RESUMO
The cystine/glutamate antiporter system Xc- (SXc-) mediates the exchange of intracellular L-glutamate (L-Glu) with extracellular L-cystine (L-Cys2). Both the import of L-Cys2 and the export of L-Glu take on added significance in CNS cells, especially astrocytes. When the relative activity of SXc- overwhelms the regulatory capacity of the EAATs, the efflux of L-Glu through the antiporter can be significant enough to trigger excitotoxic pathology, as is thought to occur in glioblastoma. This has prompted considerable interest in the pharmacological specificity of SXc- and the development of inhibitors. The present study explores a series of analogues that are structurally related to sulfasalazine, a widely employed inhibitor of SXc-. We identify a number of novel aryl-substituted amino-naphthylsulfonate analogues that inhibit SXc- more potently than sulfasalazine. Interestingly, the inhibitors switch from a competitive to noncompetitive mechanism with increased length and lipophilic substitutions, a structure-activity relationship that was previously observed with aryl-substituted isoxazole. These results suggest that the two classes of inhibitors may interact with some of the same domains on the antiporter protein and that the substrate and inhibitor binding sites may be in close proximity to one another. Molecular modeling is used to explore this possibility.
Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sulfassalazina/análogos & derivados , Sulfassalazina/farmacologia , Sistema y+ de Transporte de Aminoácidos/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Antiporters/antagonistas & inibidores , Antiporters/química , Antiporters/metabolismo , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular/métodos , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Sulfassalazina/metabolismoRESUMO
Large-scale analysis of the fossil record requires aggregation of palaeontological data from individual fossil localities. Prior to computers, these synoptic datasets were compiled by hand, a laborious undertaking that took years of effort and forced palaeontologists to make difficult choices about what types of data to tabulate. The advent of desktop computers ushered in palaeontology's first digital revolution-online literature-based databases, such as the Paleobiology Database (PBDB). However, the published literature represents only a small proportion of the palaeontological data housed in museum collections. Although this issue has long been appreciated, the magnitude, and thus potential significance, of these so-called 'dark data' has been difficult to determine. Here, in the early phases of a second digital revolution in palaeontology--the digitization of museum collections-we provide an estimate of the magnitude of palaeontology's dark data. Digitization of our nine institutions' holdings of Cenozoic marine invertebrate collections from California, Oregon and Washington in the USA reveals that they represent 23 times the number of unique localities than are currently available in the PBDB. These data, and the vast quantity of similarly untapped dark data in other museum collections, will, when digitally mobilized, enhance palaeontologists' ability to make inferences about the patterns and processes of past evolutionary and ecological changes.
Assuntos
Bases de Dados Factuais/estatística & dados numéricos , Fósseis , Invertebrados , Animais , California , Museus/estatística & dados numéricos , Oregon , Paleontologia/métodos , WashingtonRESUMO
The original version of this article unfortunately contained a mistake. E. Themistou was missing from the author group and so is now included with this erratum.
RESUMO
On March 4, 2017 at the age of 68, Sidney George Shaw (Sid) unexpectedly died from complications following surgery, only four years after retiring from the University of Bern. Trained in biochemistry at Oxford University, Sid had quickly moved into molecular pharmacology and became a key investigator in the field of enzyme biochemistry, vasoactive peptide research, and receptor signaling. Sid spent half his life in Switzerland, after moving to the University of Bern in 1984. This article, written by his friends and colleagues who knew him and worked with him during different stages of his career, summarizes his life, his passions, and his achievements in biomedical research. It also includes personal memories relating to a dear friend and outstanding scientist whose intellectual curiosity, humility, and honesty will remain an example to us all.
