RESUMO
The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3ß), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3ß activity was determined by the GSK3ß ratio (rGSKß). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3ß activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons.
Assuntos
Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Neurônios/efeitos dos fármacos , Proteínas tau/metabolismo , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Cloreto de Lítio/administração & dosagem , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos WistarRESUMO
Lithium is administered for the treatment of mood and bipolar disorder. The aim of this study was to verify whether treatment with different concentrations of lithium may affect the glycogen metabolism in the salivary glands of the rats when compared with the liver. Mobilization of glycogen in salivary glands is important for the process of secretion. Two sets of experiments were carried out, that is, in the first, the rats received drinking water supplemented with LiCl (38,25 and 12 mM of LiCl for 15 days) and the second experiment was carried out by intraperitoneal injection of LiCl solution (12 mg/kg and 45 mg LiCl/kg body weight) for 3 days. The active form of glycogen phosphorylase was not affected by treatment with LiCl considering the two experiments. The active form of glycogen synthase presented higher activity in the submandibular glands of rats treated with 25 and 38 mM LiCl and in the liver, with 25 mM LiCl. Glycogen level was higher than that of control in the submandibular glands of rats receiving 38 and 12 mM LiCl, in the parotid of rats receiving 25 and 38 mM, and in the liver of rats receiving 12 mM LiCl. The absolute value of glycogen for the submandibular treated with 25 mM LiCl, and the liver treated with 38 mM LiCl, was higher than the control value, although not statistically significant for these tissues. No statistically significant difference was found in the submandibular and parotid salivary glands for protein concentration when comparing experimental and control groups. We concluded that LiCl administered to rats influences the metabolism of glycogen in salivary glands.
Assuntos
Antimaníacos/farmacologia , Glicogênio/metabolismo , Cloreto de Lítio/farmacologia , Glândula Parótida/efeitos dos fármacos , Glândula Submandibular/efeitos dos fármacos , Administração Oral , Animais , Antimaníacos/administração & dosagem , Relação Dose-Resposta a Droga , Glicogênio Fosforilase/metabolismo , Glicogênio Sintase/metabolismo , Injeções Intraperitoneais , Cloreto de Lítio/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Glândula Parótida/metabolismo , Ratos Wistar , Glândula Submandibular/metabolismoRESUMO
Taste memory depends on motivational and post-ingestional consequences after a single taste-illness pairing. During conditioned taste aversion (CTA), the taste and visceral pathways reach the nucleus of the solitary tract (NTS), which is the first relay in the CNS and has a vital function in receiving vagal chemical stimuli and humoral signals from the area postrema that receives peripheral inputs also via vagal afferent fibers. The specific aim of the present set of experiments was to determine if the NTS is involved in the noradrenergic and glutamatergic activation of the basolateral amygdala (BLA) during CTA. Using in vivo microdialysis, we examined whether chemical NTS stimulation induces norepinephrine (NE) and/or glutamate changes in the BLA during visceral stimulation with intraperitoneal (i.p.) injections of low (0.08 M) and high (0.3 M) concentrations of lithium chloride (LiCl) during CTA training. The results showed that strength of CTA can be elicited by chemical NTS stimulation (Ringer's high potassium solution; 110 mM KCl) and by intra-NTS microinjections of glutamate, immediately after, but not before, low LiCl i.p. injections that only induce a week aversive memory. However visceral stimulation (with low or high i.p. LiCl) did not induce significantly more NE release in the amygdala compared with the NE increment induced by NTS potassium depolarization. In contrast, high i.p. concentrations of LiCl and chemical NTS stimulation induced a modest glutamate sustained release, that it is not observed with low LiCl i.p. injections. These results indicate that the NTS mainly mediates the visceral stimulus processing by sustained releasing glutamate in the BLA, but not by directly modulating NE release in the BLA during CTA acquisition, providing new evidence that the NTS has an important function in the transmission of signals from the periphery to brain systems that process aversive memory formation.
Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Memória/efeitos dos fármacos , Núcleo Solitário/metabolismo , Paladar/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Injeções Intraperitoneais , Cloreto de Lítio/administração & dosagem , Cloreto de Lítio/farmacologia , Masculino , Microdiálise , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/efeitos dos fármacos , Estimulação QuímicaRESUMO
RATIONALE: Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder. OBJECTIVE: The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions. METHODS: MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing. RESULTS: MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing. CONCLUSIONS: Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium's relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms.
