RESUMO
Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.
Assuntos
Fibrose Cística/complicações , Fibrose Cística/cirurgia , Hepatopatias/cirurgia , Transplante de Fígado , Transplante de Pulmão , Adolescente , Adulto , Austrália , Criança , Feminino , Humanos , Testes de Função Hepática , Masculino , Testes de Função Respiratória , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: In November 2002, an anonymous postal survey of sheep farmers in Great Britain (GB) was conducted to identify factors associated with the flock-level occurrence of scrapie. This survey was undertaken to update an earlier postal survey in 1998, and was the first occasion in which a large-scale postal survey had been repeated. RESULTS: The results of the 2002 survey indicated that scrapie was more likely to occur in certain geographic regions; in purebred compared to commercial flocks; in larger flocks; in flocks which lambed in group pens compared to those which lambed in individual pens; in flocks which always lambed in the same location compared to those which did not; and in farms which kept certain breeds of sheep. In addition to these factors, the likelihood of the disease occurring in homebred animals was higher in flocks which bred a greater proportion of replacement animals or which bought-in lambs. Finally, within-flock transmission following exposure was more likely to occur in hill flocks compared to other farm types; in flocks which bred a greater proportion of replacement animals; and in farms which kept a certain crossbreed of ewe. CONCLUSION: The risk factors identified from the 1998 and 2002 anonymous postal surveys in Great Britain were similar. However, differences between the surveys were identified in the influence of region and of purchasing behaviour on the risk of scrapie. These differences are most likely a consequence of changes in farmer awareness and the impact of the 2001 foot-and-mouth disease epidemic, respectively.
Assuntos
Scrapie/epidemiologia , Animais , Coleta de Dados , Feminino , Masculino , Fatores de Risco , Ovinos , Inquéritos e Questionários , Reino Unido/epidemiologiaRESUMO
Clinical signs associated with bovine spongiform encephalopathy (BSE) were studied in 1008 casualty slaughter cattle over 30 months of age to compare the results with the BSE status as determined by postmortem tests. The clinical BSE status was assessed using seven different criteria based on various publications. Only one (0.10%) out of 997 casualty slaughter cattle with a matching postmortem test result was positive for BSE. The BSE case was identified by only two case definitions tailored specifically to recumbent cases. The variety and often equivocal definition of clinical signs associated with BSE is reflected by the difference in the criteria that usually identified different animals as BSE suspects. The BSE status may be more difficult to assess in recumbent animals that do not allow a full clinical examination, and BSE may not be suspected if another disease is present that may mask signs of BSE.
Assuntos
Matadouros , Comportamento Animal , Encefalopatia Espongiforme Bovina/diagnóstico , Encefalopatia Espongiforme Bovina/fisiopatologia , Animais , Bélgica , Bovinos , Diagnóstico Diferencial , Alemanha , Locomoção , Exame Físico , Sensibilidade e Especificidade , Inquéritos e Questionários , SuíçaRESUMO
In February 2003, a postal survey of 1279 sheep farmers in the Shetland Islands yielded 586 responses (46 per cent response rate). The principal aim of the survey was to gather information on the history and control of scrapie. Overall, 28.5 per cent of the respondents thought they had had a case of scrapie in their flock at some time. There was a slow increase in the proportion of affected flocks during the 1970s, followed by a more rapid increase during the 1980s and early 1990s, and a decline from the mid-1990s onwards. The peak proportion of affected flocks was approximately 6 per cent in 1994. Of the farmers who had ever had scrapie in their flock, 97.1 per cent had attempted to control the disease. The most common method of control was breeding from non-susceptible tups, used by 90.6 per cent of the affected flocks and 75.1 per cent of the flocks that had never been affected. A comparison of the characteristics of the affected and unaffected flocks indicated that an increased risk of scrapie was associated with the larger flocks, the open flocks and the flocks that bought in lambs. The basic reproduction ratio for the spread of scrapie between flocks was estimated to be 1.47, and the mean duration of an outbreak within a flock was estimated to be approximately two years.