Assuntos
Bioquímica/história , Farmacologia/história , Endotelinas/história , Inglaterra , História do Século XX , História do Século XXI , Neurofarmacologia/história , SuíçaRESUMO
Process-induced degradation of clinically relevant resorbable polymers was investigated for two thermal techniques, filament extrusion followed by fused deposition modelling (FDM). The aim was to develop a clear understanding of the relationship between temperature, processing time and resultant process-induced degradation. This acts to address the current knowledge gap in studies involving thermal processing of resorbable polymers. Poly(DL-lactide-co-glycolide) (PDLGA) was chosen for its clinically relevant resorption properties. Furthermore, a comparative study of controlled thermal exposure was conducted through compression moulding PDLGA at a selected range of temperatures (150-225 °C) and times (0.5-20 min). Differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) were used to characterise thermally induced degradation behaviour. DSC proved insensitive to degradation effects, whereas GPC demonstrated distinct reductions in molecular weight allowing for the quantification of degradation. A near-exponential pattern of degradation was identified. Through the application of statistical chain scission equations, a predictive plot of theoretical degradation was created. Thermal degradation was found to have a significant effect on the molecular weight with a reduction of up to 96% experienced in the controlled processing study. The proposed empirical model may assist prediction of changes in molecular weight, however, accuracy limitations are highlighted for twin-screw extrusion, accredited to high-shear mixing. The results from this study highlight the process sensitivity of PDLGA and proposes a methodology for quantification and prediction, which contributes to efforts in understanding the influence of manufacture on performance of degradable medical implants.
Assuntos
Materiais Biocompatíveis/química , Ácido Láctico/química , Poliésteres/química , Poliglactina 910/química , Ácido Poliglicólico/química , Alicerces Teciduais , Implantes Absorvíveis , Osso e Ossos , Varredura Diferencial de Calorimetria , Cromatografia em Gel , Portadores de Fármacos , Temperatura Alta , Peso Molecular , Reprodutibilidade dos TestesRESUMO
Alterations in hypothalamo-pituitary adrenal (HPA) function have been described in alcoholics and in rodents after chronic alcohol consumption but the role of glucocorticoids in alcohol consumption, and the mechanisms involved, has received little attention until recently. Both alcohol consumption and withdrawal from chronic alcohol intake raise circulating glucocorticoid levels, and prolonged high concentrations of glucocorticoids are known to have detrimental effects on neuronal function and cognition. This minireview covers the ways in which glucocorticoids may be involved in drinking behavior, from social drinking to dependence, and the negative consequences of alcohol consumption seen during withdrawal which may have a detrimental effect on treatment outcome. Research shows prolonged increases in brain glucocorticoid concentrations and decreased brain glucocorticoid receptor availability (consistent with increased levels of endogenous ligand) after withdrawal from chronic alcohol treatment. Evidence suggests that increased glucocorticoid levels in the brain after chronic alcohol treatment are associated with the cognitive deficits seen during abstinence which impact on treatment efficacy and quality of life. Studies on organotypic cultures also demonstrate the importance of glucocorticoids in the neuropathological consequences of alcohol dependence.
Assuntos
Alcoolismo/metabolismo , Transtornos Cognitivos/induzido quimicamente , Etanol/efeitos adversos , Glucocorticoides/metabolismo , Degeneração Neural/induzido quimicamente , Síndrome de Abstinência a Substâncias/metabolismo , Alcoolismo/patologia , Animais , Comportamento Aditivo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Receptores de Glucocorticoides/metabolismoRESUMO
Effects of the dihydropyridine, nimodipine, an antagonist at L-type calcium channels, on the memory loss in rats caused by long term alcohol consumption were examined. Either a single dose of nimodipine or 2 weeks of repeated administration was given prior to withdrawal from 8 months of alcohol consumption. Memory was measured by the object recognition test and the T maze. Both nimodipine treatments prevented the memory deficits when these were measured between 1 and 2 months after alcohol withdrawal. At the end of the memory testing, 2 months after cessation of chronic alcohol consumption, glucocorticoid concentrations were increased in specific regions of rat brain without changes in plasma concentrations. Both nimodipine treatment schedules substantially reduced these rises in brain glucocorticoid. The data indicate that blockade of L-type calcium channels prior to alcohol withdrawal protects against the memory deficits caused by prolonged alcohol intake. This shows that specific drug treatments, such as nimodipine, given over the acute withdrawal phase, can prevented the neuronal changes responsible for subsequent adverse effects of long term consumption of alcohol. The results also suggest the possibility that regional brain glucocorticoid increases may be involved in the adverse effects of long term alcohol intake on memory. Such local changes in brain glucocorticoid levels would have major effects on neuronal function. The studies indicate that L-type calcium channels and brain glucocorticoid levels could form new targets for the treatment of cognitive deficits in alcoholics.
Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Nimodipina/administração & dosagem , Síndrome de Abstinência a Substâncias/complicações , Transtornos Induzidos por Álcool , Álcoois/efeitos adversos , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corticosterona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Masculino , Transtornos da Memória/patologia , Testes Neuropsicológicos , Ratos , Síndrome de Abstinência a Substâncias/etiologiaRESUMO
The hypothalamo-pituitary-adrenal axis shows functional changes in alcoholics, with raised glucocorticoid release during alcohol intake and during the initial phase of alcohol withdrawal. Raised glucocorticoid concentrations are known to cause neuronal damage after withdrawal from chronic alcohol consumption and in other conditions. The hypothesis for these studies was that chronic alcohol treatment would have differential effects on corticosterone concentrations in plasma and in brain regions. Effects of chronic alcohol and withdrawal on regional brain corticosterone concentrations were examined using a range of standard chronic alcohol treatments in two strains of mice and in rats. Corticosterone was measured by radioimmunoassay and the identity of the corticosterone extracted from brain was verified by high performance liquid chromatography and mass spectrometry. Withdrawal from long term (3 weeks to 8 months) alcohol consumption induced prolonged increases in glucocorticoid concentrations in specific regions of rodent brain, while plasma concentrations remained unchanged. This effect was seen after alcohol administration via drinking fluid or by liquid diet, in both mice and rats and in both genders. Shorter alcohol treatments did not show the selective effect on brain glucocorticoid levels. During the alcohol consumption the regional brain corticosterone concentrations paralleled the plasma concentrations. Type II glucocorticoid receptor availability in prefrontal cortex was decreased after withdrawal from chronic alcohol consumption and nuclear localization of glucocorticoid receptors was increased, a pattern that would be predicted from enhanced glucocorticoid type II receptor activation. This novel observation of prolonged selective increases in brain glucocorticoid activity could explain important consequences of long term alcohol consumption, including memory loss, dependence and lack of hypothalamo-pituitary responsiveness. Local changes in brain glucocorticoid levels may also need to be considered in the genesis of other mental disorders and could form a potential new therapeutic target.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Corticosterona/metabolismo , Etanol/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Esquema de Medicação , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica/efeitos dos fármacos , Radioimunoensaio , Ratos , Receptores de Glucocorticoides/metabolismo , Fatores de TempoRESUMO
PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.
Assuntos
Apoptose , Proliferação de Células , Fase G1/fisiologia , Proteína Quinase C-delta/fisiologia , Transdução de Sinais , Células CACO-2 , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Humanos , Imunoprecipitação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Proteína X Associada a bcl-2/metabolismoRESUMO
RATIONALE: In humans, social stress over long and short term can increase alcohol consumption, but the mechanisms involved are not understood. OBJECTIVES: This study was conducted to examine the effects of social defeat, using the resident/intruder paradigm, on the alcohol preference of "low alcohol drinking" individuals in a colony of C57BL/10 strain mice and the effects of two anxiolytic drugs. METHODS: Alcohol preference, in a two-bottle choice (8% v/v alcohol or water), was measured, in separate experiments, after either a single experience of social defeat by a resident male mouse, five consecutive daily defeat experiences or one experience per week for 4 weeks. Comparison was made with effects of repeated social defeat on the preference for dilute sucrose. In addition, the actions of the CCKB receptor antagonist, CAM1028, and of diazepam were examined on the effects of repeated defeat experiences. RESULTS: Five consecutive daily defeat experiences had a slow onset effect in increasing alcohol preference and consumption, compared with five daily exposures to a novel environment. A single defeat, or one defeat per week, did not significantly alter alcohol preference or intake. There were no effects of five daily defeat experiences on sucrose preference or consumption. The effect of repeated defeats on alcohol preference was significantly decreased by administration of the CCKB receptor antagonist, CAM1028, prior to each experience, but not by corresponding administration of diazepam. CONCLUSION: The results show that social stress increases alcohol intake in low alcohol preference C57BL/10 mice and suggest that CCK transmission may be involved in this effect.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Receptor de Colecistocinina B/antagonistas & inibidores , Alienação Social/psicologia , Animais , Comportamento Animal/fisiologia , Diazepam/farmacologia , Indóis/farmacologia , Meglumina/análogos & derivados , Meglumina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Esquema de Reforço , Sacarose/administração & dosagem , Fatores de TempoRESUMO
