neonatal intubation mouse model may be useful for future mechanistic and genetic studies of FASD and for screening of novel therapeutic agents.
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Conducta Animal/efectos de los fármacos , Etanol/toxicidad , Factores de Edad , Animales , Etanol/sangre , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Caracteres SexualesRESUMEN
Opiate addiction is now a major public health problem. Perinatal insults and exposure to opiates such as morphine in utero are well known to affect development of the hypothalamic-pituitary-adrenal axis of the offspring adversely and are associated with a higher risk of developing neurobehavioral problems. Oxycodone is now one of the most frequently abused pain killers during pregnancy; however, limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters neurobehavioral outcomes of the offspring. We demonstrated that exposure to 0.5 mg/kg/day oxycodone in utero was associated with hyperactivity in adult rats in an open field. No significant effects of POE were detected on isolation-induced ultrasonic vocalizations in the early postnatal period or on learning and memory in the water maze in adult offspring. Our findings are consistent with hyperactivity problems identified in children exposed to opiates in utero.
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BACKGROUND: This study was initiated as part of a quality improvement audit process to create standards around goal setting with our patients to understand and improve outcomes of homeopathic treatment. METHOD: We used the Measure Yourself Medical Outcome Profile (MYMOP2) as a tool to assist clinicians in setting the treatment goals across a wide range of diagnoses and other complaints in routine clinical practice at the Bristol Homeopathic Hospital. The data collected from the MYMOP2 is of significance in its own right and the results are now reported in this paper. RESULTS: A total of 198 patients with a wide range of complaints attended one to five consultations with 20 homeopathic doctors. Diagnostic categories were most commonly neoplasms (16.7%), psychological (13.9%) and genitourinary complaints (12.3%), with 66.7% suffering from these problems for at least one year. The three symptoms that bothered patients the most were pain, mental symptoms and tiredness/fatigue. A paired-samples t-test using an intention-to-treat analysis showed that the MYMOP2 profile score improved from 4.25 (IQR 3.50-5.00), with a mean change of 1.24 (95% CI 1.04, 1.44) from the first to the last consultation (p<0.001). Results were statistically significant both for completers (n=91) (p<0.001) and non-completers (n=107) (p<0.001) using last-observation-carried-forward, although completers did better than non-completers (p<0.001). The overall clinical significance of improvements was at least moderate. A repeated measures ANOVA test also showed statistically significant improvements (p<0.001). CONCLUSION: The MYMOP2 results add to a growing body of observational data which demonstrates that when patients with long term conditions come under homeopathic care their presenting symptoms and wellbeing often improve. Offering a low cost high impact intervention to extend the range of choice to patients and to support self-care could be an important part of the NHS.
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Homeopatía , Medición de Resultados Informados por el Paciente , Encuestas y Cuestionarios , Análisis de Varianza , Enfermedad Crónica , Fatiga/terapia , Humanos , Salud Mental , Manejo del Dolor , Derivación y ConsultaRESUMEN
BACKGROUND: Ethanol (EtOH) causes neurotoxicity via several mechanisms including neuroinflammation (during EtOH exposure), and excitotoxicity (during EtOH withdrawal [EWD]). Alpha7 nicotinic acetylcholine receptor (nAChR) selective agonists have the potential to reduce both. The aim of this study was to evaluate the anti-inflammatory and neuroprotective potential of rhamnetin, a dietary flavonoid with alpha7 nAChR selective activity, in an in vitro model of EtOH-induced neurotoxicity. METHODS: The anti-inflammatory and neuroprotective properties of rhamnetin were assessed in neonatal organotypic hippocampal slice cultures undergoing EWD (or not) and challenged with N-methyl-D-aspartate (NMDA) and/or lipopolysaccharide (LPS). Neurotoxicity was determined using propidium iodide uptake, and the inflammatory response was evaluated by measuring the release of tumor necrosis factor (TNF)-alpha (NO; quantified by ELISA) and nitric oxide (quantified by the Griess reaction) into culture media. RESULTS: As predicted, rhamnetin reduced LPS-induced release of TNF-alpha and NO both under control conditions and during EWD. Additionally, rhamnetin had no effect on NMDA-induced neurotoxicity under control conditions, but significantly reduced NMDA toxicity during EWD. In contrast, rhamnetin had no effect on neurotoxicity induced by NMDA and LPS combined despite reducing TNF-alpha and NO levels under these conditions. CONCLUSIONS: Rhamnetin is anti-inflammatory and neuroprotective during EWD and therefore has potential value in treating neurotoxicity caused by EtOH.
