THIEZA GRAZIELLA ARAUJO DA SILVA GOES DE MELO
ANTIDEPRESSIVOS MODIFICAM A EXTINÇÃO DE UMA MEMÓRIA
AVERSIVA EM RATAS
Dissertação
apresentada
à
Universidade Federal do Rio Grande
do Norte, para obtenção do título de
Mestre em Psicobiologia.
Natal
2011
1
THIEZA GRAZIELLA ARAUJO DA SILVA GOES DE MELO
ANTIDEPRESSIVOS MODIFICAM A EXTINÇÃO DE UMA MEMÓRIA
AVERSIVA EM RATAS
Dissertação
apresentada
à
Universidade Federal do Rio Grande do
Norte, para obtenção do título de
Mestre em Psicobiologia.
Orientadora: Profª. Drª. Regina Helena da Silva
Co-Orientador: MSc PhD Geison de Souza
Izídio
Natal
2011
2
Título: ANTIDEPRESSIVOS MODIFICAM A EXTINÇÃO DE UMA MEMÓRIA
AVERSIVA EM RATAS
Autor: Thieza Graziella Araújo da Silva Góes de Melo
Data da defesa: 16/05/2011
Banca Examinadora:
___________________________________
Profª. Drª. Flávia Teixeira da Silva
Universidade Federal de Sergipe, SE
___________________________________
Profª. Drª. Elaine Cristina Gavioli
Universidade Federal do Rio Grande do Norte, RN
___________________________________
Profª. Drª. Regina Helena da Silva
Universidade Federal do Rio Grande do Norte, RN
3
AGRADECIMENTOS
À minha família e amigos, pela compreensão. Especialmente minha mãe, por
estar sempre presente e ter sempre me dado o melhor exemplo a ser seguido. As
minhas conquistas são tão minhas quanto dela e, algumas vezes, talvez até mais
dela que minhas. Ao meu noivo, Tiago, também sempre presente, inclusive nos
finais de semana, em experimento, me dando suporte. Ao meu padrasto, Pai-Tio
Guilherme que tem, com toda certeza, ―direito‖ a pelo menos 1 cm² do certificado. À
minha avó, meu exemplo de vida, e que me mostrou que tudo pode ser feito com
paciência, boa vontade e um pouquinho de ousadia.
À professora Regina que me acompanha desde a iniciação científica, dando
suporte acadêmico/científico e que verdadeiramente me ensinou a fazer ciência,
mesmo sob as circunstâncias mais adversas.
Ao LEME, no corpo de seus ICs, mestrandos, doutorandos, pós-docs e
professores pela ajuda durante os experimentos e dos quais recebi não menos que
amizade. Dentro do LEME agradeço especialmente às duas pessoas que
participaram mais diretamente nos experimentos e revisões, Luane e Geison.
Aos dois psiquiatras que me forneceram suporte técnico e informações
clínicas Drª Nádira Hazboun e Drº Francisco Márcio Pinheiro.
À UFRN, CAPES, CNPq, FAPERN e PPG em Psicobiologia pelo apoio
financeiro e estrutural.
A todos os professores e colegas do programa de pós-graduação em
Psicobiologia.
Por fim, mas tão importante quanto, agradeço a todos os que não citei, mas
sem os quais eu não poderia ter realizado esse trabalho.
