Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/17969 |
Resumo: | The abusive use of psychostimulant drugs is a common social problem in countries of different cultures, with increasing and alarming incidence, whose discontinuance of use is associated with anxiety and depression cases. Studies have shown the influence of early exposure to stress on patterns of dependency, which can play an important role on the vulnerability to drug abuse in adulthood. On the other hand, procedures such as neonatal tactile stimulation (TS) and neonatal isolation (NI), have been described by interfering with behavioral and neurophysiological parameters that can persist into adulthood. Thus, we first investigated the influence of neonatal handling on conditioned place preference (CPP) induced by amphetamine (AMPH), as well as anxiety-like symptoms and oxidative status related to drug abstinence, in young rats. Male pups of Wistar rats were submitted to TS or NI, for 10 min, from postnatal day 1 (PND1) to 21, while the CPP with AMPH or vehicle (NaCl 0.9% i.p.) was initiated on PND40. AMPH-conditioning evoked drug-preference and abstinence-symptoms in unhandled animals, accompanied by oxidative damage in cortex, hippocampus and striatum, while TS favored a decrease on drug-preference, showing no abstinence symptoms, as observed by reduced anxiety-like symptoms. Oxidative status pointed to a neuroprotective influence of TS by reducing lipid and protein damage in cortex, hippocampus and striatum, and increasing antioxidant markers in blood. Secondly, we aimed to identify the neonatal period in which TS exerts greater influence on animals’ development. Male pups of Wistar rats were submitted to TS (10 min) from PND1 to 7, PND8 to 14 or PND15 to 21. In adulthood, the animals were assessed using behavioral, biochemical and molecular analysis. According to these parameters, it was observed that the animals handled between PND8 and 14 had lower anxiety index, better working memory and increased ability to cope with adverse situations. TS in the second week of pups' lives was capable of reduce plasma corticosterone levels and improve the oxidative status of animals, observed by the slightest damage to lipids, and increased catalase activity in the hippocampus. In addition, TS from PND8 to 14 increased brain derived neurotrophic factor (BDNF) in the hippocampus of animals, while glucocorticoid receptors were reduced in all handling periods, except on PND8 to 14, in the same brain area. Considering the correlation between psychostimulants use and depression-like symptoms, in the 3rd study, the antidepressant effects of TS in association with a subtherapeutic dose of sertraline were evaluated during cocaine withdrawal period. Male pups of Wistar rats were submitted to TS (10 min) from PND8 to 14. For 14 consecutive days, adolescent rats received 3 daily doses of cocaine or vehicle (0.9% NaCl ip). Seven days after cocaine withdrawal, animals received 0.3 mg/kg of sertraline and 30 min later were evaluated for depression- and anxiety-like symptoms. Brain oxidative status and dopamine (D2) and glucocorticoid receptors (GR) were also determined. TS was able to protect animals against the depression-like symptoms, demonstrated by the absence of anhedonia and increased swimming activity in the forced swimming test. TS animals had lower levels of anxiety and stress, as well as reduction of oxidative damage in 8 plasma and brain of animals, besides best response of plasma antioxidant defense system. The molecular analysis also showed that TS was able to alters D2 and GR immunocontent in the striatum and hippocampus of animals. In summary, TS modified AMPH-induced preference, reducing anxiety-like behaviors that are common during drug withdrawal. Moreover, TS is able to stimulate the antioxidant defense system, and protect brain areas closely related to addiction, in young rats. Besides, it was possible to demonstrate that TS may be more effective when applied during the intermediate phase of neonatal development, reflecting reduced emotionality and improved ability to deal with stressful situations later in life. Finally, it was also possible to show that TS in association with sertraline is able to prevent against the deleterious effects of cocaine withdrawal, such as depression and anxiety. |
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Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratosInfluence of neonatal handling on behavioral, biochemical and molecular parameters after use of psychostimulant drugs in ratsEstimulação tátil neonatalPreferência condicionada de lugarAnfetaminaCocaínaEstresse oxidativoGlicocorticoidesDepressãoNeonatal tactile stimulationConditioned place preferenceAmphetamineCocaineOxidative stressGlucocorticoidsDepressionCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAThe abusive use of psychostimulant drugs is a common social problem in countries of different cultures, with increasing and alarming incidence, whose discontinuance of use is associated with anxiety and depression cases. Studies have shown the influence of early exposure to stress on patterns of dependency, which can play an important role on the vulnerability to drug abuse in adulthood. On the other hand, procedures such as neonatal tactile stimulation (TS) and neonatal isolation (NI), have been described by interfering with behavioral and neurophysiological parameters that can persist into adulthood. Thus, we first investigated the influence of neonatal handling on conditioned place preference (CPP) induced by amphetamine (AMPH), as well as anxiety-like symptoms and oxidative status related to drug abstinence, in young rats. Male pups of Wistar rats were submitted to TS or NI, for 10 min, from postnatal day 1 (PND1) to 21, while the CPP with AMPH or vehicle (NaCl 0.9% i.p.) was initiated on PND40. AMPH-conditioning evoked drug-preference and abstinence-symptoms in unhandled animals, accompanied by oxidative damage in cortex, hippocampus and striatum, while TS favored a decrease on drug-preference, showing no abstinence symptoms, as observed by reduced anxiety-like symptoms. Oxidative status pointed to a neuroprotective influence of TS by reducing lipid and protein damage in cortex, hippocampus and striatum, and increasing antioxidant markers in blood. Secondly, we aimed to identify the neonatal period in which TS exerts greater influence on animals’ development. Male pups of Wistar rats were submitted to TS (10 min) from PND1 to 7, PND8 to 14 or PND15 to 21. In adulthood, the animals were assessed using behavioral, biochemical and molecular analysis. According to these parameters, it was observed that the animals handled between PND8 and 14 had lower anxiety index, better working memory and increased ability to cope with adverse situations. TS in the second week of pups' lives was capable of reduce plasma corticosterone levels and improve the oxidative status of animals, observed by the slightest damage to lipids, and increased catalase activity in the hippocampus. In addition, TS from PND8 to 14 increased brain derived neurotrophic factor (BDNF) in the hippocampus of animals, while glucocorticoid receptors were reduced in all handling periods, except on PND8 to 14, in the same brain area. Considering the correlation between psychostimulants use and depression-like symptoms, in the 3rd study, the antidepressant effects of TS in association with a subtherapeutic dose of sertraline were evaluated during cocaine withdrawal period. Male pups of Wistar rats were submitted to TS (10 min) from PND8 to 14. For 14 consecutive days, adolescent rats received 3 daily doses of cocaine or vehicle (0.9% NaCl ip). Seven days after cocaine withdrawal, animals received 0.3 mg/kg of sertraline and 30 min later were evaluated for depression- and anxiety-like symptoms. Brain oxidative status and dopamine (D2) and glucocorticoid receptors (GR) were also determined. TS was able to protect animals against the depression-like symptoms, demonstrated by the absence of anhedonia and increased swimming activity in the forced swimming test. TS animals had lower levels of anxiety and stress, as well as reduction of oxidative damage in 8 plasma and brain of animals, besides best response of plasma antioxidant defense system. The molecular analysis also showed that TS was able to alters D2 and GR immunocontent in the striatum and hippocampus of animals. In summary, TS modified AMPH-induced preference, reducing anxiety-like behaviors that are common during drug withdrawal. Moreover, TS is able to stimulate the antioxidant defense system, and protect brain areas closely related to addiction, in young rats. Besides, it was possible to demonstrate that TS may be more effective when applied during the intermediate phase of neonatal development, reflecting reduced emotionality and improved ability to deal with stressful situations later in life. Finally, it was also possible to show that TS in association with sertraline is able to prevent against the deleterious effects of cocaine withdrawal, such as depression and anxiety.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO uso abusivo de drogas psicoestimulantes é um problema social comum em países de diferentes culturas, com incidência crescente e alarmante, cuja descontinuidade do uso está associada à síndrome de abstinência, caracterizada por quadros de ansiedade e depressão. Estudos têm mostrado a influência da exposição precoce ao estresse sobre padrões de dependência, a qual pode cumprir um importante papel sobre a vulnerabilidade para o abuso de drogas na idade adulta. Por outro lado, procedimentos como a estimulação tátil (ET) neonatal e o isolamento neonatal (IN), têm sido descritos por interferir em parâmetros comportamentais e neurofisiológicos, que podem persistir até a vida adulta. Assim, primeiramente investigou-se a influência do manuseio neonatal sobre a preferência condicionada de lugar (PCL) induzida por anfetamina (ANF), bem como sintomas de ansiedade e o status oxidativo relacionados à abstinência da droga, em ratos jovens. Filhotes machos de ratos Wistar foram submetidos à ET ou IN, por 10 minutos, do dia pós-natal 1 (DPN1) ao 21, enquanto a PCL com ANF ou veículo (NaCl 0.9% i.p) foi iniciada no DPN40. O condicionamento com ANF causou preferência e sintomas de abstinência em animais não manuseados, acompanhado por dano oxidativo no córtex, hipocampo e estriado, enquanto a ET favoreceu a redução da preferência pela droga, não mostrando sintomas de abstinência, a qual foi quantificada através do menor grau de ansiedade. O status