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Etanol/toxicidad , Agonistas de Aminoácidos Excitadores/toxicidad , Flavonoides/farmacología , Hipocampo/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Quercetina/análogos & derivados , Animales , Femenino , Flavonoides/uso terapéutico , Hipocampo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Técnicas de Cultivo de Órganos , Quercetina/farmacología , Quercetina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/metabolismoRESUMEN
BACKGROUND: Ethanol (EtOH) causes neurotoxicity by several mechanisms including excitotoxicity and neuroinflammation, but little is known about the interaction between these mechanisms. Because neuroinflammation is known to enhance excitotoxicity, we hypothesized that neuroinflammation contributes to the enhanced excitotoxicity, which is associated with EtOH withdrawal (EWD). The aim of this study was to evaluate the lipopolysaccharide (LPS)-induced inflammatory response of cultured hippocampal tissue during EWD and its effects on the enhanced N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, which occurs at this time. METHODS: Using a neonatal organotypic hippocampal slice culture (OHSC) model, we assessed the effects of NMDA and LPS (separately or combined) during EWD after 10 days of EtOH exposure. Neurotoxicity was assessed using propidium iodide uptake, and the inflammatory response was evaluated by measuring the release of tumor necrosis factor (TNF)-alpha (quantified by enzyme-linked immunosorbent assay) and nitric oxide (NO; quantified by the Griess reaction) into culture media. Furthermore, we explored the potential role of the microglial cell type using immortalized BV2 microglia treated with EtOH for 10 days and challenged with LPS during EWD. RESULTS: As predicted, NMDA-induced toxicity was potentiated by LPS under control conditions. However, during EWD, the reverse was observed and LPS inhibited peak NMDA-induced toxicity. Additionally, LPS-induced release of TNF-alpha and NO during EWD was reduced compared to control conditions. In BV2 microglia, following EtOH exposure, LPS-induced release of NO was reduced, whereas TNF-alpha release was potentiated. CONCLUSIONS: During EWD following chronic EtOH exposure, OHSC exhibited a desensitized inflammatory response to LPS and the effects of LPS on NMDA toxicity were reversed. This might be explained by a change in microglia to an anti-inflammatory and neuroprotective phenotype. In support, studies on BV2 microglia indicate that EtOH exposure and EWD do alter the response of these cells to LPS, but this cannot fully explain the changes observed in the OHSC. The data suggest that neuroinflammation and excitotoxicity do interact during EWD. However, the interaction is not as simple as we originally proposed. This in turn illustrates the need to assess the extent, importance, and relation of these mechanisms in models of EtOH exposure producing neurotoxicity.
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Etanol/farmacología , Hipocampo/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos/farmacología , N-Metilaspartato/toxicidad , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Interacciones Farmacológicas , Etanol/administración & dosificación , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxido Nítrico/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato , Técnicas de Cultivo de Tejidos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and showed excellent activity in every screen with a potency 5-200x that of the FDA-approved anti-relapse agent, acamprosate. This chapter will present a review of the background and rationale for this approach and some of the findings garnered from this approach as well as patents targeting the glutamatergic system especially the NMDAR.
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Alcoholismo/tratamiento farmacológico , Guanidinas/farmacología , Poliaminas/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/psicología , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Guanidinas/síntesis química , Guanidinas/uso terapéutico , Terapia Molecular Dirigida , Fármacos Neuroprotectores/farmacología , Patentes como Asunto , EmbarazoRESUMEN
Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl-d-aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1µl, i.c.v.), spermidine (0.02, 0.2 or 2nmol/site, i.c.v.) or traxoprodil (0.2, 2 or 20nmol, i.c.v.) and with PTZ (35 or 70mg/kg, i.p.). The effect of orally administered traxoprodil (60mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70mg/kg; i.p.). Traxoprodil (20nmol i.c.v.) increased the latency to generalized tonic-clonic seizures induced by PTZ (70mg/kg; i.p.). Traxoprodil (60mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.
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Pentilenotetrazol/toxicidad , Piperidinas/uso terapéutico , Convulsiones/prevención & control , Animales , Masculino , Piperidinas/farmacología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Convulsiones/inducido químicamente , Convulsiones/fisiopatologíaRESUMEN
Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.