4
Resumo
Os tratamentos de depressão, transtorno de estresse pós-traumático e outras
psicopatologias que se utilizam de antidepressivos podem estar associados à
melhora de déficits cognitivos relacionados a esses transtornos. Embora os
mecanismos pelos quais a melhora nos déficits cognitivos ocorre não estejam
totalmente esclarecidos, alterações na extinção de memórias aversivas podem estar
presentes nestas psicopatologias. Além disso, pesquisas com animais de laboratório
geralmente são realizadas com indivíduos do sexo masculino, e recentemente
verificamos que a extinção de uma tarefa aversiva é diminuída em ratas quando
comparada ao desempenho de ratos. No presente estudo, ratas Wistar foram
tratadas prolongadamente com antidepressivos utilizados na clínica (nortriptilina,
fluoxetina ou mirtazapina) e testadas na esquiva discriminativa em labirinto em cruz
elevado e no teste do nado forçado, a fim de avaliar a aprendizagem, a memória, a
extinção, a ansiedade e comportamentos relacionados à depressão. A exploração
do braço aversivo na sessão de treino foi semelhante em todos os grupos,
mostrando que todos os grupos aprenderam a tarefa, havendo, porém, uma melhora
no desempenho dos grupos tratados com nortriptilina e mirtazapina. Na sessão teste
todos os animais evocaram a tarefa. O tratamento prolongado com a fluoxetina, mas
não com os outros antidepressivos, promoveu uma melhora na extinção da memória
aversiva da EDLC. No teste de nado forçado, os animais tratados com fluoxetina e
mirtazapina apresentaram diminuição na duração da imobilidade, comparados ao
veículo. Em conclusão, os antidepressivos podem interferir no aprendizado, mas não
na evocação de memórias aversivas. Além disso, ratas tratadas com fluoxetina
apresentam um aumento da extinção da tarefa aversiva, em comparação ao veículo,
enquanto os demais tratamentos impediram a extinção dessa tarefa. Além disso,
tanto a fluoxetina como a mirtazapina foram eficazes no teste de nado forçado,
sugerindo dissociação entre os efeitos antidepressivos e extinção de memórias
aversivas.
Palavras chaves: fluoxetina, nortriptilina, mirtazapina, ratas, memória aversiva,
depressão, ansiedade.
5
Abstract
Treatment of major depression, posttraumatic stress disorder and other
psychopathologies with antidepressants can be associated with improvement of the
cognitive deficits related to these disorders. Although the mechanisms of these
effects are not completely elucidated, alterations in extinction of aversive memories
are believed to be present in these psychopathologies. Moreover, researches with
laboratory animals usually focus on male subjects, and we have recently verified that
extinction of an aversive task is reduced in female rats when compared to males. In
the present study, female rats were long-term treated with clinically used
antidepressants (fluoxetine, nortriptyline or mirtazapine) and tested in the plus-maze
discriminative avoidance and forced swimming tests in order to evaluate learning,
memory, extinction, anxiety and depression-related behaviors. All groups learned the
task, but learning was somewhat faster in nortriptyline and mirtazapine-treated
animals . Task retrieval was also showed by all experimental groups. Chronic
treatment with fluoxetine, but not with the other antidepressants, increased extinction
of the discriminative task. In the forced swimming test, animals treated with fluoxetine
and mirtazapine showed decreased immobility duration. In conclusion,
antidepressants interfere with learning and female rats treated with fluoxetine
presented increased extinction of the aversive memory task. On the other hand, both
fluoxetine and mirtazapine were effective in the forced swimming test, suggesting
dissociation between the antidepressant effects and the extinction of aversive
memories.
Keywords: discriminative avoidance task, sex differences, forced swimming test,
aversive memory, depression, anxiety.
6
Sumário
I.
INTRODUÇÃO ............................................................................................ 8
II.
OBJETIVOS .............................................................................................. 20
III.
ARTIGO PARA SUBMISSÃO................................................................... 21
IV.
CONCLUSÃO E CONSIDERAÇÕES FINAIS........................................... 55
V.
REFERÊNCIAS ......................................................................................... 57
7
I.
Introdução
O uso de antidepressivos, sozinhos ou em combinação com a psicoterapia, é
largamente
difundido.
Além
da
grande
indicação
para
o
tratamento
de
psicopatologias como transtornos de humor e ansiedade (Marks et al. 1998; Brunello
et al. 2001; Nandam et al. 2007), eles são também indicados como uma opção
alternativa para doenças debilitantes funcionais como, por exemplo, a síndrome da
fadiga crônica, a fibromialgia, enxaquecas ou dores de cabeça crônicas e dores
faciais atípicas (Marks et al. 2008; Mao et al. 2010).
