Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

TORRES, F ; FILHO, M.S. ; ANTUNES, C. ; KALININE, E. ; ANTONIOLLI, E. ; PORTELA, Luis Valmor ; SOUZA, Diogo Onofre ; TORT, A. B. L. . Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model. Experimental Neurology , v. 221, p. 296-306, 2010

Determination of the highest no-effect dose (HNED) and of the elimination pattern for cocaine in horses

Cocaine is one of the most widespread illegal stimulants utilized by the human population throughout the world. The aim of this study was to establish the highest no-effect dose (HNED) of cocaine on the spontaneous locomotor activity (SLA) of horses in a behavior chamber, and thereby to determine the maximal acceptable threshold of the urinary drug concentration in horses. Twelve English thoroughbred mares received 0.02, 0.03, 0.04, 0.08 or 0.12 mg kg(-1) cocaine i.v. or saline solution (control). It was noted that doses above 0.04 mg kg(-1) induced a significant increase in SLA (P < 0.05, Tukey's test). No significant increase in SLA was seen in the mares that received 0.03 mg kg(-1), but the animals showed important behavioral changes that did not occur after the 0.02 mg kg(-1) dose. It was concluded that the HNED of cocaine for horses in a behavior chamber is 0.02 mg kg(-1). After injection of this dose in five horses, urine samples were collected at predetermined intervals through vesical catheterization. The concentrations of cocaine, norcocaine, benzoylecgonine and ecgonine methyl ester were quantified by liquid chromatography/electrospray ionization tandem mass spectrometry. Cocaine and norcocaine concentrations remained consistently below the level of detection. Benzoylecgonine reached a mean (+/- SEM) maximum concentration of 531.9 +/- 168.7 ng ml(-1) after 4 h, whereas ecgonine methyl ester peaked 2 h after injection at a concentration of 97.2 +/- 26.5 ng ml(-1). The maximum admissible concentration for cocaine and/or metabolites in the urine of horses is difficult to establish unequivocally because of the substantial individual variation in the drug elimination pattern observed in horses, which can be inferred by the large standard error of the means obtained. Copyright (C) 2002 John Wiley Sons, Ltd.

Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats

Despite the high prevalence of tobacco abuse among adolescents, the neurobiology of nicotine addiction has been studied mainly in adult animals. Repeated administration of this drug to adult rats induces behavioral sensitization. Nicotine activates the HPA axis in adult rats as measured by drug-induced increases in ACTH and corticosterone. Both behavioral sensitization and corticosterone are implicated in drug addiction. We examined the expression of behavioral sensitization induced by nicotine as well as the changes in corticosterone levels after repeated injections of nicotine in adolescent and adult animals. Adolescent and adult rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for 7 days. Three days after the last injection animals were challenged with saline or nicotine (0.4 mg/kg; s.c.). Nicotine-induced locomotion was recorded in an activity cage. Trunk blood samples were collected in a subset of adolescent and adult rats and plasma corticosterone levels were determined by radioimmunoassay. Adult, but not adolescent, rats expressed behavioral sensitization. Pretreatment with nicotine abolished corticosterone-activating effect of this drug only in adult animals, indicating the development of tolerance at this age. Our results provide evidence that adolescent rats exposed to repeated nicotine display behavioral and neuroendocrine adaptations distinct from that observed in adult animals. (c) 2004 Elsevier B.V. All rights reserved.

Effects of intra-hippocampal infusion of WAY-100635 on plus-maze behavior in mice - Influence of site of injection and prior test experience