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Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Nootrópicos/farmacología , Espermidina/farmacología , Animales , Biguanidas/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Extinción Psicológica/fisiología , Miedo/fisiología , Reacción Cataléptica de Congelación , Masculino , Pruebas Neuropsicológicas , Piperidinas/farmacología , Poliaminas/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Rat pups, in isolation, produce ultrasonic vocalizations (USVs). These USVs have been used as a diagnostic tool for developmental toxicity. We have shown that neonatal ethanol (ETOH) exposure produces deficits in this behavior. The current study was designed to examine whether agmatine (AG), which binds to imidazoline receptors and modulates n-methyl-d-aspartate receptors (NMDAR), could reduce these deficits. In addition, this study examined critical periods for ETOH's effects on USVs by administering ETOH during either the 1st or 2nd postnatal week. Neonatal rats received intragastric intubations of either ETOH (6g/kg/day), ETOH and AG (6g/kg/day and 20mg/kg/day), AG (20mg/kg/day), or maltose on postnatal days (PND) 1-7 or 8-14. A non-intubated control was also included. Subjects were tested on PND 15. Neonatal ETOH exposure significantly increased the latency to vocalize for females and reduced the rate of USVs in both males and females exposed to ETOH on PND 1-7. Agmatine reduced these deficits, in female but not male pups. Subjects exposed to ETOH on PND 8-14 showed no evidence of abnormal USVs. These findings suggest that there may be gender differences in response to AG following neonatal ETOH exposure and also provide further support that the first neonatal week is a particularly sensitive time for the developmentally toxic effects of ETOH in rodents.
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Agmatina/farmacología , Trastornos del Sistema Nervioso Inducidos por Alcohol/tratamiento farmacológico , Etanol/antagonistas & inhibidores , Trastornos Mentales/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Vocalización Animal/efectos de los fármacos , Envejecimiento/fisiología , Agmatina/uso terapéutico , Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/antagonistas & inhibidores , Depresores del Sistema Nervioso Central/toxicidad , Modelos Animales de Enfermedad , Etanol/toxicidad , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Masculino , Conducta Materna/fisiología , Trastornos Mentales/inducido químicamente , Trastornos Mentales/fisiopatología , Embarazo , Ratas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Caracteres Sexuales , Factores Sexuales , Conducta Social , Resultado del Tratamiento , Vocalización Animal/fisiologíaRESUMEN
Alcohol and nicotine (in the form of tobacco) are 2 commonly used recreational drugs and studies show a high correlation between tobacco use and alcohol consumption. In the present study, using C57BL/6J mice, we investigated the ability of mecamylamine (a nicotinic antagonist) to reduce alcohol consumption and alcohol preference with free 24-hour access using a 2-bottle choice test drinking procedure. Male C57BL/6J mice were individually housed and acclimatized to 10% alcohol. Immediately following the last day of alcohol acclimatization, the mice (n = 5/group) received subcutaneous injections of mecamylamine (0.5, 1 and 2 mg/kg) or saline consisting of either intermittent (3 injections given every other day) or daily (injections on all 5 days) exposures. Fluid consumption (alcohol and water) was recorded daily. The results showed that mecamylamine significantly reduced alcohol consumption and alcohol preference in both phases of intermittent and daily drug exposures, while the total fluid consumption was unchanged. These results provide further support that mecamylamine is effective in reducing alcohol consumption and preference, and nicotinic-receptor-based drugs could further be explored as potential treatments for alcoholism.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Conducta de Elección/efectos de los fármacos , Mecamilamina/farmacología , Antagonistas Nicotínicos/farmacología , Animales , Modelos Animales de Enfermedad , Ingestión de Líquidos/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Masculino , Mecamilamina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Antagonistas Nicotínicos/administración & dosificaciónRESUMEN
Lobeline is a partial nicotinic agonist and is currently being investigated as a therapeutic drug for several addictive disorders particularly for smoking cessation. The present study evaluated the effects of repeated (continuous and recurring) administration of lobeline on alcohol consumption (10% alcohol vs. water) and alcohol preference using a 2-bottle choice test procedure. Male C57BL/6J mice were individually housed and acclimatized to 10% alcohol. Immediately following the last day of alcohol acclimatization and attainment of consistent drinking pattern, mice (n=5/group) received subcutaneous injections of lobeline (3, 5, or 10 mg/kg) or saline. Groups received either repeated-recurring (3 injections, given every other day) or repeated-continuous (daily injections for 5 days) subcutaneous injections of lobeline. Fluid consumption (alcohol and water) was recorded daily. Results showed that lobeline significantly reduced alcohol consumption and alcohol preference during the repeated (recurring and continuous) administration phases, while total fluid consumption remained unchanged. These results provide support that nicotinic receptor based drugs may be useful as potential treatments for alcoholism.