No description available.

No description available.

No description available.

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

A adolescência é caracterizada como um período de grande estresse na vida humana, sendo o bullying um dos principais estressores desencadeantes de distúrbios psiquiátricos. Modelos animais de depressão usam o estresse social prolongado como indutores de depressão. Utilizamos o modelo de subjugação (ou derrota) social prolongada em camundongos machos adolescentes para estudar a regulação do BDNF neste contexto. Os animais submetidos ao estresse psicossocial apresentaram anedonia no teste de preferência por sacarose e esquiva social no teste de interação social. Explorando a variabilidade comportamental, identificamos grupos suscetíveis e resilientes ao estresse. Animais suscetíveis apresentaram uma redução na expressão do transcrito Bdnf4 e dos níveis proteicos de BDNF total e sua isoforma truncada somente no estriado dorsal, área ainda pouco relacionada à depressão, enquanto que não ocorreram alterações no córtex pré-frontal e hipocampo, áreas comumente afetadas durante a depressão. / Adolescence is characterized by a period of life with great amount of stress, being the bullying one of the main stressors leading to psychiatry disorders. Animal models of depression use prolonged social stress to model depression. We used the prolonged social defeat model in adolescent male mice to study BDNF regulation in this context. Defeated mice showed anhedonia in the sucrose preference test, and social avoidance in the social interaction test. We took advantage of the behavioral outcome variability to identify susceptible and resilient groups to the stress. The susceptible mice showed a reduction in Bdnf4 transcripts, and in total BDNF protein levels, as well as its truncated form in the dorsal striatum, a brain area not much related to depression. However, BDNF gene or protein expression did not differ in the prefrontal cortex and hippocampus, areas commonly associated with depression.

A adolescência é caracterizada como um período de grande estresse na vida humana, sendo o bullying um dos principais estressores desencadeantes de distúrbios psiquiátricos. Modelos animais de depressão usam o estresse social prolongado como indutores de depressão. Utilizamos o modelo de subjugação (ou derrota) social prolongada em camundongos machos adolescentes para estudar a regulação do BDNF neste contexto. Os animais submetidos ao estresse psicossocial apresentaram anedonia no teste de preferência por sacarose e esquiva social no teste de interação social. Explorando a variabilidade comportamental, identificamos grupos suscetíveis e resilientes ao estresse. Animais suscetíveis apresentaram uma redução na expressão do transcrito Bdnf4 e dos níveis proteicos de BDNF total e sua isoforma truncada somente no estriado dorsal, área ainda pouco relacionada à depressão, enquanto que não ocorreram alterações no córtex pré-frontal e hipocampo, áreas comumente afetadas durante a depressão. / Adolescence is characterized by a period of life with great amount of stress, being the bullying one of the main stressors leading to psychiatry disorders. Animal models of depression use prolonged social stress to model depression. We used the prolonged social defeat model in adolescent male mice to study BDNF regulation in this context. Defeated mice showed anhedonia in the sucrose preference test, and social avoidance in the social interaction test. We took advantage of the behavioral outcome variability to identify susceptible and resilient groups to the stress. The susceptible mice showed a reduction in Bdnf4 transcripts, and in total BDNF protein levels, as well as its truncated form in the dorsal striatum, a brain area not much related to depression. However, BDNF gene or protein expression did not differ in the prefrontal cortex and hippocampus, areas commonly associated with depression.

Initiation of smoking mainly occurs during adolescence. Adolescents experience more stressful life events; therefore, stress may be a factor that contributes to this high risk of smoking initiation. The current study examines the effects of three different stressors (yohimbine, intermittent footshock and social defeat) on nicotine self-administration (NSA) in adolescent and adult rats. The effects of yohimbine and footshock were examined after the establishment of NSA behavior, while the effect of social defeat was tested on the initiation of NSA behavior. Yohimbine increased NSA, but the other two stressors did not. The increase in NSA induced by yohimbine tended to be higher in adults than in adolescents. No marked age differences in response to the other two stressors were observed. These results suggest that stress increases NSA in a stressor-specific manner, and that adolescents do not show enhanced vulnerability to the effect of stress on NSA.