The positive profile of systemically-administered 5-HT(1A) receptor antagonists in several rodent models of anxiolytic activity suggests an important role for postsynaptic 5-HT(1A) receptor mechanisms in anxiety. To test this hypothesis, we investigated the effects of WAY-100635 microinfusions (0, 0.1, 1.0 or 3.0 mug in 0.2 mul) into the dorsal (DH) or ventral (VH) hippocampus an behaviours displayed by male Swiss-Webster mice in the elevated plus-maze. As prior experience is known to modify pharmacological responses in this test, the effects of intra-hippocampal infusions were examined both in maze-naive and maze-experienced subjects. Test videotapes were scored for conventional indices of anxiety (% open arm entries/time) and locomotor activity (closed arm entries), as well as a range of ethological measures (e.g. risk assessment). In maze-naive mice, intra-VH (but not intra-M) infusions of WAY-100635 (3.0 mug but not lower doses) increased open arm exploration and reduced risk assessment. These effects were observed in the absence of significant changes in locomotor activity. In contrast, neither intra-VH nor intra-DH infusions of WAY-100635 altered the behaviour of maze-experienced mice. These Findings suggest that postsynaptic 5-HT(1A) receptors in the ventral (but not dorsal) hippocampus play a significant role both in the mediation of plus-maze anxiety in mice and in experientially-induced alterations in responses to this test. (C) 2002 Elsevier B.V. BY All rights reserved.

Mutagenic activity promoted by amentoflavone and methanolic extract of Byrsonima crassa Niedenzu

Byrsonima crassa is a plant pertaining to the Brazilian central savannah-like belt of vegetation and popularly used for the treatment of gastric dysfunctions and diarrhoea. The methanol extract contains catechin, tannins, terpenes and flavonoids; both mutagenic potential and antioxidant properties have been ascribed to flavonoids. The mutagenicity of some flavonoids is believed to be associated with the formation of reactive oxygen species and seems to depend on the number and position of hydroxyl groups. In the present study the mutagenic activity of the methanol, chloroform and 80% aqueous methanol extracts, as well as acetate and aqueous sub-fractions, of this medicinal plant were evaluated by Salmonella typhimurium assay, using strains 100, TA98, TA102 and TA97a, and in mouse reticulocytes. The results showed mutagenic activity of the methanolic extract in the TA98 strain without S9, but no mutagenicity to mouse cells in any of the extracts. The acetate fraction showed strong signs of mutagenicity without S9, suggesting that in this enriched fraction were concentrated the compounds that induced mutagenic activity. The aqueous fraction showed no mutagenic activity. The TLC and HSCCC analyses of the acetate fraction with some standard compounds permitted the isolation of the quercetin-3-O-beta-D-galactopyranoside, quercetin-3-O-alpha-L-arabinopyranoside, amentoflavone, methyl gallate and (+)-catechin, of which only the amentoflavone exhibited positive mutagenicity to TA98 (+S9, -S9). (c) 2006 Elsevier B.V.. All rights reserved.

Effect of cocaine on periadolescent rats with or without early maternal separation

Cocaine-induced behavioral sensitization and weight loss were investigated in periadolescent Wistar rats kept with their mothers or subjected to repeated maternal separation. Litters allocated to the separation procedure were placed in a temperature-controlled (33ºC) chamber for 3 h per day from postnatal day 6 (P6) to P20. Non-handled rats were left undisturbed until weaning. Treatments were started on P30-31 and the test was performed on P36-37. Animals received injections of saline or cocaine (10 mg/kg, sc) twice daily for 5 days. on day 6 all animals received saline. on day 7 animals were challenged with 10 mg/kg cocaine and their locomotion was evaluated in activity cages. A third group received saline throughout the 7-day period. Body weights were recorded on P30-31 and P36-37. Two-way ANOVA on body weights showed a main effect of treatment group (F(1,35) = 10.446, P = 0.003; N = 10-12). Non-handled rats treated with cocaine for 5 days gained significantly less weight, while no significant effect was observed in maternally separated rats. Two-way ANOVA revealed a main effect of drug treatment on locomotor activity (F(2,32) = 15.209, P<0.001; N = 6-8), but not on rearing condition (F(1,32)<0.001, P = 0.998). Animals pretreated with cocaine showed a clear behavioral sensitization relative to the saline group. No difference in the magnitude of sensitization was found between separated and non-handled animals. Only the effect of cocaine on weight gain was significantly affected by repeated episodes of early maternal separation during the pre-weaning period.