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Preferencias Alimentarias/efectos de los fármacos , Lobelina/farmacología , Agonistas Nicotínicos/farmacología , Análisis de Varianza , Animales , Conducta de Elección/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Esquema de Medicación , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Stress increases the risk for alcohol abuse and relapse behaviors. However, there are hardly any medications to counteract stress-induced alcoholism and relapse behaviors. The present study examined the effects of topiramate (intraperitoneal injections of 10, 20, and 30 mg/kg) in its ability to attenuate alcohol consumption on exposure to restraint stress in C57BL/6J mice on a 2-choice test procedure. Mice were either restrained for 1h/day for 5 successive days or left unrestrained. Subsequently, the effects of topiramate were studied in post-restraint days. Results showed that restrained animals increased alcohol consumption and alcohol preference significantly compared to control group on day 5. On post-restraint days, topiramate reduced alcohol consumption and alcohol preference on days 2-5 compared to saline. This experiment suggests that one mechanism of topiramate in reducing alcohol consumption and alcohol preference may involve an interaction with stress.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Preferencias Alimentarias/efectos de los fármacos , Fructosa/análogos & derivados , Fármacos Neuroprotectores/farmacología , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Conducta de Elección/efectos de los fármacos , Modelos Animales de Enfermedad , Fructosa/farmacología , Fructosa/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/uso terapéutico , Restricción Física/métodos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/etiología , Factores de Tiempo , TopiramatoRESUMEN
Neonatal ethanol (EtOH) exposure is associated with central nervous system dysfunction and neurotoxicity in rats. Increases in polyamine levels have been implicated as one underlying mechanism for some of EtOH's effects on the developing brain. In this study we addressed whether the inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) could reduce behavioral deficits induced by early EtOH exposure. Male and female rat pups received ethanol (6 g/kg/day EtOH i.g.), or isocaloric maltose (control) from postnatal days (PND) 1-8. On PND 8, animals were injected with either saline or DFMO (500 mg/kg, s.c.) immediately following the final neonatal treatment. Subjects were tested for isolation-induced ultrasonic vocalizations (USV) on PND 16; spontaneous activity in an open field apparatus on PND 20 and 21; and balance on PND 31. Animals exposed to EtOH neonatally displayed an increased latency to the first USV and reduced frequencies of USV, hyperactivity and preference for the center of the open field and poorer balance relative to controls. DFMO minimized these deficits in latency to the first USV and balance. These data provide further support that polyamines play a role in some of the functional deficits associated with EtOH exposure during early development and that reducing polyamine activity can improve outcome.
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Animales Recién Nacidos/fisiología , Depresores del Sistema Nervioso Central/toxicidad , Eflornitina/farmacología , Inhibidores Enzimáticos/farmacología , Etanol/toxicidad , Equilibrio Postural/efectos de los fármacos , Aislamiento Social , Vocalización Animal/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Inhibidores de la Ornitina Descarboxilasa , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The ethanol withdrawal (EWD) syndrome is typically treated using benzodiazepines such as diazepam. However there is concern that benzodiazepines may not prevent neurotoxicity associated with EWD. Antagonists of glutamate/N-Methyl-D-Aspartate receptors (NMDARs) such as MK801 have been shown to be effective against both EWD-induced neurotoxicity in vitro and seizures in vivo. However, most of these agents have adverse side effects. An exception is the moderate affinity NMDAR channel blocker memantine, used in Alzheimer's dementia. The present studies examined the ability of memantine to protect against EWD-related toxicity in vitro and seizures in vivo. METHODS: Organotypic hippocampal slice cultures from neonatal rat pups were treated starting at 15 days in vitro with 100 mM ethanol for 10 days followed by a 24-hour EWD period. During the 24-hour EWD period cultures were treated with memantine (15 or 30 microM). MK801 (10 microM) was utilized as a positive control. For the in vivo studies, the ability of memantine (2, 5, 10, and 15 mg/kg) to reduce convulsions was analyzed in Swiss-Webster mice using the handling induced convulsion test paradigm. RESULTS: In vitro studies demonstrated that memantine is effective at blocking EWD-induced neurotoxicity. In vivo experiments showed that memantine also significantly reduced convulsions induced by EWD in mice. CONCLUSIONS: Memantine may be of therapeutic value during alcohol detoxification by virtue of its having neuroprotective effects in addition to anti-seizure activity. The potential role of memantine in treatment of alcoholism is deserving of further study.