Assuntos
Criação de Animais Domésticos/métodos , Surtos de Doenças/veterinária , Scrapie/epidemiologia , Animais , Cruzamento/métodos , Surtos de Doenças/prevenção & controle , Surtos de Doenças/estatística & dados numéricos , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Fatores de Risco , Scrapie/transmissão , Estações do Ano , Ovinos , Conglomerados Espaço-Temporais , Inquéritos e Questionários , Reino Unido/epidemiologiaRESUMO
An anonymous postal survey was conducted in 2002 to estimate the proportion of farms in Great Britain affected with scrapie and to gather information on the likely risk factors for the occurrence of the disease; the response rate was 53 per cent. The survey showed that 1 per cent of the respondents thought they had had scrapie in their flock in the previous 12 months, and that 12 per cent thought they had had scrapie in the past. The results of the survey were consistent with the results of a similar survey carried out in 1998, and with notification patterns, but in 1998 approximately 3 per cent of farmers reported having had scrapie in the previous 12 months. It is not clear whether the apparent decrease in the prevalence of scrapie is real or whether it may be due to factors such as sampling biases, or to the increasing knowledge of the signs of scrapie shown by the respondents in 2002.
Assuntos
Scrapie/epidemiologia , Scrapie/prevenção & controle , Animais , Cabras , Incidência , Vigilância da População , Scrapie/etiologia , Ovinos , Inquéritos e Questionários , Reino Unido/epidemiologiaRESUMO
Between October 2001 and January 2003 the prion protein (PrP) genotypes of over 250,000 sheep were determined through the operation of the National Scrapie Plan (NSP); the results for 38 breeds were analysed to provide an estimate of the underlying PrP genotype distribution of the British sheep population. Although there was marked variability among the genotype profiles of the different breeds, several trends emerged. A comparison of the allele frequencies demonstrated that the breeds could be grouped into three categories: breeds dominated by ARR and ARQ in which the frequency of ARR exceeded the frequency of ARQ; breeds dominated by ARR and ARQ in which the frequency of ARQ exceeded the frequency of ARR; and breeds with significant levels of either AHQ, ARH or VRQ. Hill breeds were more likely to have a lower proportion of animals at low risk of scrapie (NSP type 1) and a higher proportion of animals at an intermediate risk of scrapie (NSP type 3) than other breeds. Most breeds had a small proportion of animals at high risk of scrapie (NSP type 5). The frequency of ARR/VRQ (NSP type 4) was variable.
Assuntos
Príons/genética , Scrapie/epidemiologia , Ovinos/genética , Animais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Masculino , Fatores de Risco , Scrapie/genética , Reino Unido/epidemiologiaRESUMO
Agonists and antagonists of gamma-aminobutyric acid, i.e. GABAergic drugs, such as muscimol, baclofen or bicuculline, alone or in combination, exhibited analgesic effects per se and enhanced the analgesia induced by morphine. The analgesic effects of GABAergic drugs were unaffected by administration of naloxone in a dose which antagonized the analgesia induced by morphine. The ED50 for the antinociceptive effect of muscimol, bicuculline, picrotoxin, gabaculline or aminooxyacetic acid (AOAA) was not affected in the morphine-tolerant group as compared to the control group, in contrast to the increase in the ED50 for morphine under similar conditions; this indicated that there was no development of cross-tolerance between morphine and GABAergic drugs. Muscimol suppressed the abrupt withdrawal-jumping induced by morphine and enhanced the suppression of this phenomenon by morphine. The GABAergic drugs also shared with morphine the property of inhibiting gastrointestinal (GIT) motility. Naloxone reversed the inhibition of motility induced by morphine but failed to influence that induced by GABAergic drugs. In the morphine-tolerant state, the sensitivity of gastrointestinal motility to morphine decreased, whereas, the sensitivity to GABAergic drugs remained unaltered. The results indicate that GABAergic drugs share some of the classical properties of morphine, such as analgesia and inhibition of gastrointestinal motility, but they probably do so by different mechanisms.