Behavioral and neuroendocrine effects of the exposure to chronic restraint or variable stress in early adolescent rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Stress induces behavioral sensitization, increases nicotine-seeking behavior and leads to a decrease of CREB in the nucleus accumbens

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Participação da neurotransmissão dopaminergica no efeito hiperlocomotor do neuropeptideo S

Neuropeptide S (NPS) is an endogenous 20-aminoacid peptide which binds a G protein-coupled receptor named NPSR. This peptidergic system is involved in the modulation of several biological functions, such as locomotion, anxiety, nociception, food intake and motivational behaviors. Studies have shown the participation of NPSR receptors in mediating the hyperlocomotor effects of NPS. A growing body of evidence suggests the participation of adenosinergic, dopaminergic and CRF systems on the hyperlocomotor effects of NPS. Considering that little is known about the role of dopaminergic system in mediating NPS-induced hyperlocomotion, the present study aims to investigate the locomotor actions of intracerebroventricular (icv) NPS in mice pretreated with α-metil-p-tirosine (AMPT, inhibitor of dopamine synthesis), reserpine (inhibitor of dopamine vesicle storage) or sulpiride (D2 receptor antagonist) in the open field test. A distinct group of animals received the same pretreatments described above (AMPT, reserpine or sulpiride) and the hyperlocomotor effects of methylphenidate (dopamine reuptake inhibitor) were investigated in the open field. NPS and methylphenidate increased the mouse locomotor activity. AMPT per se did not change the locomotion of the animals, but it partially reduced the hyperlocomotion of methylphenidate. The pretreatment with AMPT did not affect the psychostimulant effects of NPS. Both reserpine and sulpiride inhibited the stimulatory actions of NPS and methylphenidate. These findings show that the hyperlocomotor effects of methylphenidate, but not NPS, were affected by the pretreatment with AMPT. Furthermore, methylphenidate- and NPS-induced hyperlocomotion was impaired by reserpine and sulpiride pretreatments. Together, data suggests that NPS can increase locomotion even when the synthesis of catecholamines was impaired. Additionally, the hyperlocomotor effects of NPS and methylphenidate depend on monoamines vesicular storaged, mainly dopamine, and on the activation of D2 receptors. The psychostimulant effects of NPS via activation of dopaminergic system display clinical significance on the treatment of diseases which involves dopaminergic pathways, such as Parkinson s disease and drug addiction

O Tratamento com a fluoxetina (mas não com outros farmacos antidepressivo e ansioíiticos) reverte o déficit de memória aversiva causado por estresse agudo de contenção em camundongos

The physiologist H. Selye defined stress as the nonspecific response of the body to any factors that endanger homeostasis (balance of internal environment) of the individual. These factors, agents stressors, are able to activate the Hypothalamic-Pituitary-Adrenal (HPA) axis, thus resulting in the physiological responses to stress by the release of glucocorticoids that leads to psychophysiological changes, including effects on cognitive functions such as learning and memory. When this axis is acutely stimulated occurs a repertoire of behavioral and physiological changes can be adaptive to the individual. Notwithstanding, when the HPA axis is chronically stimulated, changes may favor the development of, such as anxiety disorders. Some drugs used in the clinic for the treatment of anxiety disorders these can exert effects on cognitive function, on the HPA axis and on the anxiety. In this context, the aim of our study was to investigate the effects of administration i.p. acute of diazepam (DZP, 2 mg/kg), buspirone (BUS, 3 mg/kg), mirtazapine (MIR, 10 mg/kg) and fluoxetine (FLU, 10 mg/kg) in male mice submitted to acute restraint stress, and evaluated using plus-maze discriminative avoidance task (PMDAT), which simultaneously evaluates parameters such as learning, memory and anxiety. Our results demonstrated that (1) the administration of DZP and BUS, but not FLU, promoted anxiolytic effects in animals; (2) administration mirtazapine caused sedative effect to animals; (3) in the training session, the animals treated with BUS, MIR and FLU learned the task, on the other hand DZP group showed impairment in learning; (4) in the test session, animals treated with DZP, BUS, and MIR showed deficits in relation to discrimination between the enclosed arms, aversive versus non-aversive arm, demonstrating an impairment in memory, however, animals treated with FLU showed no interference in the retrieval of this memory; (5) acute stress did not interfere in locomotor activity, anxiety, or learning on the learning task, but induced impairment in retrieval memory, and the group treated with FLU did not demonstrated this deficit of memory . These results suggest that acute administration of drugs with anxiolytic and antidepressant activity does not interfere with the learning process this aversive task, but impair its retrieval, as well as the acute restraint stress. However, the antidepressant fluoxetine was able to reverse memory deficits promoted by acute stress, which may suggest that modulation, even acutely serotonergic neurotransmission, by selectively inhibiting the reuptake of this neurotransmitter, interferes on the process of retrieval of an aversive memory