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Convulsiones por Abstinencia de Alcohol/tratamiento farmacológico , Alcoholismo/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Memantina/farmacología , Memantina/uso terapéutico , Convulsiones por Abstinencia de Alcohol/fisiopatología , Alcoholismo/fisiopatología , Animales , Hipocampo/fisiopatología , Masculino , Ratones , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: We report findings from a pilot data collection study within a programme of quality assurance, improvement and development across all five homeopathic hospitals in the UK National Health Service (NHS). AIMS: (1) To pilot the collection of clinical data in the homeopathic hospital outpatient setting, recording patient-reported outcome since first appointment; (2) to sample the range of medical complaints that secondary-care doctors treat using homeopathy, and thus identify the nature and complexity of complaints most frequently treated nationally; (3) to present a cross section of outcome scores by appointment number, including that for the most frequently treated medical complaints; (4) to explore approaches to standard setting for homeopathic practice outcome in patients treated at the homeopathic hospitals. METHODS: A total of 51 medical practitioners took part in data collection over a 4-week period. Consecutive patient appointments were recorded under the headings: (1) date of first appointment in the current series; (2) appointment number; (3) age of patient; (4) sex of patient; (5) main medical complaint being treated; (6) whether other main medical complaint(s); (7) patient-reported change in health, using Outcome Related to Impact on Daily Living (ORIDL) and its derivative, the ORIDL Profile Score (ORIDL-PS; range, -4 to +4, where a score
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Homeopatía/organización & administración , Servicio Ambulatorio en Hospital/organización & administración , Pacientes Ambulatorios/estadística & datos numéricos , Satisfacción del Paciente/estadística & datos numéricos , Pautas de la Práctica en Medicina , Adolescente , Adulto , Distribución por Edad , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Proyectos Piloto , Relaciones Profesional-Paciente , Distribución por Sexo , Medicina Estatal/organización & administración , Encuestas y Cuestionarios , Reino Unido/epidemiologíaRESUMEN
In the present study, we examined the effects of acamprosate for its ability to reduce handling induced convulsions (HICs) during alcohol withdrawal. Diazepam was used as a positive control. Swiss Webster male mice received three daily IP injections of alcohol (2.5 g/kg) or alcohol (2.5 g/kg)+methylpyrazole (4-MP) (9 mg/kg). (4-MP, being an alcohol dehydrogenase inhibitor slows down the breakdown of alcohol. 4-MP in combination with alcohol exhibits a dramatic increase in blood alcohol level compared to alcohol alone). Ten hours following the last alcohol injection, the mice were picked up by the tail and examined for their seizure susceptibility (HICs). Diazepam, a benzodiazepine known to reduce seizures during alcohol withdrawal, significantly reduced these HICs at doses of 0.25, 0.5 and 1 mg/kg (p's<0.001). Acamprosate, an anti-relapse compound used clinically in newly abstinent alcoholics, also reduced these HICs at doses of 100, 200 and 300 mg/kg (p's<0.05). This study supports the use of acamprosate during periods of alcohol withdrawal as well as during abstinence.