Assuntos
Analgesia , Baclofeno/farmacologia , Bicuculina/farmacologia , Digestão/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Digestório , Morfina/farmacologia , Muscimol/farmacologia , Nociceptores/fisiologia , Oxazóis/farmacologia , Ácido gama-Aminobutírico/fisiologia , Ácido Amino-Oxiacético/farmacologia , Animais , Ácidos Cicloexanocarboxílicos/farmacologia , Sistema Digestório/efeitos dos fármacos , Tolerância a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naloxona/farmacologia , Picrotoxina/farmacologiaRESUMO
This study attempted to distinguish between mu (morphine) and delta [(D-Ala2-D-Leu5)-enkephalin; DADLE] receptors, with regard to both in vivo effects (analgesia and gastrointestinal motility) and the location of binding activity in the brain. Analgesia and motility are distinguishable both by dose (intracerebroventricular) and by ligand selectivity with mu ligands more potent for the former and delta for the latter. Tolerance and cross-tolerance are exhibited for both effects, with the relationships between mu and delta ligand potencies preserved. In vitro receptor binding revealed an affinity decrease for delta in medulla and an increase in medulla and diencephalon for mu receptors after tolerance development to morphine. The results indicate that the mu receptors in medulla and diencephalon mediate analgesia, while medullary delta receptors control motility.
Assuntos
Analgesia , Encéfalo/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Entorpecentes/farmacologia , Receptores Opioides/fisiologia , Animais , Tolerância a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfina/farmacologia , Receptores Opioides delta , Receptores Opioides muRESUMO
The present study examined the modulatory role of dopamine (DA) on striatonigral preprotachykinin (PPT) and prodynorphin (PD) gene expression, employing the DA uptake inhibitor, GBR-12909 (GBR), as a tool. The striatal and nigral levels of tachykinin (substance P (SP), neurokinin A (NKA)) and dynorphin (dynorphin A(1-8) (DYN)) peptides were determined by radioimmunoassays. The abundance of mRNAs in the striatum was quantified by Northern blot analysis. The rate of transcription of PPT and PD genes in the striatum was measured by transcription run-on assays. A regimen of repeated administration of GBR (20 mg/kg/day, i.p., for 1-4 days) to female Sprague-Dawley rats increased striatal and nigral SP, NKA, and DYN peptide levels. The increased peptide levels were associated with increases in the abundance of PD mRNA and PPT mRNA and increases in the rate of transcription of PD and PPT genes in the striatum, suggesting a GBR-induced activation of the striatonigral tachykinin and dynorphin neurons. Dopaminergic denervation with 6-hydroxydopamine (6OHDA) blocked the GBR-induced increases in SP and DYN and PPT and PD mRNAs. The concurrent administration of the D1 DA antagonist, SCH-23390, blocked the GBR-induced increases in SP, NKA and PPT mRNA but failed to affect DYN or PD mRNA levels; the concurrent administration of the D2 DA antagonist, spiperone, blocked the GBR-induced increases in SP, NKA and PPT mRNA and also DYN and PD mRNA. The study reveals that repeated administration of GBR enhances the levels of tachykinin and dynorphin peptides in striatonigral neurons by a stimulus-transcription-biosynthesis coupling mechanism. The GBR-induced effects are dependent on the integrity of nigrostriatal dopaminergic neurons and the presence of D1 and/or D2 DA receptors.