Assuntos
Eletrocoagulação/efeitos adversos , Hipercinese/tratamento farmacológico , Cloreto de Lítio/administração & dosagem , Agitação Psicomotora/tratamento farmacológico , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/patologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Ansiedade/psicologia , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/psicologia , Eletrocoagulação/métodos , Hipercinese/patologia , Hipercinese/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agitação Psicomotora/patologia , Agitação Psicomotora/psicologia , Comportamento Estereotipado/efeitos dos fármacos , Resultado do TratamentoRESUMO
Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.
Assuntos
Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Animais , Aprendizagem por Associação/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Cloreto de Lítio/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Fatores de TempoRESUMO
The aim of this study was to examine the effects of GSK-3 ß inhibitors compared with PRE and POS in spontaneously hypertensive rats (SHR). Isolated hearts were submitted to the following protocols: IC: 45 min global ischemia (GI) and 1-hour reperfusion (R); PRE: a cycle of 5 min GI and 10 minutes of R prior to 45 min GI; POS: three cycles of 30 sec GI/30 sec R at the start of R. Other hearts received lithium chloride (LiCl) or indirubin-3'-monoxime,5-iodo-(IMI) as GSK-3 ß inhibitors. All interventions reduced the infarct size observed in IC group. The expressions of P-GSK-3 ß and P-Akt decreased in IC and were restored after PRE, POS, and GSK-3 ß inhibitors treatments. An increase of cytosolic MnSOD activity and lipid peroxidation and a decrease of GSH content observed in IC hearts were attenuated in PRE, POS, and LiCl or IMI treatments. An increase of P-GSK-3 ß /VDAC physical association and a partial recovery of mitochondrial permeability were also detected after interventions. These data show that, in SHR hearts, GSK-3 ß inhibitors mimic the cardioprotection afforded by PRE and POS and suggest that a decrease in mitochondrial permeability mediated by P-GSK-3 ß /VDAC interaction is a crucial event.
Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Técnicas de Cultura de Órgãos/métodos , Traumatismo por Reperfusão/genética , Animais , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Hipertensão/patologia , Indóis/administração & dosagem , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico , Peroxidação de Lipídeos/genética , Cloreto de Lítio/administração & dosagem , Oximas/administração & dosagem , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Two experiments explored whether forgetting of an association depended on previous extinction of a different association in rats. Experiment 1 found that when rats were conditioned and extinguished with flavor X, a subsequently acquired conditioned aversion to flavor Y was reduced by a 19-day retention interval, something that did not occur when X and the US were initially presented unpaired. Experiment 2 found that when rats received training and extinction in one of two tasks (conditioned aversion to sucrose in Experiment 2a, and running for water in a straight alley in Experiment 2b), subsequent learning of the alternative task was partially forgotten over the 19-day retention interval. These results are similar to those previously found when manipulating physical and conceptual contexts in rats and humans, respectively, and suggest that the passage of time may play a role similar to the one played by the change in physical or conceptual contexts on information retrieval.
Assuntos
Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Retenção Psicológica/fisiologia , Paladar/fisiologia , Animais , Antimaníacos/administração & dosagem , Feminino , Cloreto de Lítio/administração & dosagem , Ratos , Ratos Wistar , Esquema de Reforço , Projetos de Pesquisa , Cloreto de Sódio/administração & dosagem , Sacarose/administração & dosagem , Fatores de TempoRESUMO
A aversão alimentar condicionada é uma técnica que pode ser utilizada em animais para evitar a ingestão de plantas tóxicas. A técnica foi utilizada em uma fazenda para controlar a intoxicação por Turbina cordata e em outra para Ipomoea carnea subsp. fistulosa. Os caprinos eram presos à noite, e na manhã do dia seguinte lhes era ofertada a planta verde, recém-colhida, por dez minutos. Os caprinos que ingerissem qualquer quantidade da planta eram identificados, pesados e tratados com LiCl na dose de 175mg/kg peso vivo através de sonda esofágica. No rebanho da fazenda na que havia T. cordata a técnica foi aplicada a cada dois meses durante o período em que a planta é encontrada. Durante todo o experimento, de dezembro de 2009 a abril de 2011 não ocorreu nenhum novo caso de intoxicação no rebanho e diminuiu gradualmente o número de animais avertidos e a quantidade de planta que ingeriam os mesmos durante o processo de aversão. Na fazenda na que ocorria intoxicação