Asunto(s)
Disuasivos de Alcohol/uso terapéutico , Convulsiones por Abstinencia de Alcohol/tratamiento farmacológico , Manejo Psicológico , Taurina/análogos & derivados , Acamprosato , Convulsiones por Abstinencia de Alcohol/sangre , Alcoholes/efectos adversos , Alcoholes/sangre , Análisis de Varianza , Animales , Anticonvulsivantes/uso terapéutico , Antídotos/uso terapéutico , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Diazepam/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fomepizol , Masculino , Ratones , Pirazoles/uso terapéutico , Taurina/uso terapéuticoRESUMEN
BACKGROUND: Polyamines are synthesized and released in high concentrations during CNS development. These agents can potentiate N-methyl-D-aspartate receptor (NMDAR) function and appear to play an important role in CNS development. Previous work has shown that polyamine release is increased during ethanol withdrawal (EWD). This likely promotes NMDAR overactivity and contributes to neurotoxicity during EWD, however, little is known regarding such effects in early neonatal brain. The present study compared the effects of EWD and polyamine exposure on toxicity in hippocampal slice cultures derived from postnatal day 2 (PND 2) or postnatal day 8 (PND 8) day-old rats. Due to changes in NMDAR subtypes and response to polyamines, we predicted that slices taken from PND 2 pups would be more sensitive to EWD and polyamine challenge. METHODS: Organotypic hippocampal slice cultures were obtained from neonatal rats either 2 or 8 days of age (PND 2 or PND 8). Five days after explantation, cultures were exposed to ETOH (50 mM- typically subthreshold for EWD induced cell death) for 10 days and then withdrawn from ETOH for 24-hour in the presence of 100 microM of the polyamine spermidine and/or 100 microM ifenprodil, an NMDAR antagonist that blocks the NMDAR that is the most sensitive to polyamine modulation. Cytotoxicity was measured after 24-hour by visualization of propidium iodide (PI) fluorescence. RESULTS: There were clear age and gender-dependent differences in response to EWD and to polyamines. EWD produced significant increases in PI uptake in all subregions (CA1, CA3 and DG) of cultures derived from PND 2 pups, but not PND 8 pups. Exposure of cultures to spermidine for 24-hour also produced significant increases in cytotoxicity in all 3 regions of PND 2 cultures with no gender differences. In contrast, there were both gender and region-specific differences in response to spermidine in cultures from PND 8. While the CA1 region of both sexes displayed increased cytotoxicity following spermidine exposure, only females showed increased cytotoxicity in the CA3 region while the DG appeared relatively insensitive to spermidine. Exposure to spermidine during EWD produced enhanced toxicity in all 3 hippocampal subregions in tissue from both PND 2 and PND 8 rats and this was reduced or prevented by co-exposure to ifenprodil. Of interest, the PND 2 hippocampus was significantly more sensitive than the PND 8 hippocampus to the toxic effects of EWD and to spermidine during EWD in the DG and CA3 regions. CONCLUSIONS: Hippocampal slice cultures derived from PND 2 rats were more sensitive to the toxic effects of both EWD and EWD + spermidine exposure than were those derived from PND 8 rats. These findings are similar to recent behavioral data collected from our lab showing greater sensitivity to ETOH's behavioral teratogenic effects when ETOH exposure in vivo occurred during the first postnatal week relative to the second postnatal week. Ifenprodil's ability to block the toxic effects of spermidine during EWD suggests that excess activity of NR2B subunits of the NMDAR contributed to the excitatory and cytotoxic effects of EWD plus spermidine. While no sex differences in toxicity were observed in cultures taken from pups during the first postnatal week, these data do suggest that later in neonatal life (i.e., the second postnatal week), the female hippocampus may be more sensitive to polyamine-induced neurotoxicity than males.
Asunto(s)
Envejecimiento , Animales Recién Nacidos , Etanol , Hipocampo/efectos de los fármacos , Caracteres Sexuales , Espermidina/farmacología , Animales , Femenino , Hipocampo/fisiología , Masculino , Técnicas de Cultivo de Órganos , Piperidinas/farmacología , Propidio/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Síndrome de Abstinencia a SustanciasRESUMEN
UNLABELLED: Topiramate has emerged as one of the promising drugs for the treatment of alcoholism and alcohol addiction. Recent studies have shown that topiramate reduces harmful drinking and initiates abstinence in humans, but little is known as to why this drug is effective. AIMS: In the present study, we examined the effects of topiramate in reducing convulsions during alcohol withdrawal using a procedure called the handling-induced convulsion (HIC) test in male Swiss-Webster mice. In addition, we examined the ability of topiramate to reduce alcohol conditioned and anxiety related behaviours during conditioned abstinence using the elevated plus maze (EPM) test. METHODS: HICs were examined 10 h after the 3rd daily alcohol (2.5 g/kg; 20% w/v)+4 methylpyrazole (4MP) (9 mg/kg) intraperitoneal (i.p.) injection with topiramate (0, 10 or 20 mg/kg ip) administered 30 min before testing. In the EPM, alcohol (1.75 g/kg; 20%, i.p.) or saline was administered daily for 9 days and subjects were immediately placed on the maze. Anxiety related behaviours included the amount of time spent and number of entries in the open or closed arms and grooming bouts, and conditioned behaviours including the stretched-attend posture were examined 24 h after the last day of alcohol injection. RESULTS: Topiramate (10 and 20 mg/kg) significantly reduced HIC scores (P<0.05) compared to the alcohol/saline group. In the EPM, topiramate (20 mg/kg) reduced the stretched-attend postures (P<0.001) compared to the alcohol/saline group. CONCLUSION: These findings suggest that topiramate reduces HICs during alcohol withdrawal and alcohol-conditioned behaviours during conditioned abstinence in Swiss-Webster mice.
