RESUMO
Amphetamine (AMPH) abuse is a serious public health problem due to the high addictive potential of this drug, whose use is related to severe brain neurotoxicity and memory impairments. So far, therapies for psychostimulant addiction have had limited efficacy. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have shown beneficial influences on the prevention and treatment of several diseases that affect the central nervous system. Here, we assessed the influence of fish oil (FO), which is rich in n-3 PUFA, on withdrawal and relapse symptoms following re-exposure to AMPH. Male Wistar rats received d,l-AMPH or vehicle in the conditioned place preference (CPP) paradigm for 14 days. Then, half of each experimental group was treated with FO (3 g/kg, p.o.) for 14 days. Subsequently, animals were re-exposed to AMPH-CPP for three additional days, in order to assess relapse behavior. Our findings have evidenced that FO prevented relapse induced by AMPH reconditioning. While FO prevented AMPH-induced oxidative damages in the prefrontal cortex, molecular assays allowed us to observe that it was also able to modulate dopaminergic cascade markers (DAT, TH, VMAT-2, D1R and D2R) in the same brain area, thus preventing AMPH-induced molecular changes. To the most of our knowledge, this is the first study to show a natural alternative tool which is able to prevent psychostimulant relapse following drug withdrawal. This non-invasive and healthy nutraceutical may be considered as an adjuvant treatment in detoxification clinics.
Assuntos
Anfetamina/toxicidade , Ácidos Graxos Ômega-3/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Ácidos Graxos/metabolismo , Óleos de Peixe/farmacologia , Masculino , Córtex Pré-Frontal/metabolismo , Carbonilação Proteica , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Comportamento Espacial/efeitos dos fármacosRESUMO
The dentate gyrus (DG) is a neurogenic structure that exhibits functional and structural reorganization after injury. Neurogenesis and functional recovery occur after brain damage, and the possible relation between both processes is a matter of study. We explored whether neurogenesis and the activation of new neurons correlated with DG recovery over time. We induced a DG lesion in young adult rats through the intrahippocampal injection of kainic acid and analyzed functional recovery and the activation of new neurons after animals performed a contextual fear memory task (CFM) or a control spatial exploratory task. We analyzed the number of BrdU+ cells that co-localized with doublecortin (DCX) or with NeuN within the damaged DG and evaluated the number of cells in each population that were labelled with the activity marker c-fos after either task. At 10 days post-lesion (dpl), a region of the granular cell layer was devoid of cells, evidencing the damaged area, whereas at 30 dpl this region was significantly smaller. At 10 dpl, the number of BrdU+/DCX+/c-fos positive cells was increased compared to the sham-lesion group, but CFM was impaired. At 30 dpl, a significantly greater number of BrdU+/NeuN+/c-fos positive cells was observed than at 10 dpl, and activation correlated with CFM recovery. Performance in the spatial exploratory task induced marginal c-fos immunoreactivity in the BrdU+/NeuN+ population. We demonstrate that neurons born after the DG was damaged survive and are activated in a time- and task-dependent manner and that activation of new neurons occurs along functional recovery.
Assuntos
Giro Denteado/lesões , Giro Denteado/patologia , Rememoração Mental/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Mapeamento Encefálico , Bromodesoxiuridina , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Giro Denteado/diagnóstico por imagem , Proteína Duplacortina , Agonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Ácido Caínico/toxicidade , Masculino , Rememoração Mental/efeitos dos fármacos , Microscopia Confocal , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The rewarding properties of drugs in zebrafish can be studied using the conditioned place preference (CPP) paradigm. Most devices that have been used for CPP consist of two-half tanks with or without a central chamber. Here we evaluated the rewarding effects of nicotine and caffeine using a tank with five arms distributed radially from a central chamber that we have denoted Fish Tank Radial Maze (FTRM). Zebrafish were trained to associate nicotine or caffeine with a coloured arm. In testing sessions to assess CPP induction, between two and five different arms were available to explore. We found that when offering the two arms, one of them associated to the drug mediating conditioning for 14â¯days, zebrafish showed nicotine-induced CPP but not caffeine-induced CPP. When zebrafish had the option to explore drug-paired arms together with new coloured arms as putative distractors, the nicotine-CPP strength was maintained for at least three days. The presence of novel environments induced caffeine-CPP, which was still positive after three days of testing sessions. Complementary behavioural data supported these findings. Nicotine-CPP was prevented by the histone deacetylase inhibitor phenylbutyrate administered during conditioning; however, there were no effects on caffeine-CPP. The specific acetylation of lysine 9 in histone 3 (H3-K9) was increased in nicotine-conditioned zebrafish brains. This study suggests that novel environmental cues facilitate drug-environment associations, and hence, the use of drugs of abuse.
Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Acetilação/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Testes Neuropsicológicos , Fenilbutiratos/farmacologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Peixe-ZebraRESUMO
BACKGROUND: In studies that measure social behavior of a freely interacting pair rats social behavior of one rat is strongly influenced by the behavior of the other. This prevents evaluating social behavior of one single rat. NEW METHOD: We assessed the motivation to interact socially in a modified open-field, by measuring the time a rat attempted to interact with a co-specific separated by a grid in a birdcage outside of the apparatus. We propose time in front of the birdcage is an indicator of social behavior. RESULTS: We showed that the focal rat allocates more time in front of the birdcage, interacting with another rat through the grid. Also, that the presence of the other rat that attracts the focal rat. Habituation to the apparatus, repeated testing and illumination condition did not alter the proximity measures of rats. Finally, treatment with chlordiazepoxide (3.0mg/kg) either increased the time spent in front of the cage by males and females or (5.6mg/kg) increased the proximity measure of females. COMPARING WITH EXISTING METHOD: Our method prevents partners from influencing the target rat's social behavior; existing methods do not. Also, it is more sensitive to the effect of chlordiazepoxide than the broadly used method proposed by File and Hyde (1978). CONCLUSIONS: Proximity is an advantageous measure: it allows the assessment of only one focal animal without the interference of a partner; it is simple to take; it requires little interpretation skills or training from the experimenter, no special equipment or conditions.
Assuntos
Comportamento Animal , Modelos Psicológicos , Ratos Wistar/psicologia , Comportamento Social , Comportamento Espacial , Animais , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Feminino , Habituação Psicofisiológica , Iluminação , Masculino , Motivação/efeitos dos fármacos , Testes Psicológicos , Psicotrópicos/farmacologia , Distribuição Aleatória , Reprodutibilidade dos Testes , Comportamento Espacial/efeitos dos fármacos , Fatores de TempoRESUMO
Pain and anxiety are common symptoms in head and neck cancer patients. The anticonvulsant pregabalin has therapeutic indication for the treatment of pain and anxiety, and may represent a useful drug for both conditions. Thus, the aim of this study was to investigate the relationship between pain and anxiety in rats with facial carcinoma, as the influence of pregabalin treatment in both aspects. Facial carcinoma was induced by subcutaneous inoculation of Walker-256 tumor cells in the vibrissa pad of Wistar rats. On day 6 after inoculation spontaneous facial grooming and conditioned place preference were assessed as non-evoked pain measurements and facial mechanical hyperalgesia were assessed 3 and 6 days after tumor cells inoculation. Moreover, anxiety-like behavior was evaluated on the elevated plus maze and light-dark transition tests at the same time points. The effect of pregabalin treatment (30 mg/kg, p.o.) was evaluated in all tests. Our results demonstrated that pregabalin treatment reduced the spontaneous facial grooming and induced conditioned place preference 6 days post tumor inoculation. Tumor-bearing rats developed mechanical hyperalgesia starting 3 days post tumor induction, which was also significant on day 6, but the anxiety-like behavior was detected only in tumor-bearing rats that developed mechanical hyperalgesia and only six days after tumor cells inoculation. Both, the mechanical hyperalgesia and the anxiety-like behavior related to the tumor were significantly reduced by pregabalin treatment on day 6. Pregabalin treatment resulted in antinociceptive and anxiolytic-like effects on facial tumor-bearing rats and may represent a promising therapeutic option for cancer patients.
Assuntos
Analgésicos/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Neoplasias Faciais/tratamento farmacológico , Dor Facial/tratamento farmacológico , Pregabalina/farmacologia , Animais , Ansiedade/fisiopatologia , Dor do Câncer/tratamento farmacológico , Dor do Câncer/fisiopatologia , Linhagem Celular Tumoral , Condicionamento Psicológico/efeitos dos fármacos , Neoplasias Faciais/fisiopatologia , Neoplasias Faciais/psicologia , Dor Facial/fisiopatologia , Asseio Animal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Transplante de Neoplasias , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Ratos Wistar , Comportamento Espacial/efeitos dos fármacos , Tato , VibrissasRESUMO
The neuropsychopharmacological basis of fear- or panic-related behavior has been the focus of several studies. Some mesencephalic tectum (MT) structures, such as the superior colliculus (SC) and dorsal periaqueductal gray matter (dPAG), are considered to be responsible for the control of defensive responses evoked during threatening situations. Furthermore, the pars reticulata of the substantia nigra (SNpr) sends inputs to the SC that can work as a sensory channel to MT neurons fundamental for the elaboration of defensive responses. The purpose of the present study was to investigate the role of striato-nigral GABAergic inputs in the activity of nigro-tectal outputs during the elaboration of defensive behavior using a GABA(A) receptor selective blockade in the MT of mice confronted pre-treated with Bothrops alternatus. Mice with injections of physiological saline into the SNpr and treated with a GABA(A) receptor selective antagonist in the MT displayed an increase in panic-related behavior, expressed by an increase in the duration of freezing, frequency of nonoriented escape and frequency of total escape responses during the confrontation with the snake. However, intra-SNpr injections of cobalt chloride followed by MT injections of bicuculline caused a significant decrease in the duration of freezing and total escape responses. In addition, intra-SNpr injections of lidocaine followed by MT injections of bicuculline caused an increase in panic-related behavior. The results highlight the involvement of SNpr and MT structures in the organization of defensive behaviors and suggest an inhibitory control of striatonigral-nigrotectal pathways during the elaboration of fear- and panic-related behavior.