Assuntos
Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Dopamina/fisiologia , Encefalinas/biossíntese , Regulação da Expressão Gênica , Piperazinas/farmacologia , Precursores de Proteínas/biossíntese , Substância Negra/metabolismo , Taquicininas/biossíntese , Transcrição Gênica/efeitos dos fármacos , Animais , Núcleo Celular/metabolismo , Corpo Estriado/efeitos dos fármacos , Denervação , Relação Dose-Resposta a Droga , Dinorfinas/biossíntese , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cinética , Especificidade de Órgãos , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacosRESUMO
The analgesic effect of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin (DADLE), leuenkephalin, metenkephalin, and beta-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was beta-endorphin greater than morphine = DAM greater than DADLE greater than ketocyclazocine = leuenkephalin = metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and beta-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine = DADLE = beta-endorphin greater than DAM = ketocyclazocine = metenkephalin greater than leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.
Assuntos
Analgésicos/farmacologia , Endorfinas/farmacologia , Morfina/farmacologia , Receptores Opioides/efeitos dos fármacos , Animais , Tolerância a Medicamentos , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores Opioides/metabolismo , Receptores Opioides delta , Receptores Opioides kappa , Receptores Opioides muRESUMO
This study examined whether a relationship exists between the degree of dopamine (DA) loss and the changes in opioid (Met5-enkephalin, ME; dynorphin A (1-8) (DYN)) or tachykinin (substance P, SP) peptidergic systems in basal ganglia (caudate and putamen) and limbic (frontal cortex) regions of postmortem tissue samples derived from patients who died of Parkinson's disease (PD). The levels of ME, SP and DYN were determined by radioimmunoassays. The levels of DA and 5-hydroxytryptamine (5-HT) and their metabolites were determined by HPLC with electrochemical detection. The degree of loss of DA in PD tissues was classified into two major categories, those with less than 80% and those with more than 80% loss as compared to control. The results reveals that only the category with greater than 80% DA loss exhibited lower levels of ME in caudate and SP in putamen whereas no differences were observed in the levels of DYN in these regions. The frontal cortical region exhibited no changes in the levels of peptides. In other studies, experimental DA deficiency in rodents induced by neurotoxin such as 6-hydroxydopamine (6-OHDA) produced an increase in ME and a decrease in SP in basal ganglia. However, the levels of both peptides were lower in postmortem Parkinsonian basal ganglia in the present study. It appears that there is a DA-dependent, secondary loss of enkephalin and tachykinin peptides in PD. In view of the involvement of these peptidergic systems in the regulation of behaviour, movement, memory and other functions, derangements in these systems should be considered as additional factors in the progression of symptoms of PD.
Assuntos
Núcleo Caudado/metabolismo , Dopamina/metabolismo , Encefalinas/metabolismo , Doença de Parkinson/metabolismo , Putamen/metabolismo , Substância P/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Cromatografia Líquida de Alta Pressão , Dinorfinas/metabolismo , Lobo Frontal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Radioimunoensaio , Ratos , Serotonina/metabolismoRESUMO
This study examined the influence of selected monoamine oxidase (MAO) inhibitors on basal ganglia neurotransmitters (dopamine and 5-hydroxytryptamine) and neuropeptide (dynorphin) systems of Sprague-Dawley rats. The striatum or substantia nigra or both were used for biochemical determinations. The striatal concentrations of DA, 5-hydroxytryptamine (5-HT) and their metabolites were determined by HPLC. The levels of striatal and nigral dynorphin A (1-8) (DYN) were determined by radioimmunoassay. The abundance of striatal prodynorphin (PD) mRNA was determined by Northern blot analysis using a cRNA probe. Deprenyl, a MAO-B selective inhibitor (0.25, 0.5, 5, 10 or 20 mg/kg/day, subcutaneously (s.c.) for 4 d) and clorgyline, a MAO-A inhibitor (0.5, 5, 10 or 20 mg/kg/day, s.c. for 4 d) produced a dose-related increase in DA and 5-HT and a decrease in their metabolites in the striatum. Only high doses (20 mg/kg) of deprenyl or clorgyline induced an increase in DYN levels in the striatum and substantia nigra (DYN terminal region); the increased level of DYN was accompanied by an increase in PD-mRNA levels in striatum (DYN cell-body region). Co-administration of low doses (2.5 mg/kg/day, s.c. for 4 d) of deprenyl and clorgyline, that would selectively inhibit MAO-B and MAO-A respectively, produced a marked increase in DA and 5-HT, a decrease in DOPAC and 5-HIAA, an increase in DYN levels in the striatum and substantia nigra and an increase in PD-mRNA levels in the striatum. The results indicate that concurrent inhibition of MAO-B and MAO-A, that results in markedly elevated levels of DA and 5-HT in the striatum, is associated with an increase in dynorphin biosynthesis in the striatonigral neurons.