A depressão é uma psicopatologia já devidamente classificada no Manual de
Diagnóstico e Estatística de Doenças Mentais (em inglês Diagnostic and Statistical
Manual of Mental Disorders), com suas últimas modificações na classificação para
diagnóstico em sua quarta edição e no Texto Revisado (2000). Também consta na
Classificação Estatística Internacional de Doenças e Problemas Relacionados (CID10) na sessão de transtornos mentais e comportamentais. Estima-se que o
transtorno depressivo acometa aproximadamente 10% da população mundial e é
considerado um dos maiores males da atualidade. A sua incidência também é
destacada incorrendo até duas vezes mais em mulheres que em homens (Fava &
Kendler 2000; Mahendran & Yap 2005; Bekker & van Mens-Verhulst 2007). A
depressão pode se apresentar como um episódio único (episódio depressivo),
caracterizado por ser um período mínimo de duas semanas, durante as quais há um
humor deprimido ou perda de interesse ou prazer por quase todas as atividades. Em
crianças e adolescentes o humor pode ser irritável ao invés de triste. Nesse período
é comum que se apresentem pelo menos quatro sintomas adicionais, extraídos de
uma lista que inclui: alterações no apetite ou peso, no sono e na atividade
8
psicomotora; diminuição da energia; sentimentos de desvalia ou culpa; dificuldades
para pensar, concentrar-se ou tomar decisões, ou pensamentos recorrentes sobre
morte ou ideação suicida; planos ou tentativas de suicídio. Sintomas físicos são
comumente encontrados no episódio depressivo maior: propensão ao choro,
irritabilidade, ruminação obsessiva, ansiedade, fobias, preocupação com a saúde
física e queixas de dores, tanto de cabeça, quanto no corpo (APA 2000; Fava &
Kendler 2000). Alguns indivíduos podem apresentar ataques de pânico que ocorrem
segundo um padrão que satisfaz os critérios para transtorno de pânico. Em crianças
pode ocorrer ansiedade de separação. Alguns indivíduos observam dificuldade nos
relacionamentos íntimos, diminuição das interações sociais satisfatórias ou
dificuldades no funcionamento sexual (APA 2000). A manifestação de episódios
depressivos pode ainda vir como um transtorno depressivo maior, o qual é
caracterizado pela ocorrência de um ou mais episódios depressivos, sem história de
episódios maníacos, mistos ou hipomaníacos.
Usualmente, pacientes diagnosticados com depressão apresentam também
sintomas de ansiedade, com variadas intensidades, tais como: preocupação,
nervosismo, ataques de pânico, sintomas de fobia, transtornos obsessivocompulsivos, entre outros (APA 2000). Os pacientes depressivos que possuem
elevados níveis de ansiedade podem apresentar quadros mais severos e
recuperação mais demorada. Além disso, a depressão pode ainda se apresentar
comorbidamente com outros transtornos de ansiedade (Marques 2001; Aragonès et
al. 2009) e transtornos relacionados a substâncias, transtorno de pânico, transtorno
obsessivo-compulsivo,
anorexia
nervosa,
bulimia
nervosa
e
transtorno
da
personalidade borderline (APA 2000). Assim, não é surpreendente que se aplique o
9
uso de antidepressivos também ao tratamento de outros transtornos como os da
ansiedade (APA 2000; Marques 2001).