por I. carnea a maioria de rebanho foi avertido em dezembro de 2010, 15-20 dias antes do início das chuvas, e os animais não ingeriram a planta espontaneamente no campo até setembro-outubro de 2011, durante o período da seca, quando havia extrema carência de forragem e iniciaram a ingerir a planta no campo. Posteriormente, apesar de três tratamentos aversivos com 21 dias de intervalo, os animais continuaram a ingerir a planta e ocorreram casos clínicos. A técnica de aversão alimentar condicionada demonstrou ser eficiente e viável para o controle da intoxicação por T. cordata. Para a intoxicação por I. carnea a técnica impediu a ingestão da planta somente durante a época de chuvas, mas não durante a seca, quando há pouca disponibilidade de forragem. A diferença nos resultados com as duas plantas é, aparentemente, resultante das condições epidemiológicas diferentes nas que ocorrem as intoxicações. T. cordata desaparece durante a maior parte do período de seca. A planta rebrota e fica verde durante o fim de seca, quando diminui a oferta de forragem, por curto espaço de tempo, permanecendo verde durante a época de chuvas. I. carnea, por crescer próximas as fontes de água, em áreas húmidas, permanece verde durante todo o período da seca, quando é maior a escassez de forragem, favorecendo desta forma a ingestão da planta pelos animais.
Conditioned food aversion is used to train livestock to avoid the ingestion of toxic plants. This technique was used to control Turbina cordata poisoning in goats in one farm, and to control Ipomoea carnea subsp. fistulosa poisoning in another farm. The goats were penned at night and the next morning the green plants were offered for 10 minutes. Goats that ingested any amount of the plant were treated through a gastric tube with 175mg of LiCl/kg body weight. In the flock in which the poisoning by T. cordata was occurring, the goats were averted every two months during the period that the plant was found in the pastures. During the experiment, from December 2009 to April 2011, new cases of poisoning were not observed, and there was a progressive decrease in the number of goats that ingested the plant and were averted. In the farm where I. carnea poisoning was occurring, most of the goats were averted in December 2010, 15-20 days before the first rains. The goats of this flock did not ingest the plant spontaneously in the field until September-October 2011, when, due to the dry season, there was a severe forage shortage, and the goats started to ingest the plant in the field. Later, despite three aversive treatments with 21 days intervals, the goats continued to ingest the plant and some animals became poisoned. In conclusion, conditioned food aversion was effective in to control intoxication by T. cordata. The technique was also effective in conditioning goats to avoid consuming I. carnea during the rainy season, but not during the dry season, with low forage availability in the field. The differences in these results seem to be due to the epidemiology of both poisonings: T. cordata is senescent and unavailable during most of the dry period, and green biomass is typically available either at the very end of the dry season, for a short period of time, and during the rainy season when there is no shortage of forage. In contrast, I. carnea grows in wet areas near water sources, and stays green during the dry period when there is a lack of other forage.
Assuntos
Animais , Cloreto de Lítio/administração & dosagem , Comportamento Alimentar , Comportamento Alimentar , Ipomoea/toxicidade , Ovinos/imunologia , Convolvulaceae/toxicidade , Intoxicação por Plantas/veterinária , Swainsonina/toxicidadeRESUMO
A aversão alimentar condicionada é uma técnica que pode ser utilizada em animais para evitar a ingestão de plantas tóxicas. A técnica foi utilizada em uma fazenda para controlar a intoxicação por Turbina cordata e em outra para Ipomoea carnea subsp. fistulosa. Os caprinos eram presos à noite, e na manhã do dia seguinte lhes era ofertada a planta verde, recém-colhida, por dez minutos. Os caprinos que ingerissem qualquer quantidade da planta eram identificados, pesados e tratados com LiCl na dose de 175mg/kg peso vivo através de sonda esofágica. No rebanho da fazenda na que havia T. cordata a técnica foi aplicada a cada dois meses durante o período em que a planta é encontrada. Durante todo o experimento, de dezembro de 2009 a abril de 2011 não ocorreu nenhum novo caso de intoxicação no rebanho e diminuiu gradualmente o número de animais avertidos e a quantidade de planta que ingeriam os mesmos durante o processo de aversão. Na fazenda na que ocorria intoxicação por I. carnea a maioria de rebanho foi avertido em dezembro de 2010, 15-20 dias antes do início das chuvas, e os animais não ingeriram a planta espontaneamente no campo até setembro-outubro de 2011, durante o período da seca, quando havia extrema carência de forragem e iniciaram a ingerir a planta no campo. Posteriormente, apesar