Nutritional deficiencies associated with long-term ethanol consumption may cause neuronal damage in ethanol-dependent individuals. Thiamine deficiency, in particular, is thought to contribute to ethanol-associated cerebellar degeneration, although damage may occur in adequately nourished alcoholics. Thus, the present study examined the effects of thiamine depletion and ethanol exposure on cytotoxicity in rat cerebellum. Organotypic cerebellar slice cultures were treated starting at 25 days in vitro with 100 mM ethanol for 11 days or 10 days followed by a 24-h withdrawal period. This exposure paradigm has previously been shown in hippocampal slice cultures to result in spontaneous cytotoxicity upon ethanol withdrawal. Additional cerebellar cultures were exposed to the thiamine depleting agent pyrithiamine (10-500 microM) for 10 or 11 days, some in the presence of ethanol exposure or withdrawal. Other cultures were co-exposed to thiamine (1-100 microM), 500 microM pyrithiamine, and ethanol for 10 or 11 days. The results demonstrated that neither 11-day ethanol treatment nor withdrawal from 10-day exposure significantly increased cerebellar cytotoxicity, as measured by propidium iodide fluorescence. The 11-day treatment with 100 or 500 microM pyrithiamine significantly increased propidium iodide fluorescence approximately 21% above levels observed in control tissue. Cultures treated with both ethanol (11 days or 10 days plus withdrawal) and 500 microM pyrithiamine displayed a marked increase in cytotoxicity approximately 60-90% above levels observed in control cultures. Pyrithiamine and ethanol-induced cytotoxicity was prevented in cultures co-exposed to thiamine (10-100 microM) for the duration of pyrithiamine treatment. Findings from this report suggest that the cerebellum may be more sensitive to the toxic effects of thiamine deficiency, as compared with alcohol withdrawal, associated with alcohol dependence.
Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Etanol/toxicidade , Deficiência de Tiamina/fisiopatologia , Animais , Feminino , Masculino , Técnicas de Cultura de Órgãos , Piritiamina/farmacologia , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/fisiopatologia , Deficiência de Tiamina/induzido quimicamenteRESUMO
This study investigated interactions between ethanol and nicotine on dopamine-sensitive neurone firing in the ventral tegmental area (VTA), recorded in midbrain slices. No changes in spontaneous activity of the neurones were seen with nicotine at 10, 25, or 100 nM; at 250 nM there was a small significant increase in firing rate. Ethanol, applied alone, caused a significant increase in firing rate at 40 mM and at 60 nM but not at 20 mM. Combinations of 10 or 25 nM nicotine with 20 or 40 mM ethanol did not result in increased firing rates compared with either drug alone. However, nicotine 100 nM plus ethanol 60 mM significantly increased the rate of spontaneous firing compared with that after either drug alone at these concentrations. In contrast, nicotine at 250 nM plus ethanol at 60 mM did not increase firing rate, compared with each drug alone. Ketanserin, 2 microM, prevented the potentiating effect of nicotine 100 nM plus ethanol 60 mM. The results show synergism between ethanol and nicotine at specific concentrations that are likely to be present in the brain during the behavioural effects of these drugs, but the interaction is complex and may involve multiple drug actions.
Assuntos
Dopamina/fisiologia , Etanol/administração & dosagem , Etanol/farmacocinética , Neurônios/efeitos dos fármacos , Nicotina/administração & dosagem , Nicotina/farmacocinética , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Camundongos , Neurônios/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/fisiologiaRESUMO
RATIONALE AND OBJECTIVE: Effects of corticosterone on place conditioning to ethanol were investigated in mice using two conditioning schedules; the conventional method and a rapid conditioning schedule in which exposure to the CS+ followed immediately on exposure to the CS-. METHODS: Effects of administration of corticosterone, 10 mg/kg, on the acquisition of place conditioning produced by ethanol, 1-2.5 g/kg, were investigated using the conventional method of conditioning, with exposure to the CS+ and the CS- on alternate days, and also using the rapid conditioning method. Total and free blood corticosterone concentrations were measured after administration of ethanol and corticosterone. RESULTS: In the conventional, alternate day, conditioning schedule, ethanol produced significant place preference at 2 and at 2.5 g/kg, but when these alcohol doses were given with corticosterone 10 mg/kg, significant place conditioning was not seen. In contrast, in the rapid, same day, conditioning schedule corticosterone significantly decreased the dose at which ethanol produced an apparent place preference, with significant place conditioning being seen with ethanol at 1 and 1.5 g/kg in combination with corticosterone, 10 mg/kg. Total and free corticosterone concentrations were increased after ethanol, 1.5 g/kg, compared with controls, and administration of corticosterone, 10 mg/kg, caused a significantly greater increase. There were no significant differences in spontaneous locomotor activity or brain alcohol concentrations between any of the treatment groups. CONCLUSIONS: The effects of corticosterone on ethanol-induced place conditioning are substantially affected by the conditioning schedule used.
Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Corticosterona/farmacologia , Etanol/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Anti-Inflamatórios/sangue , Encéfalo/metabolismo , Depressores do Sistema Nervoso Central/metabolismo , Corticosterona/sangue , Interações Medicamentosas , Etanol/metabolismo , Masculino , CamundongosRESUMO
The effects of acute administration of the dihydropyridine calcium channel antagonist, nimodipine, were studied on the actions of scopolamine in the object recognition test. Scopolamine at 0.125 mg/kg decreased the difference in the time spent exploring novel and familiar objects when given either 15 min before, or immediately after, exposure to objects. Administration of nimodipine at 10 mg/kg, or 1 mg/kg, at the same time as the scopolamine completely prevented the deleterious effects on memory in this task. This effect was seen when nimodipine and/or scopolamine were given prior to the object exposure and also when the drugs were given after the experience of seeing the objects. Nimodipine had no effects on performance when given in the absence of scopolamine. This lack of change in total time spent exploring the objects indicated that the effects of scopolamine and nimodipine were not due to changes in motor coordination or alertness. The results are discussed in the light of the role of cholinergic transmission in memory and the known actions of dihydropyridines on brain function.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Percepção de Forma/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Nimodipina/farmacologia , Escopolamina/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Injeções Intraperitoneais , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Escopolamina/farmacologiaRESUMO
The effects of acute administration of the dihydropyridine calcium channel antagonist, nimodipine, were studied on the actions of ethanol in the radial arm maze and the object recognition test. In the former test, the effects of the drugs were examined on the performance in finding the four baited arms, after previous training in this task. Ethanol, at 1 g/kg, increased both the number of re-entries into baited arms (counted as errors of working memory) and the total number of arm choices required to complete the task. Administration of nimodipine, 10 mg/kg, with the ethanol, completely prevented the deleterious effects on memory in this task, but had no effects on the performance when given in the absence of ethanol. In the object recognition task, ethanol, 1 g/kg, significantly decreased the differences in the time spent exploring novel and familiar objects. Nimodipine, 10 mg/kg, given with the ethanol, completely prevented this effect, but nimodipine alone had no effects. The lack of changes in total exploration times indicated that the effects of ethanol in these tests were not due to loss of motor co-ordination or of alertness. The results are discussed in the light of the known actions of the drugs on brain function.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Memória/efeitos dos fármacos , Nimodipina/farmacologia , Animais , Depressores do Sistema Nervoso Central/antagonistas & inibidores , Etanol/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologiaRESUMO
RATIONALE: To determine the effects of multiple saline injections on alcohol drinking by male and female C57/BL10 mice with low preference for alcohol. OBJECTIVE: An investigation of the effects of multiple saline injections on alcohol consumption, with a comparison of corresponding effects on sucrose consumption. METHODS: The effects of a range of injection schedules on preference for 8% alcohol, or 1% sucrose, compared with tap water, were measured in two-bottle choice tests. RESULTS: The multiple saline injection schedule significantly increased the alcohol preference, even when no alcohol was available during the injection period. The actual administration of fluid was not necessary for the increase in alcohol preference, since sham injections without fluid administration also increased alcohol preference. A single injection of saline did not alter the alcohol preference 3 weeks later. Daily saline injections for 3 weeks did not alter the consumption of the dilute sucrose solution. In the population of mice used, the preference for sucrose over water was found to follow a biphasic distribution, similar to that reported earlier in these mice for alcohol preference, but there was no correlation between alcohol preference and sucrose preference. CONCLUSIONS: The results suggest that lasting changes in the areas of the brain that specifically control alcohol intake are produced by repetition of a routine laboratory procedure.