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Dinorfinas/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Clorgilina/farmacologia , Corpo Estriado/metabolismo , Ácido Hidroxi-Indolacético/análise , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Selegilina/farmacologia , Substância Negra/metabolismoRESUMO
This study examined whether the postnatal development of the biosynthesis of an opioid peptide, dynorphin A (1-8) (DYN) is influenced by dopamine (DA) deficiency. The neurotoxin 6-hydroxydopamine (6-OHDA) was used as a tool to induce DA deficiency on the third day of the postnatal period in Sprague-Dawley rat pups. During the postnatal period, the levels of striatal DYN steadily increased in an age-dependent fashion and appeared to peak between 35 and 45 days. In neonatal 6-OHDA-lesioned animals, the category with 95% or more DA loss exhibited a reduction in the levels of DYN in the postnatal period whereas the category with less than 95% DA loss did not show significant changes in DYN levels. The results indicate that the normal development of striatal DYN is negatively affected only when there is a near-total loss of DA during early postnatal period.
Assuntos
Dopamina/fisiologia , Dinorfinas/fisiologia , Neostriado/citologia , Neostriado/crescimento & desenvolvimento , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Cromatografia Líquida de Alta Pressão , Denervação , Feminino , Neostriado/metabolismo , Oxidopamina/farmacologia , Gravidez , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Simpatolíticos/farmacologiaRESUMO
Repeated administration of the antimanic drug lithium (4 mEq/kg/day for 2, 4 or 6 days, i.p.) to rats produced a progressive decline and eventual depletion of dynorphin-A (1-8) (DYN) concentration whereas Met5-enkephalin (ENK) was only marginally decreased in the neurointermediate lobe of the pituitary (NIL). Administration of a neuroleptic haloperidol neither affected ENK and DYN levels nor influenced lithium-induced changes. The study reveals that lithium produces a preferential perturbation in the dynorphin system relative to the enkephalin system. These results taken together with other evidence, indicate that dynorphin is possibly coreleased with vasopressin following lithium administration and provide a pharmacological support to the previously described colocalization and corelease of these endogenous peptides in the NIL.
Assuntos
Dinorfinas/análise , Encefalinas/análise , Haloperidol/farmacologia , Lítio/farmacologia , Fragmentos de Peptídeos/análise , Hipófise/efeitos dos fármacos , Animais , Masculino , Hipófise/análise , Ratos , Ratos Endogâmicos F344RESUMO
The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.
Assuntos
Corpo Estriado/metabolismo , Dopamina/fisiologia , Encefalina Metionina/metabolismo , Receptores Dopaminérgicos/metabolismo , Automutilação/metabolismo , Substância P/metabolismo , Substância Negra/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Antagonistas de Dopamina , Hidroxidopaminas , Oxidopamina , Ratos , Ratos Endogâmicos , Receptores de Dopamina D1 , Automutilação/fisiopatologia , Substância Negra/efeitos dos fármacos , Substância Negra/fisiopatologiaRESUMO
A regimen of repeated administration of GBR (10 or 20 mg/kg/day, i.p., for 4 days) to female Sprague-Dawley rats induced a dose-and time-related increase in the incidence of self-injurious behavior (SIB) that consisted of injury to body areas, paws and tail. The treatment regimen decreased striatal DA and DOPAC levels. Dopaminergic denervation with 6-hydroxydopamine (6-OHDA) or D1 DA antagonist, SCH-23390 or D2 DA antagonist, spiperone, blocked the GBR-induced SIB. Male rats were less sensitive than female rats to exhibit a comparable incidence of SIB. Taken together, the study reveals that repeated administration of GBR induces SIB that is dependent on the integrity of nigrostriatal dopaminergic system and the presence of D1 and/or D2 DA receptors.
