5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behaviour in mice

It is widely acknowledged that the indoleamine neurotransmitter serotonin (5-HT) plays a dual role in the regulation of anxiety, a role that in part depends upon neuroanatomical locus of action. Thus, whereas stimulation of 5-HT1A or 5-HT2 receptors in the limbic forebrain (amygdala, hippocampus) enhances anxiety-like responding in rodents, activation of corresponding receptor populations in the midbrain periaqueductal grey (PAG) more often than not reduce anxiety-like behaviour. The present study specifically concerns the anxiety-modulating influence of 5-HT2 receptors within the mouse PAG. Experiment 1 assessed the effects of intra-PAG infusions of the 5-HT2B/2C receptor agonist mCPP (0, 0.03, 0.1 or 0.3 nmol/0.1 mu l) on the behaviour of mice exposed to the elevated plus-maze. As mCPP acts preferentially at 5-HT2B and 5-HT2C receptors, Experiment 2 investigated its effects in animals pretreated with ketanserin, a preferential 5-HT2A/2C receptor antagonist. In both cases, test sessions were videotaped and subsequently, scored for anxiety-like behaviour (e.g., percentage of open arm entries and percentage of open arm time) as well as general locomotor activity (closed arm entries). The results of Experiment I showed that mCPP microinfusions (0.03 and 0.1 nmol) into the PAG of mice decreased behavioural indices of anxiety without significantly altering general activity measures. In Experiment 2, the anxiolytic-like profile of intra-PAG mCPP (0.03 nmol) was substantially attenuated by intra-PAG pretreatment with an intrinsically inactive dose of the preferential 5-HT2A/2C receptor antagonist, ketanserin (10 nmol/0.1 mu l). Together, these data suggest that 5HT(2C) receptor populations within the midbrain PAG play an inhibitory role in plus-maze anxiety in mice. (C) 2007 Elsevier B.V. All rights reserved.

Bases neurofisiológicas da dependência do tabaco

A maioria dos estudos pré-clínicos e clínicos aponta a nicotina como o principal agente responsável pelo desenvolvimento da dependência ao tabaco. Muitos trabalhos têm demonstrado que as bases neurais da dependência à nicotina são semelhantes àquelas das outras drogas de abuso. A nicotina induz preferência condicionada por lugar e auto-administração e, portanto, atua como reforçador positivo, esse efeito parece ser mediado pelo sistema dopaminérgico mesolímbico. A nicotina também induz à sensibilização comportamental que é provavelmente resultante de alterações da expressão gênica do núcleo acumbens induzidas pela exposição prolongada a essa substância. A suspensão do uso de nicotina resulta em síndrome de abstinência. As evidências indicam que esses sinais e sintomas sejam mediados por receptores colinérgicos nicotínicos centrais e periféricos. Outros neurotransmissores, como por exemplo a serotonina e os peptídeos opióides, também podem estar envolvidos na mediação da dependência e síndrome de abstinência à nicotina. A revisão da literatura mostra a complexidade dos efeitos da nicotina no organismo. A integração entre as abordagens comportamental, neuroquímica e molecular possibilitará a compreensão dos mecanismos neurais da dependência ao tabaco e fornecerá as bases para o desenvolvimento racional de agentes terapêuticos que possam ser utilizados para o tratamento da dependência e síndrome de abstinência ao tabaco.

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)

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28%, WKY = 64%, 3 days) and (SHR = 141%, WKY = 122%, 13 weeks). SHR had higher values of AP than WKY (174 ± 4 vs 111 ± 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28%, WKY = 36%) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19%, WKY = 15%). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18%, WKY = 19%), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.