Initiation of smoking mainly occurs during adolescence. Adolescents experience more stressful life events; therefore, stress may be a factor that contributes to this high risk of smoking initiation. The current study examines the effects of three different stressors (yohimbine, intermittent footshock and social defeat) on nicotine self-administration (NSA) in adolescent and adult rats. The effects of yohimbine and footshock were examined after the establishment of NSA behavior, while the effect of social defeat was tested on the initiation of NSA behavior. Yohimbine increased NSA, but the other two stressors did not. The increase in NSA induced by yohimbine tended to be higher in adults than in adolescents. No marked age differences in response to the other two stressors were observed. These results suggest that stress increases NSA in a stressor-specific manner, and that adolescents do not show enhanced vulnerability to the effect of stress on NSA.

Following social defeat, male hamsters exhibit behavioral changes characterized by a breakdown of normal territorial aggression and an increase in submissive/defensive behaviors in the presence of a non-aggressive intruder (NAI). We have termed this phenomenon conditioned defeat (CD). By contrast, only a small subset of defeated females exhibit submissive/defensive behavior in the presence of a NAI. We hypothesized that fluctuations in gonadal hormones might contribute to differences in the display of submissive behavior in intact female hamsters. Following social defeat, proestrous females (higher endogenous estradiol) were more likely to display conditioned defeat compared with diestrous 1 (lower endogenous estradiol) females. This finding suggests that there is an estrous cycle-dependent fluctuation in the display of CD in female hamsters and suggests that increased estradiol might contribute to increased submissive behavior. We then demonstrated that ovariectomized females given estradiol prior to CD testing exhibited significantly higher submissive behavior in the presence of a NAI suggesting that estradiol increases the expression of CD in female hamsters. We have also shown that castrated males that were singly housed for four weeks displayed significantly more submissive behavior than did their intact counterparts. Interestingly, castrated and intact males that were singly housed for 10 days prior to behavioral testing displayed similar behavior during CD testing. Together these data suggest that androgens and isolation modulate the display of CD in male hamsters. Finally, we examined brain activation following CD testing in defeated males and females (in diestrus 1 and proestrus). Defeated male and proestrous females exhibited increased Fos activation in the dorsal lateral septum and hypothalamic paraventricular nucleus relative to defeated diestrous 1 females. Diestrous 1 females exhibited increased Fos expression in the lateral bed nucleus of the stria terminalis compared with both defeated groups. Collectively, these data suggest that gonadal hormones and duration of individual housing modulate the display of CD in female and male hamsters and that those animals which display CD exhibit differences in patterns of neuronal activation than do those that do not display CD.