A incidência desses demais transtornos também pode ser relacionada à
comorbidade deles com a depressão. Os transtornos de ansiedade mais comuns em
mulheres, em sua grande maioria (Bekker & van Mens-Verhulst 2007) são os de
maiores índices de comorbidade com a depressão. Dessa forma é imperativa a
necessidade de uma maior atenção à sintomatologia diferenciada apresentada pelos
indivíduos do sexo feminino. Mulheres e crianças podem apresentar mais
comumente o humor irritado (APA 2000) e essa alteração no humor pode ser
sintoma apenas da depressão e não ter nenhuma relação com outros transtornos de
humor ou ansiedade. Paralelamente, a perda de peso pode estar associada mais
facilmente aos transtornos alimentares, que podem ser a causa da depressão (APA
2000; Mischoulon et al. 2010; Modrzejewska 2010).
O tratamento de transtornos do humor é geralmente complexo, prolongado e
adequado a cada indivíduo. Estudos com indivíduos saudáveis sugerem que a
percepção de faces com expressões negativas começam a aparecer após o 7º dia
de tratamento (Harmer et al. 2010), diminuição de perceptção essa, associada aos
efeitos terapêuticos do uso contínuo de antidepressivos. Existem várias classes de
drogas
antidepressivas
disponíveis
farmacodinâmicas distintas. De
forma
na
atualidade,
geral,
com
propriedades
tais fármacos aumentam as
concentrações de monoaminas na fenda sináptica, mas apenas esse aumento,
embora necessário, não é suficiente para explicar a remissão dos sintomas
(Arantes-Gonçalves & Coelho 2006).
As primeiras teorias para explicar as bases fisiológicas da depressão surgiram
em torno da hipótese da redução das concentrações de serotonina (5-HT) e
10
noradrenalina (NA) na fenda sináptica, visto que drogas que depletam as reservas
desses neurotransmissores são indutoras de quadros depressivos (Freis 1954; Guay
2010; Tian et al 2010; Aia et al 2011; Ghia et al 2011), e o mecanismo de ação dos
agentes depressivos mais utilizados envolve aumento da disponibilidade desses
neurotransmissores (Kent 2000). Contudo, uma hipótese mais recente sobre a
fisiopatologia e tratamento da depressão envolve também adaptação e plasticidade
neural. De acordo com essa hipótese, a depressão seria resultado de uma falha na
execução de respostas adaptativas apropriadas ao estresse e a estímulos aversivos,
ou seja, perda da plasticidade sináptica. A isso pode se associar o fato de que a
exposição crônica a situações de estresse induz um quadro semelhante à
depressão, com redução dos níveis hipocampais de fator neurotrófico derivado do
encéfalo (BDNF – do inglês brain-derived neutrophic factor) (Gould et al. 1999; Sen
et al. 2003; Arantes-Gonçalves & Coelho 2006), componente da família das
neurotrofinas,
que,
entre
várias
outras
moléculas,
apresenta
um
papel
reconhecidamente importante na plasticidade sináptica (Arantes-Gonçalves &
Coelho 2006; Monfils 2007; Kalueff 2007).
Essa plasticidade em adultos também pode ocorrer através da neurogênese
(Gould & Gross 2002), que também é regulada pelos antidepressivos (Santarelli et
al. 2003). Normalmente é restrita ao hipocampo, nas zonas subventricular e
subgranular do giro denteado (Garcia-Vendugo et al. 1998; Santarelli et al. 2003).
Isso corrobora os estudos que mostram hipocampo diminuído em indivíduos
deprimidos (Manji et al. 2002; Nestler & Carlezon Jr. 2006) e atividade aumentada
na amígdala (Drevets 2001). Existe também a evidência de que o estresse impede a
neurogênese e estaria relacionado a essa diminuição hipocampal (Kloet et al. 2005;
Gerritsen et al. 2011).
11
Dentre as várias opções de antidepressivos os mais prescritos são os
inibidores seletivos de recaptação de serotonina (ISRS) tanto para adultos como
para crianças (Dunlop & Davis 2008; Denizot et al. 2009). Introduzidos na clínica no
final da década de 80 (Kent 2000), os ISRS agem bloqueando a ação do
transportador de serotonina. Dessa forma eles impedem a recaptação do
neurotransmissor, o que prolonga a sua exposição ao receptor, (Vázquez-Palacios
2004) e aumentando a atividade do sistema monoaminérgico no cérebro (Tsai et al.