de três tratamentos aversivos com 21 dias de intervalo, os animais continuaram a ingerir a planta e ocorreram casos clínicos. A técnica de aversão alimentar condicionada demonstrou ser eficiente e viável para o controle da intoxicação por T. cordata. Para a intoxicação por I. carnea a técnica impediu a ingestão da planta somente durante a época de chuvas, mas não durante a seca, quando há pouca disponibilidade de forragem. A diferença nos resultados com as duas plantas é, aparentemente, resultante das condições epidemiológicas diferentes nas que ocorrem as intoxicações. T. cordata desaparece durante a maior parte do período de seca. A planta rebrota e fica verde durante o fim de seca, quando diminui a oferta de forragem, por curto espaço de tempo, permanecendo verde durante a época de chuvas. I. carnea, por crescer próximas as fontes de água, em áreas húmidas, permanece verde durante todo o período da seca, quando é maior a escassez de forragem, favorecendo desta forma a ingestão da planta pelos animais.(AU)
Conditioned food aversion is used to train livestock to avoid the ingestion of toxic plants. This technique was used to control Turbina cordata poisoning in goats in one farm, and to control Ipomoea carnea subsp. fistulosa poisoning in another farm. The goats were penned at night and the next morning the green plants were offered for 10 minutes. Goats that ingested any amount of the plant were treated through a gastric tube with 175mg of LiCl/kg body weight. In the flock in which the poisoning by T. cordata was occurring, the goats were averted every two months during the period that the plant was found in the pastures. During the experiment, from December 2009 to April 2011, new cases of poisoning were not observed, and there was a progressive decrease in the number of goats that ingested the plant and were averted. In the farm where I. carnea poisoning was occurring, most of the goats were averted in December 2010, 15-20 days before the first rains. The goats of this flock did not ingest the plant spontaneously in the field until September-October 2011, when, due to the dry season, there was a severe forage shortage, and the goats started to ingest the plant in the field. Later, despite three aversive treatments with 21 days intervals, the goats continued to ingest the plant and some animals became poisoned. In conclusion, conditioned food aversion was effective in to control intoxication by T. cordata. The technique was also effective in conditioning goats to avoid consuming I. carnea during the rainy season, but not during the dry season, with low forage availability in the field. The differences in these results seem to be due to the epidemiology of both poisonings: T. cordata is senescent and unavailable during most of the dry period, and green biomass is typically available either at the very end of the dry season, for a short period of time, and during the rainy season when there is no shortage of forage. In contrast, I. carnea grows in wet areas near water sources, and stays green during the dry period when there is a lack of other forage.(AU)
Assuntos
Animais , Ovinos/imunologia , Comportamento Alimentar , Comportamento Alimentar , Cloreto de Lítio/administração & dosagem , Ipomoea/toxicidade , Intoxicação por Plantas/veterinária , Convolvulaceae/toxicidade , Swainsonina/toxicidadeRESUMO
Lithium is a drug widely used to treat bipolar disorder. It has been shown to inhibit the total activity of phosphoglucomutase (PGM) from rat brains. In this work, we show that lithium inhibits in vitro PGM activity in the cortex, hippocampus, striatum, brainstem and cerebellum. As a compensatory effect, chronic lithium treatment of Wistar rats for 6 weeks caused a 1.6-fold upregulation of cortex PGM activity. No difference was observed in the other areas tested. Another effect of chronic lithium administration was a drastic reduction of glycogen content in rat brains, as PGM activity is essential for its synthesis. In a primary culture of astrocytes, which are the main cellular components of the brain that produce glycogen, administration of 1mM lithium for 3 days markedly reduced the steady state of glycogen content. In agreement with this result, lithium did not cause insulin-like effects as previously observed in hepatocytes where lithium activated glycogen synthesis. Reduction of glycogen content was due to inhibition of glycogen synthesis, as incorporation of [(14)U(-)C]-glucose into glycogen was impaired by lithium. Consistent with these results, incubation of glucose-starved astrocytes with lithium did not stimulate dephosphorylation of glycogen synthase, which normally occurs with re-feeding of glucose. Furthermore, in a chronically treated astrocyte culture, glycogen synthase was phosphorylated constitutively. Our results indicate that chronic lithium treatment can inhibit glycogen synthesis in brain suggesting that this effect might contribute to lithium's therapeutic effect.