Effects of extracts from Brazilian sun-mushroom (Agaricus blazei) on the NK activity and lymphoproliferative responsiveness of Ehrlich tumor-bearing mice

Agaricus blazei Murrill, is an edible and medicinal mushroom which is popularly consumed due to its antitumoral properties. The immunomodulatory effects of methanol (METH), dichloromethane (DM) and n-hexane (HEX) extracts of this mushroom were evaluated in Ehrlich tumor-bearing mice. Subcutaneous inoculation of Ehrlich tumor cells inhibited the natural killer (NK) activity of spleen cells (specific lysis = 6.18 +/- 2.56%) compared with normal mice (17.59 +/- 7.77%). Treatment of tumor-bearing mice with the extracts for 10 days restored the natural killer activity against Yac-1 target cells and the best results were observed by treatment with the HEX extract (21.48 +/- 15.26%). Treatment of the animals with the HEX extract for 10 days was also able to stimulate the mitogen-induced lymphoproliferative activity of spleen cells. Thirty days after the treatment, all groups presented low proliferative activity. Specific antibody production was observed to be higher in the groups treated with the DM or METH extract 30 days after the treatment. Analysis of the 3 extracts by gas chromatography mass spectrum (GCMS) and magnetic nuclear resonance (MNR) showed that the HEX extract contains mainly sugar and fatty acids and that the METH extract also contains sugar and possibly amino acids. (C) 2004 Elsevier Ltd. All rights reserved.

Energy substrate utilization during nightly vocal activity in three species of Scinax (Anura/Hylidae)

Anuran amphibians exhibit different patterns of energy substrate utilization that correlate with the intensity of vocal and locomotor activities. Given the remarkable differences among species in breeding and feeding strategies, and the different ways energy is used in the whole animal, the suggested correlations between calling and locomotor behavior and the level of energy substrates in the muscles responsible for such activities are more complex than previously reported. We explored the relationships between calling and locomotor behavior and energy supply to trunk and hindlimb muscles, respectively, within the ecologically diverse tree-frog genus Scinax. Specifically, we measured the relative amount of carbohydrates and lipids in these two groups of muscles, and in the liver of three species of Scinax that differ in vocal and locomotor performance, and compared our results with those of two other species for which comparable data are available. We also compared the contents of lipids and carbohydrates of conspecific males collected at the beginning and after 4 h of calling activity. The stomach content to potential feeding opportunities across species was also assessed in both groups of males. Scinax hiemalis and S. rizibilis exhibit comparatively low and episodic calling during long periods of activity whereas S. crospedospilus calls at higher rates over shorter periods. Male S. hiemalis had highest levels of trunk muscle glycogen followed by those of S. rizilbilis and S. crospedospilus, respectively. There was no correlation between total lipid content in trunk muscle and calling rate among different species, suggesting that other metabolic aspects may be responsible for the energetic support for vocal activity. The levels of lipids and carbohydrates in trunk and hindlimb muscles and liver of males collected at the beginning and 4 h into the calling period were similar across species, so the extent of energetic reserves does not appear to constrain vocal or locomotor activity. Finally, we found exceptionally high levels of carbohydrates and lipids in the liver of S. rizibilis, a trait perhaps related to a long and demanding breeding period.