Assuntos
Corpo Estriado/fisiologia , Reação de Fuga/fisiologia , Pânico/fisiologia , Substância Negra/fisiologia , Teto do Mesencéfalo/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Bothrops , Corpo Estriado/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Pânico/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Substância Negra/efeitos dos fármacos , Teto do Mesencéfalo/efeitos dos fármacosRESUMO
The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 µmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1ß, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1ß and TNF-α levels. Concomitantly, MMA increased levels of IL-1ß, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Erros Inatos do Metabolismo dos Aminoácidos/psicologia , Córtex Cerebral/metabolismo , Mediadores da Inflamação/metabolismo , Transtornos da Memória/induzido quimicamente , Ácido Metilmalônico/toxicidade , Comportamento Espacial/efeitos dos fármacos , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Córtex Cerebral/imunologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/metabolismo , Ácido Metilmalônico/administração & dosagem , Neuroimunomodulação , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
The brain is extremely vulnerable to teratogenic insults during the brain growth spurt, a period that starts during the third trimester of human gestation and is characterized by synaptogenesis establishment of neuronal circuits. While the treatment of epilepsy during pregnancy increases the risk of neurodevelopmental disorders in offspring, the consequences of exposure to anticonvulsants during the brain growth spurt remain poorly known. Here we investigate whether exposure to sodium valproate (VPA) during a similar period in rats impairs spatial learning of juvenile rats. Long-Evans rats were exposed to VPA (200mg/kg) or saline solution (SAL) every other day between postnatal day (PN) 4 and PN10. At PN23 and PN30, Morris water maze performance was evaluated during 6 consecutive days. In the group of animals which started their tests at PN23, the VPA exposure impaired both, swimming speed and learning/memory performance. Interestingly, no differences were observed between VPA and control animals tested from PN30 to PN35. Our data suggests that the neurobehavioral deficits caused by VPA exposure during the brain growth spurt are transitory.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Aprendizagem em Labirinto/efeitos dos fármacos , Ácido Valproico/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/fisiologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Long-Evans , Maturidade Sexual , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Taxa de Sobrevida , Fatores de TempoRESUMO
We recently reported that early undernourishment and seizures to the rat brain resulted in morphological changes and progressive learning and memory disability, which started at around 6 week later and is representative of human adolescence. The purpose of the present study was to examine whether enriched environmental can recovery this slowly progressing deficits in early undernourished and in two different models for seizures. Undernourished groups were maintained on a nutritional deprivation regimen from post-natal day 2 (P2) to P15. From P8 to P10, recurrent seizures (RS) groups were exposed to three seizures per day, while status epilepticus (SE) groups experienced status epilepticus at P16, both induced by flurothyl. Next, animals were exposed to enriched environment between P30 and P60. Beginning at P61, all groups were trained and tested in the Morris water maze (MWM). Enriched environment led to a significant benefit in learning and retention of visual-spatial memory, being able to reverse the cognitive impairment generated by undernourishment and SE.
Assuntos
Meio Ambiente , Desnutrição/complicações , Aprendizagem em Labirinto/fisiologia , Retenção Psicológica/fisiologia , Convulsões , Comportamento Espacial/fisiologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Convulsivantes/toxicidade , Modelos Animais de Doenças , Feminino , Flurotila/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Ratos , Tempo de Reação , Retenção Psicológica/efeitos dos fármacos , Convulsões/complicações , Convulsões/etiologia , Convulsões/enfermagem , Comportamento Espacial/efeitos dos fármacos , Fatores de TempoRESUMO
The aim of this study was to characterize the interaction of adenosine A1-receptor and cannabinoid CB1-receptor antagonists in the water maze and object-location tasks, and to evaluate the participation of glutamatergic neurotransmission in the hippocampus in the learning enhancement induced by the coadministration of both antagonists. Our results show that coadministration of ineffective doses of DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (an A1-receptor antagonist) and AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (a CB1-receptor antagonist) in different proportions enhanced the acquisition of spatial learning. N-methyl-D-aspartate receptor blockade disrupted the effects of the selected drug combination [AM251 0.25 mg/kg intraperitoneally (i.p.)+DPCPX 0.30 mg/kg i.p.] either in the water maze or in the object-location task. Moreover, this drug combination induced a significant ex-vivo enhancement in glutamate release into hippocampal slices. In addition, the blockade of N-methyl-D-aspartate receptors with MK-801 (0.25 µg/site) infused into the hippocampal CA1 area reversed the effects of coadministration, as evaluated in the object-location task. In conclusion, this is the first study to show that A1-receptor and CB1-receptor antagonists might interact on hippocampal neurons to enhance spatial memory in mice.