Influência da adição de carga na marcha em esteira de crianças com paralisia cerebral hemiparética espástica

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Parametric analyses of anxiety in zebrafish scototaxis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação comportamental e neuroquímica de ratos em dessincronização forçada: possíveis implicações para um modelo animal de oscilações no humor

Bipolar disorder has been growing in several countries. It is a disease with high mortality and has been responsible by the social isolation of the patients. Bipolar patients have alterations in circadian timing system, showing a phase shift in various physiological variables. There are several arguments demonstrating alterations in circadian rhythms may be part of the bipolar disorder pathophysiology. Given the necessity for further elucidation, the goal of this study was to validate the forced desynchronization protocol as an animal model for bipolar disorder. To do this, Wistar rats were submitted to a forced desynchronization protocol which consists in a symmetrical light dark cycle with 22h. Under this protocol, rats dissociate the locomotor activity rhythm into two components: one synchronized to the light / dark cycle with 22h, and another component with period longer than 24 hours following the animal endogenous period. These rhythms with different periods sometimes there is coincidence, which we named CAP (Coincidence Active Phase) and the opposite phase, non-coincidence, called NCAP (Non-Concidence Active Phase). The hypothesis is that in CAP animals present a mania-like behavior and animals in NCAP depressive-like behavior. We found some evidence described in detail throughout this thesis. In sum, the animals under forced desynchronization protocol were more stressed, showed an increase in stereotypic behaviors such as grooming and reduction in other behaviors such as risk assessment and vertical exploration when compared to the control group. The CAP animals showed increased locomotor activity, especially during the dark phase when compared to controls (rats under T24) and less depressive behavior in the forced swim test. The animals in NCAP showed a higher anxiety in elevated plus maze, but they don t have ahnedonia. The animals under dissociation have more labeled 5HT1A cells at the amygdala area, which appoint that they have more amygdala inhibition. Taking these data together, we could partially validated the forced desynchronization protocol as an animal model for mood oscillations

Efeitos da cafeína sobre a memória de saguis (Callithrix jacchus)

Caffeine is considered the most consumed psychostimulant in the world, presenting several central and peripheral effects. In the Central Nervous System the major effect occur by its antagonistic activity at the A1 and A2a subtypes of the adenosine receptors. These receptors are responsible for the slow-wave sleep induction, and their binding, caused by the consumption of foods and beverages that contain caffeine, cause behaviors like increase of alertness, mood and locomotion. The effects of caffeine on memory are still discussed because of the diversity of experimental protocols. Also, it does not have the same effects on all stages of the processing of memory - acquisition, consolidation and recall. Thus, using the marmoset (Callitrhix jacchus) as subject, we aim to evaluate the effects of caffeine on the memory of this primate through the conditioned place preference paradigm, where the animal selects a context by presence of food. This cognitive task consists of five phases. The first phase was two sessions of pre-exposure, in which they were evaluated for preference for any compartment of the apparatus. Then, we proceeded the training, conditioning the animals to the food-present context for 8 days. Then, there was administration of caffeine or placebo (10mg/kg) for 8 consecutive days, during the pre-sleep phase, where the 20 animals were distributed in two groups: placebo and repeated. The forth phase was one day of retraining, a re-exposure of the apparatus to the marmosets followed by the administration of caffeine (for the repeated group and a new group called abstinence) or placebo (for placebo and abstinence groups). Finally, was the test where we evaluated if the subjects learned where the food was present. Moreover, in this work we evaluate the existence of differences between females and males on the task, and the locomotor activity for the experimental groups. The results showed that in the pre-exposure phase the animals were habituated on the apparatus and did not present differences for any contexts. In training, they were able to learn the conditioning task, independent of gender. For the retraining, the two groups exhibited more interactions in rewarded context than that in non-rewarded context. Nevertheless, in the locomotor activity, the repeated group moved similarly in contact with the apparatus and outside of it. In the other hand, the animals of the placebo group moved more when in contact with the apparatus. In the test phase, the marmosets under influence of caffeine presented an increase in the locomotor activity when compared with the placebo group, corroborating works that show this increase in locomotion. In the learning evaluation, the continuous and abstinence groups had a bad performance in the task in relation to the placebo and acute groups. This suggests that the prolonged administration of caffeine disrupts the memories because it affected sleep, which is largely responsible offline processing of memories