Efeito do lítio sobre a hiperatividade locomotora induzida pela lesão eletrolítica da região do núcleo mediano da rafe em ratos

A lesão do núcleo mediano da rafe (NMR) produz sintomas que sugerem validade de face ao episódio maníaco. Esta pesquisa avaliou o efeito do lítio sobre a hiperatividade locomotora induzida por esta lesão. Vinte e um ratos Wistar machos foram submetidos à lesão eletrolítica da região do NMR (LR) e 17 foram submetidos à lesão fictícia (LF). Após recuperação, a atividade locomotora foi avaliada na caixa de atividade (Med Associates/ENV-515). Parte dos animais destes grupos recebeu tratamentos com lítio (47,5 mg/kg/2x dia i.p.) por 10 dias, enquanto o restante foi tratado com salina no mesmo esquema. A reavaliação ao final dos tratamentos demonstrou que o lítio reduziu significantemente a atividade locomotora em relação à avaliação inicial no grupo LR (ANOVA/Bonferroni p < 0,05), tornando-a equivalente aos baixos níveis dos grupos LF. Estes dados sustentam a hipótese de que as manifestações induzidas pela lesão do NMR podem constituir um modelo animal de mania.

Locomotor and metabolic activities of Gymnostreptus olivaceus (Diplopoda, Spirostreptida) at different photoperiod conditions

In the present investigation the locomotor and the metabolic activity of Gymnostreptus olivaceus were studied, using 24-hr cycles at different photoperiods and constant temperature and RH. Locomotor activity was studied by the actography method and was reported as coefficients of nocturnalism [CN (N/N + D). 100]. The results showed a nocturnalism coefficient of 98,71% under normal photoperiod conditions and of 29,58% under inverted photoperiod conditions. In constant illumination, the CN of G. olivaceus was 88,22%, and in constant darkness, its rhythm was close to that of the normal photoperiod (CN = 94,92%). The metabolic activity was studied by manometric Warburg respirometry and lit was reported as mu l O-2 . g(-1). h(-1). The respiratory rate of G. olivaceus under normal photoperiod condition was higher at night than during the day (52,52 x 28,76), coinciding with the pattern of nocturnal locomotor activity of the animal. However, under conditions of inverted photoperiod, the millipede maintained its tendency toward a more intense nocturnal respiratory rate (50,35 x 39,14). Similar behaviours were observed under constant illumination and constant darkness, in which G. olivaceus again presented higher nocturnal respiratory rates than diurnal ones(85,84 x 53,48 and 73,18 x 57,0, respectively). The present experimental data suggests the persistence of an endogenous rhythm where the light may not be an important exogenous synchronizer of the activity of G. olivaceus, because it was insufficient to block the start of the biological clock and the natural tendency of higher nocturnal activities of millipedes, principally when the tests were performed in constant illumination or darkness (free-running tests).

Effects of diethylpropion treatment and withdrawal on aorta reactivity, endothelial factors and rat behavior

Diethylpropion (DEP) is an amphetamine-like compound used as a coadjutant in the treatment of obesity and which presents toxicological importance as a drug of abuse. This drug causes important behavioral and cardiovascular complications; however, the vascular and behavioral alterations during DEP treatment and withdrawal, have not been determined. We evaluated the effects of DEP treatment and withdrawal on the rat aorta reactivity to noradrenaline, focusing on the endothelium, and the rat behavior during DEP treatment and withdrawal. DEP treatment caused a hyporreactivity to noradrenaline in aorta, reversible after 2 days of withdrawal and abolished by both the endothelium removal and the presence of L-NAME, but not by the presence of indomethacin. Furthermore, DEP treatment increased the general activity of rats. Contrarily, DEP withdrawal caused a decrease in the locomotor activity and an increase in grooming behavior, on the 2nd and 7th days after the interruption of the treatment, respectively. DEP treatment also caused an adaptive vascular response to noradrenaline that seems to be dependent on the increase in the endothelial nitric oxide system activity, but independent of prostaglandins synthesis. The data evidenced chronological differences in the adaptive responses of the vascular and central nervous systems induced by DEP treatment. Finally, a reversion of the adaptive response to DEP was observed in the vascular system during withdrawal, whereas a neuroadaptive process was still present in the central nervous system post-DEP. These findings advance on the understanding of the vascular and behavioral pathophysiological processes involved in the therapeutic and abusive uses of DEP. (C) 2003 Elsevier B.V. (USA). All rights reserved.