Assuntos
Antimaníacos/farmacologia , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Glicogênio/biossíntese , Cloreto de Lítio/farmacologia , Animais , Antimaníacos/administração & dosagem , Astrócitos/metabolismo , Encéfalo/metabolismo , Células Cultivadas , Glicogênio Sintase/antagonistas & inibidores , Cloreto de Lítio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfoglucomutase/antagonistas & inibidores , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255%, or 0.383% of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255% lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50% higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.
Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Cloreto de Lítio/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Animais , Antimaníacos/sangue , Transtorno Bipolar/sangue , Feminino , Cloreto de Lítio/sangue , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255 percent, or 0.383 percent of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255 percent lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50 percent higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.
OBJETIVO: Além de ser usado há décadas para tratar distúrbio bipolar, o lítio, mais recentemente, demonstrou-se eficaz para Alzheimer, síndrome de Down, processos isquêmicos e excitotoxicidade mediada por glutamato. Contudo, a estreita janela terapêutica do lítio limita seu uso. Portanto, o estabelecimento de métodos preditivos de dose torna-se importante. MÉTODO: O desempenho de ratos Wistar adultos foi avaliado no campo aberto e labirinto em cruz elevado após seis semanas de tratamento com uma ração suplementada com 0,255 por cento ou 0,383 por cento de cloreto de lítio ou ração normal. Coletou-se amostras de sangue para dosagem plasmática do lítio. RESULTADOS: Os animais alimentados com a ração com 0,255 por cento de cloreto de lítio fizeram mais rearing no campo aberto e tiveram uma maior freqüência de entradas nos braços do labirinto elevado que os animais que ingeriram a dose mais alta. Apesar disso, verificou-se níveis plasmáticos de lítio semelhantes em ambos os grupos. DISCUSSÃO: A variação nos comportamentos destarte a presença de níveis plasmáticos semelhantes sugere que as diferentes doses produziram diferentes concentrações cerebrais não detectadas pela medida plasmática. CONCLUSÃO: Medidas da concentração plasmática de lítio não permitem prever de forma completa seus efeitos comportamentais.
Assuntos
Animais , Feminino , Masculino , Ratos , Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Cloreto de Lítio/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Antimaníacos/sangue , Transtorno Bipolar/sangue , Cloreto de Lítio/sangue , Ratos WistarRESUMO
Addiction profoundly alters motivational circuits so that drugs become powerful reinforcers of behavior. The interoceptive system continuously updates homeostatic and emotional information that are important elements in motivational decisions. We tested the idea that interoceptive information is essential in drug craving and in the behavioral signs of malaise. We inactivated the primary interoceptive cortex in amphetamine-experienced rats, which prevented the urge to seek amphetamine in a place preference task. Interoceptive insula inactivation also blunted the signs of malaise induced by acute lithium administration. Drug-seeking and malaise both induced Fos expression, a marker of neuronal activation, in the insula. We conclude that the insular cortex is a key structure in the perception of bodily needs that provides direction to motivated behaviors.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Comportamento Aditivo , Comportamento Animal , Córtex Cerebral/fisiologia , Fadiga/induzido quimicamente , Cloreto de Lítio/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Condicionamento Psicológico , Dextroanfetamina/administração & dosagem , Lidocaína/administração & dosagem , Lidocaína/farmacologia , Cloreto de Lítio/administração & dosagem , Masculino , RatosRESUMO
The ability of the crayfish Procambarus clarkii to develop a food aversion learning was examined. For this purpose, in crayfishes fed with trout, a novel food (chicken) was associated in a single trial with a well-known toxic substance, lithium chloride (LiCl), and food intake was recorded for 10 days afterward using a two-choice protocol. All during the experimental period, a significant effect of treatment was observed that accounted for the lower chicken intake in the LiCl-treated group, compared with the control groups (NaCl-treated group and puncture group). In contrast, LiCl-treated animals had an increased trout intake during the entire period. In addition, it was observed that total food intake was similar among the three groups. These results indicate that the crayfish may develop a food aversion learning when illness is induced by LiCl after the animal accepts and eats a novel food.