Assuntos
Comportamento Animal/efeitos dos fármacos , Etanol/administração & dosagem , Cloreto de Sódio/administração & dosagem , Cloreto de Sódio/efeitos adversos , Sacarose/administração & dosagem , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The effects of age, ethanol concentration and minor stress on the variation in alcohol preference of C57 strain mice were determined. In two bottle choice tests, an older population of mice contained slightly more low-preference mice than a younger population. A wide range of ethanol preference was consistently seen in young mice for 8% and 6% ethanol, but the previously reported biphasic pattern of distribution was revealed only with 8% ethanol. Very few animals showed high preference for concentrations of 10% or 12% ethanol. Moving low alcohol preference mice to a new location (but not repeated cage changing or ultrasonic noise) significantly increased the alcohol preference. Exploratory locomotor activity did not correlate with the subsequent alcohol consumption. Blood and brain alcohol concentrations showed that the differences in alcohol preference were not due to differences in metabolism of ethanol. The C57 strain mice with low preference for alcohol provides a valuable model for the study of the effects of minor stress on alcohol consumption.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Comportamento de Escolha/fisiologia , Meio Ambiente , Atividade Motora/genética , Estimulação Acústica/efeitos adversos , Animais , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Etanol/metabolismo , Etanol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacosRESUMO
Previous work demonstrated that the locomotor stimulant actions of amphetamine, cocaine and nicotine were increased when these drugs were given during the abstinence phase after chronic ethanol consumption. These changes were seen at 6 days and at 2 months after cessation of alcohol. The present study examined neuronal alterations which might be related to these changes in behaviour. Markedly reduced spontaneous firing rates of dopaminergic cells in the ventral tegmental area (VTA) in midbrain slices were seen 6 days into the abstinence period after cessation of chronic ethanol consumption, but by 2 months the firing rates had returned to control values. Increased affinity of striatal receptors for the D1-like receptor ligand 3H-SCH23390, but no change in the receptor density, was found both at the 6 day and the 2 month intervals. The binding properties of striatal D2-like receptors, of D1-like and D2-like receptors in the frontal cerebral cortex, and the release of tritiated dopamine from slices of striatum or frontal cerebral cortex, were unchanged at 6 days and 2 months. It is suggested that the decreased neuronal firing leads to a persistent increase in sensitivity of D1-like receptors and that these changes could explain the increased effects of the other drugs of abuse.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Dopamina/fisiologia , Sistema Límbico/fisiologia , Temperança , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Sistema Límbico/efeitos dos fármacos , Masculino , Camundongos , Receptores Dopaminérgicos/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
Previous studies have suggested that a gamma-amino-butyric acid (GABA) deficit in the caudal hypothalamus (CH) of the spontaneously hypertensive rat (SHR) contributes to elevated levels of arterial pressure. The purpose of this study was to examine if SHR that underwent exercise training demonstrated a blunted development of hypertension and greater levels of glutamic acid decarboxylase (GAD) mRNA transcripts in the caudal hypothalamus. SHR were randomly paired and assigned to either a trained group (T; n=9) or a non-trained control group (NT; n=9). Trained animals were exercised for 10 weeks on a motorized treadmill while NT animals concurrently rested on a mock-treadmill. Following the 10-week training period, Northern blot analyses of mRNA for both the 65-kDa (GAD(65)) and 67-kDa (GAD(67)) isoforms of GAD were performed on tissue from caudal hypothalamic and cerebellar control brain regions. Exercise training simultaneously blunted the developmental rise in blood pressure in SHR (Delta59+/-9 mmHg in trained versus Delta77+/-9 mmHg in non-trained; P<0.03) and increased both GAD(65) (147+/-44%) and GAD(67) (162+/-77%) mRNA transcript levels in the CH (P<0.05). In contrast, no difference was detected in GAD mRNA levels in the cerebellum between T and NT SHR. These findings are consistent with our previous functional studies and demonstrate that exercise can significantly and specifically upregulate GAD gene transcript levels in the caudal hypothalamus of hypertensive rats.
Assuntos
Glutamato Descarboxilase/metabolismo , Hipertensão/metabolismo , Hipotálamo/metabolismo , Condicionamento Físico Animal , Animais , Pressão Sanguínea , Northern Blotting , Glutamato Descarboxilase/genética , Masculino , RNA Mensageiro/metabolismo , RatosRESUMO
Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the "sucrose-fading" training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.