Assuntos
Corpo Estriado/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/fisiologia , Piperazinas/farmacologia , Comportamento Autodestrutivo , Substância Negra/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Benzazepinas/farmacologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Espiperona/farmacologiaRESUMO
This study examined whether dopamine (DA) is necessary for the normal development of striatal enkephalin and striatonigral tachykinin peptide systems. The neurotoxin, 6-hydroxydopamine (6-OHDA) was used to induce DA deficiency on the third day of the postnatal period in Sprague-Dawley rat pups. The animals were sacrificed at 60 days of age. The levels of Met5-enkephalin (ME) and substance P (SP) were determined by radioimmunoassay and preproenkephalin (PPE) and preprotachykinin (PPT) mRNA abundance in the striatum were assessed by hybridization analysis. The concentrations of DA, 5-hydroxytryptamine (5-HT) and their acid metabolites were determined by high-pressure liquid chromatography with electrochemical detection. The lesioned animals were grouped on the basis of the degree of loss of DA, and changes in ME, SP and 5-HT systems were correlated with respect to the degree of DA loss. The nature and extent of the changes in these systems were dependent on the degree of DA depletion. A loss of more than 90% DA was necessary to result in increased levels of ME and its PPE mRNA and reduced levels of SP and its PPT mRNAs; however, increased levels of 5-HT could be observed at a lower degree of DA loss. The results indicate that the normal development of enkephalin and tachykinin and 5-HT systems of basal ganglia are dependent on the availability of DA and/or the integrity of the nigrostriatal dopaminergic neurons. The results are relevant to our further understanding of the neurobiology of DA deficiency disorders.
Assuntos
Adaptação Fisiológica/fisiologia , Animais Recém-Nascidos/fisiologia , Gânglios da Base/fisiologia , Dopamina/fisiologia , Neurônios/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Gânglios da Base/efeitos dos fármacos , Monoaminas Biogênicas/fisiologia , Cromatografia Líquida de Alta Pressão , Denervação , Dopamina/metabolismo , Encefalina Metionina/genética , Encefalina Metionina/fisiologia , Feminino , Hidroxidopaminas , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Hibridização de Ácido Nucleico , Oxidopamina , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Endogâmicos , Serotonina/metabolismo , Substância P/genética , Substância P/fisiologiaRESUMO
The purpose of this study was to explore the dopaminergic control of the striatonigral dynorphin system by measuring the levels of dynorphin A1-8-like immunoreactivity (DN-LI) after repeated injections of a dopaminergic receptor agonist or antagonist. Seven daily injections of different doses of apomorphine (0.5, 1.0, 2.5 and 5.0 mg/kg, s.c.) caused a significant dose-related increase of DN-LI in the striatum (26, 34, 63, 85% over control at each corresponding dose). Similar increases were observed in the substantia nigra (22, 52, 50 and 62% over control). In another experiment, rats received 5 mg/kg of apomorphine for 1, 3, and 7 days. There was a significant time-related increase in DN-LI both in the striatum (37, 50 and 85% over control at each corresponding period) and in the substantial nigra (32, 78 and 62%). Repeated administration of haloperidol (1 mg/kg, i.p.) failed to change the striatal level of DN-LI, but, when given at the same time as apomorphine, significantly attenuated the effect of apomorphine. These results suggest that dopamine exerts a modulatory influence on the metabolism of dynorphin in the striatonigral pathway.