O efeito da dessincronização circadiana sobre o metabolismo

The lost of phase relationship between rhythms and behaviour can, and often do, undesirable consequences. The purpose os study was to ascertain the effect of circadian desynchronization in T22 about metabolism of wistar rats. The subjects consisted of 24 animals separated in two groups: control (n=12) T24 with 8 weeks of aged and experimental group (n=12) T22, also with 8 weeks of aged. Both the groups were subject to register of locomotor actitivity, body temperature, body weight and food intake in all the experiment. And more, both the groups were subject to food deprivation, running in treadmill and forced swimming. The results show rhythm of locomotor activity and body temperature desynchronized. Dont exist diference in body weight between both the groups (T24 = 386,75±40,78g e T22 380,83±44,28g) . However, the food intake was different between the phases, light and dark, in intergroup and intragroup. The body temperature was not different in food deprivation. The same ocurred for running in treadmill and forced swimming. Since similar alterations occur in shift workers, it is proposed that the experimental paradigm presented in this manuscript is a useful model of shift work. That is, alterations in activity/rest cycles and consummatory behavior can affect the health of organism

Influência de fotoperíodo artificial no comportamento de um primata neotropical diurno (Callithrix jacchus)

One of the main environmental cues for the adjustment of temporal organization of the animals is the light-dark cycle (LD), which undergoes changes in phase duration throughout the seasons. Photoperiod signaling by melatonin in mammals allows behavioral changes along the year, as in the activity-rest cycle, in mood states and in cognitive performance. The aim of this study was to investigate if common marmoset (Callithrix jacchus) exhibits behavioral changes under short and long photoperiods in a 24h cycle, assessing their individual behaviors, vocal repertoire, exploratory activity (EA), recognition memory (RM) and the circadian rhythm of locomotor activity (CRA). Eight adult marmosets were exposed to a light-dark cycle of 12:12; LD 08:16; LD 12:12 and LD 16:08, sequentially, for four weeks in each condition. Locomotor activity was recorded 24h/day by passive infrared motion detectors above the individual cages. A video camera system was programmed to record each animal, twice a week, on the first two light hours. From the videos, frequency of behaviors was registered as anxiety-like, grooming, alert, hanging position, staying in nest box and feeding using continuous focal animal sampling method. Simultaneously, the calls emitted in the experimental room were recorded by a single microphone centrally located and categorized as affiliative (whirr, chirp), contact (phee), long distance (loud shrill), agonistic (twitter) and alarm (tsik, seep, see). EA was assessed on the third hour after lights onset on the last week of each condition. In a first session, marmosets were exposed to one unfamiliar object during 15 min and 24h later, on the second session, a novel object was added to evaluate RM. Results showed that long days caused a decreased of amplitude and period variance of the CRA, but not short days. Short days decreased the total daily activity and active phase duration. On long days, active phase duration increased due to an advance of activity onset in relation to symmetric days. However, not all subjects started the activity earlier on long days. The activity offset was similar to symmetric days for the majority of marmosets. Results of EA showed that RM was not affected by short or long days, and that the marmosets exhibited a decreased in duration of EA on long days. Frequency and type of calls and frequency of anxiety-like behaviors, staying in nest box and grooming were lower on the first two light hours on long days. Considering the whole active phase of marmosets as we elucidate the results of vocalizations and behaviors, it is possible that these changes in the first two light hours are due to the shifting of temporal distribution of marmoset activities, since some animals did not advance the activity onset on long days. Consequently, the marmosets mean decreased because the sampling was not possible. In conclusion, marmosets synchronized the CRA to the tested photoperiods and as the phase angle varied a lot among marmosets it is suggested that they can use different strategies. Also, long days had an effect on activity-rest cycle and exploratory behaviors

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

Efeitos do tratamento com lítio na memória aversiva, comportamentos relacionados à ansiedade e depressão e na expressão de BDNF em ratos