Asunto(s)
Anticonvulsivantes/farmacología , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Fructosa/análogos & derivados , Manejo Psicológico , Convulsiones/prevención & control , Síndrome de Abstinencia a Sustancias/prevención & control , Animales , Ansiolíticos , Ansiedad/prevención & control , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/efectos adversos , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Etanol/efectos adversos , Fructosa/farmacología , Masculino , Ratones , Postura , Convulsiones/etiología , Síndrome de Abstinencia a Sustancias/complicaciones , Síndrome de Abstinencia a Sustancias/psicología , TopiramatoRESUMEN
In general, 'drinkers smoke', and a high proportion of the alcohol-dependent population is also nicotine-dependent. Statistically, the majority of alcoholics will die of smoking-related, rather than alcohol-related, disease. This co-dependent sub-population may have higher levels of nicotine dependence, and find smoking cessation more difficult. Major reasons are that concurrent alcohol use, and/or prior alcohol exposure, may change the reinforcing effects of nicotine, and that each drug becomes a pharmacological cue for the expectation of the other. If so, then smokers whose nicotine dependence is impacted by alcohol, represent a large and distinct sub-population in which both the therapeutic and molecular targets for smoking cessation are altered. This, in turn, has implications for the validity of animal models of nicotine reinforcement, and for the development of novel smoking cessation medications. It is no longer possible to ignore the fact that the two most prevalent and damaging addictive drugs in our society are very commonly used by the same individuals. Without a better understanding of the psychological and pharmacological interactions between alcohol and nicotine that impact dependence, we cannot hope to provide appropriate medications for this large and problematic patient group. Our intention in this opinion overview is to use the current literature to provide a framework for future studies into the impact of alcohol use on the reinforcing effects of nicotine.
Asunto(s)
Alcoholismo/metabolismo , Etanol/metabolismo , Nicotina/metabolismo , Refuerzo en Psicología , Fumar/metabolismo , Tabaquismo/metabolismo , Alcoholismo/epidemiología , Alcoholismo/psicología , Comorbilidad , Etanol/efectos adversos , Humanos , Nicotina/efectos adversos , Receptores de Glutamato/metabolismo , Receptores Nicotínicos/metabolismo , Receptores Opioides/metabolismo , Fumar/mortalidad , Fumar/psicología , Tabaquismo/epidemiología , Tabaquismo/psicologíaRESUMEN
BACKGROUND: Ethanol exposure and withdrawal during central nervous system development can cause oxidative stress and produce severe and long-lasting behavioral and morphological alterations in which polyamines seem to play an important role. However, it is not known if early ethanol exposure causes long-lasting protein oxidative damage and if polyamines play a role in such a deleterious effect of ethanol. METHODS: In this study we investigated the effects of early ethanol exposure (6 g/kg/d, by gavage), from postnatal day (PND) 1 to 8, and of the administration of difluoromethylornithine (DFMO, 500 mg/kg, i.p., on PND 8), a polyamine biosynthesis inhibitor, on the extent of oxidative modification of proteins. Indices of oxidative modification of proteins included protein carbonyls, 3-nitrotyrosine (3-NT), and protein bound 4-hydroxynonenal (HNE) in the hippocampus, cerebellum, hypothalamus, striatum, and cerebral cortex of Sprague-Dawley rats at PND 40. RESULTS: Both ethanol and DFMO administration alone increased protein carbonyl immunoreactivity in the hippocampus at PND 40, but the combination of DFMO and ethanol resulted in no effect on protein carbonyl levels. No alterations in the content of protein-bound HNE, 3-NT, or carbonyl were found in any other cerebral structure. CONCLUSIONS: These results suggest that the hippocampus is selectively affected by early ethanol exposure and by polyamine synthesis inhibition. In addition, the results suggest a role for polyamines in the long-lasting increase of protein carbonyls induced by ethanol exposure and withdrawal.