Assuntos
Corpo Estriado/análise , Dopamina/fisiologia , Dinorfinas/análise , Fragmentos de Peptídeos/análise , Substância Negra/análise , Animais , Apomorfina/farmacologia , Corpo Estriado/fisiologia , Haloperidol/farmacologia , Masculino , Ratos , Ratos Endogâmicos F344 , Substância Negra/fisiologia , Transmissão SinápticaRESUMO
The influence of chronic activation of the gamma-aminobutyric acid (GABA) system on dopaminergic function was evaluated in male rats. Activation of the GABA system was achieved by raising the brain concentration of GABA with aminooxyacetic acid (AOAA), a GABA-transaminase (GABA-T) inhibitor. Repeated i.p. injection (40 or 80 mg/kg/day for 8 days) of AOAA produced a sustained elevation of GABA concentration in the striatum. Beginning 26 h following the last dose of a regimen of AOAA treatment (80 mg/kg/day for 8 days), the animals exhibited a characteristic spontaneous 'sham-fighting' behavioral stereotypy which peaked at 34 h after the last dose of AOAA; this spontaneous behavior dissipated by 38 h postdose. When challenged with apomorphine, the sham-fighting behavior was interspersed with intense fighting episodes; these precipitated behaviors were evident for up to 2 weeks posttreatment observation period. Animals given a lower dose of AOAA (40 mg/kg/day X 8) did not show signs of spontaneous sham-fighting, but responded with fighting upon apomorphine challenge. Qualitatively similar behavioral effects were obtained when gamma-acetylenic GABA (30 mg/kg/day, i.p. for 8 days) was used as the inhibitor of GABA-T. Measurement of dopamine and its acid metabolites in the striatum showed an enhanced turnover of dopamine during the spontaneous behavioral response, suggesting a rebound phenomenon. The levels of 5-hydroxytryptamine or its acid metabolite or neuroactive amino acids such as glutamate, aspartate, taurine, glycine, glutamine in the striatum were not altered by any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Gânglios da Base/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Aminoácidos/metabolismo , Ácido Amino-Oxiacético/farmacologia , Animais , Comportamento Animal/fisiologia , Corpo Estriado/metabolismo , Interações Medicamentosas , Resistência a Medicamentos , Masculino , Ratos , Ratos Endogâmicos F344 , Serotonina/metabolismo , Fatores de TempoRESUMO
The aim of this study was to understand the possible influence of the antimanic drug, lithium, and the neuroleptic, haloperidol, alone or in combination, on the regulation of dynorphin biosynthesis in the striatum. The study was done using male Fisher-344 rats subjected to a regimen of subchronic administration of lithium chloride (4 mEq/kg/day for 1,2,4 or 6 days, i.p.) or a regimen of chronic oral administration of a diet containing lithium carbonate (1.5 g/kg of the diet). Subchronic administration of lithium increased striatal dynorphin A(1-8)-like immunoreactivity (DN-LI) in a time-related fashion. Immunocytochemistry revealed an increase in DN-LI in fibers and cells clustered in 'patches' throughout striatum. The increase in DN-LI was reversible on cessation of lithium administration. Concurrent administration of lithium and an opiate antagonist, naltrexone, or a dopamine receptor antagonist, haloperidol, did not influence the changes induced by lithium. Chronic oral administration of lithium for 21 days led to an increase in DN-LI in the striatum. Co-administration of haloperidol with the 21 day regimen of lithium administration failed to affect the increase in DN-LI. The prodynorphin mRNA abundance in the striatum was quantitated by a molecular hybridization procedure using a prodynorphin 32P-cRNA probe generated from the Riboprobe system. Evidence from the Northern blot analysis reveals that lithium increases the prodynorphin mRNA abundance in the striatum. These results indicate that lithium affects the dynamics of prodynorphin biosynthesis in the striatum, presumably increasing transcription and/or translational processes.