oxidativo apontou ação neuroprotetora da ET ao reduzir o dano lipídico e proteico no córtex, hipocampo e estriado, aumentando alguns marcadores antioxidantes sanguíneos. Em um segundo estudo, visou-se identificar o período neonatal em que a ET exerce maior influência sobre o desenvolvimento dos animais. Filhotes machos de ratos Wistar foram submetidos à ET (10 min) do DPN1 ao 7, DPN8 ao 14, ou DNP15 ao 21. Na idade adulta, os animais foram avaliados através de análises comportamentais, bioquímicas e moleculares. De acordo com estes parâmetros, foi possível observar que os animais manuseados entre o DPN8 e 14 apresentaram menor índice de ansiedade, melhor memória de trabalho e maior capacidade de lidar com situações adversas. A ET na segunda semana de vida foi capaz de reduzir os níveis de corticosterona e melhorar o status oxidativo dos animais, observado pelo menor dano aos lipídios e aumento na atividade da catalase, no hipocampo. Além disso, a ET do DPN8 ao 14 aumentou o fator neurotrófico derivado do encéfalo (BDNF) no hipocampo dos animais, enquanto que os receptores de glicocorticoides foram reduzidos em todos os períodos de manuseio, exceto do DPN8 ao 14. Considerando a correlação existente entre o uso de psicoestimulantes e sintomas de depressão, no 3º estudo, os efeitos antidepressivos da ET em associação com uma dose subterapêutica de sertralina foram avaliados durante o período de abstinência de cocaína. Filhotes machos de ratos Wistar foram submetidos à ET (10 min) do DPN8 ao 14. Durante 14 dias consecutivos, os ratos adolescentes receberam 3 doses diárias de cocaína ou veículo (NaCl 0.9% i.p). Após 7 dias de retirada da droga, os animais receberam 0.3 mg/kg de sertralina e 30 min depois foram avaliados quanto a sintomas de depressão e ansiedade. O status oxidativo cerebral e os receptores de dopamina (D2) e de glicocorticoides (GR) também foram determinados. A ET foi capaz de proteger os animais 6 contra os sintomas de depressão, demonstrado através da ausência de anedonia e aumento da atividade de natação no teste do nado forçado. Os animais estimulados ainda apresentaram menores índices de ansiedade e estresse, bem como redução dos danos oxidativos no plasma e cérebros dos animais e melhor resposta do sistema de defesa antioxidante plasmático. As análises moleculares também mostraram que a ET foi capaz de alterar o imunoconteúdo de D2 e GR no estriado e hipocampo dos animais. Em resumo, a ET modificou a PCL induzida por ANF, reduzindo comportamentos de ansiedade comuns na abstinência da droga. Além disso, a ET é capaz de estimular o sistema de defesa antioxidante, e proteger áreas cerebrais intimamente relacionadas à adicção, em ratos jovens. Ainda, foi possível demonstrar que a ET pode ser mais eficiente quando aplicada no período intermediário do desenvolvimento neonatal, refletindo em emocionalidade reduzida e maior habilidade para lidar com situações estressantes na idade adulta. Finalmente, também foi possível mostrar que a ET foi capaz de otimizar os efeitos da sertralina administrada em dose subterapêutica, prevenindo contra os efeitos prejudiciais da retirada da cocaína, como depressão e ansiedade.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em FarmacologiaCentro de Ciências da SaúdeBurger, Marilise Escobarhttp://lattes.cnpq.br/9128090974948413Garcia, Solange Cristinahttp://lattes.cnpq.br/6687355709603379Rubin, Maribel Antonellohttp://lattes.cnpq.br/7237734243628134Wagner, Carolinehttp://lattes.cnpq.br/4004565241849091Rocha, Juliana Trevisan dahttp://lattes.cnpq.br/2173530592429464Antoniazzi, Caren Tatiane de David2019-08-20T12:12:33Z2019-08-20T12:12:33Z2016-09-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/17969porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2019-08-21T06:02:40Zoai:repositorio.ufsm.br:1/17969Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2019-08-21T06:02:40Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos Influence of neonatal handling on behavioral, biochemical and molecular parameters after use of psychostimulant drugs in rats |
title |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
spellingShingle |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos Antoniazzi, Caren Tatiane de David Estimulação tátil neonatal Preferência condicionada de lugar Anfetamina Cocaína Estresse oxidativo Glicocorticoides Depressão Neonatal tactile stimulation Conditioned place preference Amphetamine Cocaine Oxidative stress Glucocorticoids Depression CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
title_full |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
title_fullStr |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
title_full_unstemmed |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
title_sort |
Influência do manuseio neonatal sobre parâmetros comportamentais, bioquímicos e moleculares após o uso de drogas psicoestimulantes em ratos |
author |
Antoniazzi, Caren Tatiane de David |
author_facet |
Antoniazzi, Caren Tatiane de David |
author_role |
author |
dc.contributor.none.fl_str_mv |
Burger, Marilise Escobar http://lattes.cnpq.br/9128090974948413 Garcia, Solange Cristina http://lattes.cnpq.br/6687355709603379 Rubin, Maribel Antonello http://lattes.cnpq.br/7237734243628134 Wagner, Caroline http://lattes.cnpq.br/4004565241849091 Rocha, Juliana Trevisan da http://lattes.cnpq.br/2173530592429464 |