Submitted by Bruna Rodrigues (bruna92rodrigues@yahoo.com.br) on 2016-09-14T13:01:32Z No. of bitstreams: 1 TeseACC.pdf: 1221580 bytes, checksum: fd3199b489e81df5b5b589830f8ed420 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-15T13:51:39Z (GMT) No. of bitstreams: 1 TeseACC.pdf: 1221580 bytes, checksum: fd3199b489e81df5b5b589830f8ed420 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-15T13:51:55Z (GMT) No. of bitstreams: 1 TeseACC.pdf: 1221580 bytes, checksum: fd3199b489e81df5b5b589830f8ed420 (MD5) / Made available in DSpace on 2016-09-15T13:52:06Z (GMT). No. of bitstreams: 1 TeseACC.pdf: 1221580 bytes, checksum: fd3199b489e81df5b5b589830f8ed420 (MD5) Previous issue date: 2015-05-15 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Stressful situations are a real or potential threat for psychological or physiological integrity of an individual. The underlying neurobiological substrates involved in these processes were substancially investigated through the use of animal models of stress. In this context, a crescent number of studies have used more naturalistic animal tests, such as the social defeat test. Regarding neurobiological substrates, it is known that the amygdala plays an important role in the modulation of defensive responses. This forebrain structure has several neurotransmitters and receptors with important implications in emotional states. In this context, the neuropeptide Corticotropin Releasing Factor (CRF) and its receptors, CRF1 and CRF2, have been recently investigated as an important modulatory system of defensive reactions to aversive situations. Activation CRF mechanisms in the amygdala has been postulated as a possible neurochemical substrate underlying the emotional disorders, especially anxiety disorders, induced by stress in humans. To study anxiety-related responses induced by stressors in animals, the elevated plus maze (EPM) test has been widely used. While previous studies have emphasized the role of CRF1 receptors in modulation of anxiety in rodents exposed to the EPM, the involvement of CRF2 receptors remains unclear. Few studies, however, have investigated the effects of CRF and CRF1 and CRF2 antagonists injected directly into the amygdala on the defensive responses in mice. In addition, several studies are needed to clarify the complex relationship between CRF neurotransmission of the amygdala in the etiology of anxiety disorders related to previous exposure to stress. This study investigated the role of CRF in the amygdala upon the defense reactions evaluated in the EPM in mice previously exposed to acute social defeat. Therefore, we carried out experiments to (i) characterize the effects of acute social defeat on behavior in the EPM and on the levels of plasma corticosterone; (ii) to investigate the effects of intraamygdala microinjection of CRF, CRF1 and CRF2 antagonists on the behavior of mice in the EPM and (iii) to investigate the effects of intra-amygdala microinjections of CRF1 and CRF2 antagonists on anxiety-related behaviors of mice pre-exposed to acute social defeat. Results showed that the exposure to acute social defeat stress produces anxiogenesis at short and long terms (i.e, assessed 5 min and 10 days after stress exposure), however short-term anxiety response is variable. Stress-short term effects are accompanied by increased plasma corticosterone levels. In addition, while intra-amygdala CRF increases anxiety, local injection of CRF1 (but not CRF2) receptor antagonists produced anxiolytic-like effects, suggesting a tonic role of CRF1 in the modulation of anxiety in mice exposed to the EPM. However, it was not possible to determine what is the role of CRF neurotransmission in the responses displayed by mice pre-exposed to social defeat and submitted to EPM. / O estresse é uma ameaça real ou potencial para a integridade psicológica ou fisiológica de um indivíduo e que resulta em respostas fisiológicas e/ou comportamentais. Os conhecimentos sobre estas respostas bem como sobre os substratos neurobiológicos envolvidos nestes processos só foram possíveis com o desenvolvimento de modelos animais de estresse. Dentre os vários modelos utilizados, destaca-se o modelo de derrota social por suas características mais etológicas. Em relação aos substratos neurobiológicos, é sabido que a amídala tem um importante papel na modulação de respostas defensivas. Esta estrutura encefálica possui diversos neurotransmissores e respectivos receptores com importantes implicações em estados emocionais, dentre eles o Fator de Liberação de Corticotropina (CRF). Os mecanismos de ação do CRF se dão por sua interação com os receptores CRF1 e CRF2. A ativação destes receptores na amídala tem sido postulada como um dos possíveis substratos neuroquímicos das alterações queocorrem nos transtornos comportamentais induzidos por estresse em humanos, destacando-se os transtornos de ansiedade por serem os mais prevalentes na população. Como ferramenta de estudo desses transtornos, temos o labirinto em cruz elevado (LCE), um dos mais populares modelos animais de ansiedade. Estudos no LCE apontam que o CRF1 modula a ansiedade, enquanto o papel do CRF2 não está claro. Poucos estudos, no entanto, têm investigado os efeitos do CRF, bem como de antagonistas para CRF1 e CRF2 injetados diretamente na amídala sobre as respostas defensivas de camundongos. Além disso, ainda se fazem necessários diversos estudos para entender a complexa relação entre a neurotransmissão CRFérgica da amídala na etiologia de transtornos de ansiedade relacionados a prévia exposição ao estresse. Sendo assim, o objetivo deste estudo é investigar o papel do CRF na amídala, nas reações de defesa avaliadas no LCE em camundongos previamente expostos ao estresse de derrota social agudo. Para tanto, realizou-se experimentos para (i) caracterizar os efeitos do estresse de derrota social agudo sobre o comportamento de camundongos no LCE e sobre os níveis de corticosterona plasmática; (ii) investigar os efeitos de microinjeções intra-amídala de CRF e de antagonistas CRF1 e CRF2 sobre os comportamentos de camundongos no LCE e (iii) investigar os efeitos de microinjeções intra-amídala de antagonistas CRF1 e CRF2 em camundongos pré-expostos ao estresse de derrota social agudo e submetidos ao LCE. Os resultados obtidos demonstram que o estresse de derrota social agudo é ansiogênico a curto e longo prazos, entretanto a resposta de ansiedade a curto prazo é variável. Estes mesmos efeitos a curto prazo são acompanhados por aumento do nível de corticosterona plasmática. Ainda demonstram que o CRF na amídala é ansiogênico e que há uma modulação tônica via CRF1, já o papel do CRF2 continua indeterminado. Entretanto, não foi possível determinar o papel da neurotransmissão CRFérgica nas respostas exibidas por camundongos pré-expostos ao estresse de derrota social e submetidos ao LCE.