Lithium (Li) is the first choice to treat bipolar disorder, a psychiatric illness characterized by mood oscillations between mania and depression. However, studies have demonstrated that this drug might influence mnemonic process due to its neuroprotector, antiapoptotic and neurogenic effects. The use of Li in the treatment of cognitive deficits caused by brain injury or neurodegenerative disorders have been widely studied, and this drug shows to be effective in preventing or even alleviating the memory impairment. The effects of Li on anxiety and depression are controversial and the relationship of the effects of lithium on memory, anxiety and depression remain unknown. In this context, this study aims to: evaluate the effects of acute and chronic administration of lithium carbonate in aversive memory and anxiety, simultaneously, using the plus maze discriminative avoidance task (PMDAT); test the antidepressant effect of the drug through the forced swimming test (FS) and analyze brainderived neurotrophic factor (BDNF) expression in structures related to memory and emotion. To evaluation of the acute effects, male Wistar rats were submitted to i.p. administration of lithium carbonate (50, 100 or 200 mg/kg) one hour before the training session (PMDAT) or lithium carbonate (50 or 100 mg/kg) one hour before the test session (FS). To evaluation of the chronic effects, the doses administered were 50 or 100 mg/kg or vehicle once a day for 21 days before the beginning of behavioral tasks (PMDAT and FS). Afterwards, the animals were euthanized and their brains removed and submitted to immunohistochemistry procedure to quantify BDNF. The animals that received acute treatment with 100 and 200 mg/kg of Li did not discriminated between the enclosed arms (aversive and non-aversive) in the training session of PMDAT, showing that these animal did not learned the task. This lack of discrimination was also observed in the test session, showing that the animals did not recall the aversive task. We also observed an increased exploration of the open arms of these same groups, indicating an anxiolytic effect. The same groups showed a reduction of locomotor activity, however, this effect does not seem to be related with the anxiolytic effect of the drug. Chronic treatment with Li did not promote alterations on learning or memory processes. Nevertheless, we observed a reduction of open arms exploration by animals treated with 50 mg/kg when compared to the other groups, showing an anxiogenic effect caused by this dose. This effect it is not related to locomotor alterations since there were no alterations in these parameters. Both acute and chronic treatment were ineffective in the FS. Chronic treatment with lithium was not able to modify BDNF expression in hippocampus, amygdala and pre-frontal cortex. These results suggest that acute administration of lithium promote impairments on learning in an aversive task, blocking the occurrence of memory consolidation and retrieval. The reduction of anxiety following acute treatment may have prevented the learning of the aversive task, as it has been found that optimum levels of anxiety are necessary for the occurrence of learning with emotional context. With continued, treatment the animals recover the ability to learn and recall the task. Indeed, they do not show differences in relation to control group, and the lack of alterations on BDNF expression corroborates this result. Possibly, the regimen of treatment used was not able to promote cognitive improvement. Li showed acute anxiolytic effect, however chronic administration 4 promoted the opposite effect. More studies are necessary to clarify the potential beneficial effect of Li on aversive memory

Avaliação do programa de tutorização da EMATER-RN para servidores em estágio probatório

The present thesis evaluated the contributions and limitations of the tutorship program introduced in EMATER-RN, as a tactic of organizational socialization for civil servants in probationary stage. Tutorship was understood as an intensive and continuous relational process, in which a more experienced person in the organization the tutor offers psychosocial support, stimulates the development of the professional career and enables to the newcomer the tutee learning on job performance. The organizational socialization was considered in the perspective of the symbolic interactionism. The study was characterized as a program evaluation and as an action research. The practical interventions for the program implementation were conducted and, at the same time, the evaluations of process, results and reaction to the program were applied. Among the major contributions of the action research, it stood out: the diagnosis of reasons for the formation of the pair and of expectations of tutors and tutees, the improvement of the tutorship registration tools, the ascertainment of the success of the program in the socialization of the new civil servants, the confirmation of the importance of the compatibility among them and of the adequate performance of tutorship functions for achieving its benefits. Based in constraints of the program, one may quote as essential recommendations: the formation of a technical team supporting the program, the clear establishment of deadlines for each procedure and the reinforcement to its compliance, the investigation of the functions performed by the tutor, the sensitization of the managers to the resolution of problems that affect the program, the voluntary participation of the tutor and the continuous meetings of tutors and tutees. One settles for the relevance of the program and in favor of its continuation, provided that its improvement and systematic management are conducted.

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.