dc.contributor.author.fl_str_mv |
Antoniazzi, Caren Tatiane de David |
dc.subject.por.fl_str_mv |
Estimulação tátil neonatal Preferência condicionada de lugar Anfetamina Cocaína Estresse oxidativo Glicocorticoides Depressão Neonatal tactile stimulation Conditioned place preference Amphetamine Cocaine Oxidative stress Glucocorticoids Depression CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Estimulação tátil neonatal Preferência condicionada de lugar Anfetamina Cocaína Estresse oxidativo Glicocorticoides Depressão Neonatal tactile stimulation Conditioned place preference Amphetamine Cocaine Oxidative stress Glucocorticoids Depression CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
The abusive use of psychostimulant drugs is a common social problem in countries of different cultures, with increasing and alarming incidence, whose discontinuance of use is associated with anxiety and depression cases. Studies have shown the influence of early exposure to stress on patterns of dependency, which can play an important role on the vulnerability to drug abuse in adulthood. On the other hand, procedures such as neonatal tactile stimulation (TS) and neonatal isolation (NI), have been described by interfering with behavioral and neurophysiological parameters that can persist into adulthood. Thus, we first investigated the influence of neonatal handling on conditioned place preference (CPP) induced by amphetamine (AMPH), as well as anxiety-like symptoms and oxidative status related to drug abstinence, in young rats. Male pups of Wistar rats were submitted to TS or NI, for 10 min, from postnatal day 1 (PND1) to 21, while the CPP with AMPH or vehicle (NaCl 0.9% i.p.) was initiated on PND40. AMPH-conditioning evoked drug-preference and abstinence-symptoms in unhandled animals, accompanied by oxidative damage in cortex, hippocampus and striatum, while TS favored a decrease on drug-preference, showing no abstinence symptoms, as observed by reduced anxiety-like symptoms. Oxidative status pointed to a neuroprotective influence of TS by reducing lipid and protein damage in cortex, hippocampus and striatum, and increasing antioxidant markers in blood. Secondly, we aimed to identify the neonatal period in which TS exerts greater influence on animals’ development. Male pups of Wistar rats were submitted to TS (10 min) from PND1 to 7, PND8 to 14 or PND15 to 21. In adulthood, the animals were assessed using behavioral, biochemical and molecular analysis. According to these parameters, it was observed that the animals handled between PND8 and 14 had lower anxiety index, better working memory and increased ability to cope with adverse situations. TS in the second week of pups' lives was capable of reduce plasma corticosterone levels and improve the oxidative status of animals, observed by the slightest damage to lipids, and increased catalase activity in the hippocampus. In addition, TS from PND8 to 14 increased brain derived neurotrophic factor (BDNF) in the hippocampus of animals, while glucocorticoid receptors were reduced in all handling periods, except on PND8 to 14, in the same brain area. Considering the correlation between psychostimulants use and depression-like symptoms, in the 3rd study, the antidepressant effects of TS in association with a subtherapeutic dose of sertraline were evaluated during cocaine withdrawal period. Male pups of Wistar rats were submitted to TS (10 min) from PND8 to 14. For 14 consecutive days, adolescent rats received 3 daily doses of cocaine or vehicle (0.9% NaCl ip). Seven days after cocaine withdrawal, animals received 0.3 mg/kg of sertraline and 30 min later were evaluated for depression- and anxiety-like symptoms. Brain oxidative status and dopamine (D2) and glucocorticoid receptors (GR) were also determined. TS was able to protect animals against the depression-like symptoms, demonstrated by the absence of anhedonia and increased swimming activity in the forced swimming test. TS animals had lower levels of anxiety and stress, as well as reduction of oxidative damage in 8 plasma and brain of animals, besides best response of plasma antioxidant defense system. The molecular analysis also showed that TS was able to alters D2 and GR immunocontent in the striatum and hippocampus of animals. In summary, TS modified AMPH-induced preference, reducing anxiety-like behaviors that are common during drug withdrawal. Moreover, TS is able to stimulate the antioxidant defense system, and protect brain areas closely related to addiction, in young rats. Besides, it was possible to demonstrate that TS may be more effective when applied during the intermediate phase of neonatal development, reflecting reduced emotionality and improved ability to deal with stressful situations later in life. Finally, it was also possible to show that TS in association with sertraline is able to prevent against the deleterious effects of cocaine withdrawal, such as depression and anxiety. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-09-21 2019-08-20T12:12:33Z 2019-08-20T12:12:33Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/17969 |
url |
http://repositorio.ufsm.br/handle/1/17969 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1805922016731070464 |