Assuntos
Astacoidea/fisiologia , Aprendizagem da Esquiva/fisiologia , Ingestão de Alimentos/fisiologia , Cloreto de Lítio/administração & dosagem , Análise de Variância , Animais , Astacoidea/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Galinhas , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/fisiologia , Injeções , TrutaRESUMO
We studied the effect of treating rats with lithium salts on the content and in vitro phosphorylation rate of the astrocyte cell marker, glial fibrillary acidic protein (GFAP), in brain slices. Rats were fed a diet incorporating lithium chloride until the concentration of Li+ in serum reached 0.6-1.2 mM, a range similar to that achieved in clinical practice. Hippocampal tissue was analyzed for immunoreactive GFAP by a dot assay, and slices of hippocampus and caudate nucleus were labeled with [32P]phosphate to determine the in vitro rate of phosphorylation of GFAP. Compared with controls, the level of immunoreactive GFAP in the hippocampus from lithium-treated rats was increased 34%, and GFAP in hippocampal slices incorporated 39% more 32P. This effect of lithium was apparently not confined to the hippocampus because the in vitro rate of phosphorylation of GFAP in caudate slices was also increased in the treated rats.
Assuntos
Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Cloreto de Lítio/farmacologia , Animais , Autorradiografia , Núcleo Caudado/metabolismo , Esquema de Medicação , Eletroforese em Gel Bidimensional , Eletroforese em Gel de Poliacrilamida , Proteína Glial Fibrilar Ácida/análise , Proteína Glial Fibrilar Ácida/isolamento & purificação , Hipocampo/efeitos dos fármacos , Immunoblotting , Cloreto de Lítio/administração & dosagem , Fosfatos/metabolismo , Radioisótopos de Fósforo , Ratos , Ratos Wistar , Valores de ReferênciaRESUMO
1. The effect of chronic lithium (Li) administration in a learned helplessness (LH) model was investigated. Female Wistar rats (190-210 g) received either tap water ad libitum (N = 56) or 20 mM LiCl (N = 63) in the drinking water or were water restricted (35% based on lower liquid intake of rats receiving lithium, N = 40) for 30 days. On the 28th day, each of these groups was divided into three subgroups which received escapable (ES), inescapable (IS) or no shock (NS) treatment in shuttle boxes. All groups were submitted to the escape test on the 29th day and sacrificed on the 30th day, when blood samples were taken for measurement of serum lithium, sodium and potassium concentrations. 2. The NS group had lower serum Li levels (0.36 +/- 0.06, N = 15) than the ES (0.46 +/- 0.07, N = 15) or IS group (0.44 +/- 0.09, N = 25). The Li-pretreated group subjected to IS had a more effective escape performance than the IS group under water restriction and showed the same behaviour as animals not submitted to shocks. 3. We conclude that chronic treatment with Li at a serum level of 0.44 +/- 0.09 mEq/l prevents learned helplessness in rats. These results corroborate the validity of the use of this model for the assessment of the capacity of Li to protect against some depressive episodes.
Assuntos
Desamparo Aprendido , Cloreto de Lítio/administração & dosagem , Animais , Depressão/prevenção & controle , Feminino , Lítio/sangue , Lítio/farmacocinética , Análise Multivariada , Potássio/sangue , Ratos , Ratos Wistar , Sódio/sangue , Fatores de TempoRESUMO
1. The effect of chronic lithium (Li) administration in a learned helplessness (LH) model was investigated. Female Wistar rats (190-210 g) received either tap water ad libitum (N = 56) or 20 mM LiCl (N = 63) in the drinking water or were water restricted (35 per cent based on lower liquid intake of rats receiving lithium, N = 40) for 30 days. On the 28th day, each of these groups was divided into three subgroups which received escapable (ES), inescapable (IS) or no shock (NS) treatment in shuttle boxes. All groups were submitted to the escape test on the 29th day and sacrificed on the 30th day, when blood samples were taken for measurement of serum lithium, sodium and potassium concentrations. 2. The NS group had lower serum Li levels (0.36 +/- 0.06, N = 15) than the ES (0.46 +/- 0.07, N = 15) or IS group (0.44 +/- 0.09, N = 25). The Li-pretreated group subjected to IS had a more effective escape performance than the IS group under water restriction and showed the same behaviour as animals not submitted to shocks. 3. We conclude that chronic treatment with Li at a serum level of 0.44 +/- 0.09 mEq/l prevents learned helplessness in rats. These results corroborate the validity of the use of this model for the assessment of the capacity of Li to protect against some depressive episodes