2009). Dentre os antidepressivos dessa classe a fluoxetina é o mais prescrito
(Dunlop & Davis 2008). É importante ressaltar que a serotonina (5-HT) possui
também um papel regulador na divisão celular e um papel crítico no controle da
proliferação das células adultas neurais, fato que explicaria sua eficácia na melhora
dos sintomas depressivos considerando o papel da neurogênese hipocampal na
fisiopatologia da depressão (Santarelli et al. 2003; Paizanis et al. 2007)
Os antidepressivos tricíclicos são uma classe mais antiga de fármacos
utilizados no tratamento da depressão. Eles agem inibindo a recaptação
monoaminérgica não seletivamente. Alguns fármacos mais conhecidos dessa classe
são a amitriptilina, clomipramina, desipramina, imipramina, nortriptilina e a doxepina.
De interesse para o presente estudo, a nortriptilina inibe a recaptação de
noradrenalina e menos potencialmente da serotonina, sendo também agonista do
receptor 5-HT2 (Sanchez & Hyttel 1999; Wing & Shoaib 2007). Além disso, ela age
induzindo uma diminuição na expressão (downregulation) dos receptores βadrenérgicos (Morishita & Aoki 2002). Apesar de não ser largamente prescrita, a
nortriptilina continua sendo uma opção para indivíduos não responsivos a outros
antidepressivos e para sujeitos suscetíveis à síndrome de serotonina, um efeito
12
colateral importante decorrente do tratamento com ISRS (Dagtekin et al. 2010; Diaz
& Maroteaux 2011).
Os antidepressivos tetracíclicos são uma nova classe de drogas utilizadas no
tratamento da depressão, também chamados de atípicos, introduzidos depois da
década de 80 (Kent 2000). Dentre estes, o antidepressivo atípico mirtazapina atua
especificamente
sobre
as
transmissões
noradrenérgica
e
serotonérgica
(noradrenergic and serotonergic specific antidepressants, NaSSA, em inglês) e é
usado para tratar transtornos de humor e ansiedade (Gambi et al. 2005; Rauggi et
al. 2005). A mirtazapina aumenta as transmissões noradrenérgica e serotonérgica
central
através
da
inibição
dos
autoreceptores
α2
e
heteroreceptores
noradrenérgicos α2 em sinapses serotonérgicas (Bengtsson et al. 2000; Gambi et al.
2005). Além disso, é um agonista do receptor 5-HT1A (Rogóz et al. 2005) e também
age bloqueando receptores, 5-HT2A, 5-HT2C e 5-HT3 e histaminérgicos H1 (Haddjeri
1998; Davis & Wilde 1996; Arnone 2009; de Boer 1995; Rauggi et al. 2005). A
mirtazapina não possui efeitos na recaptação de monoaminas, além de apresentar
baixa afinidade para receptores dopaminérgicos e alguns subtipos de receptores
serotonérgicos.
Apesar dos efeitos clínicos de antidepressivos serem semelhantes entre os
sexos, aspectos farmacocinéticos e farmacodinâmicos de sua ação podem ser
distintos entre os sexos. Uma evidência dessa diferenciação para as respostas aos
antidepressivos é a melhor responsividade do sexo feminino aos ISRS e as altas
taxas de abandono do tratamento com tricíclicos (Dalla et al. 2009), comparando-se
aos homens. Já em modelos animais, alguns estudos mostram não haver diminuição
da imobilidade no nado forçado em fêmeas tratadas com um antidepressivo
13
tricíclico, enquanto machos respondem positivamente ao mesmo tratamento e com a
mesma dose (Barros & Ferigolo 1998).
Assim como em grande parte dos casos
de diversos transtornos
psicopatológicos, pacientes com diagnóstico de depressão, não raramente
apresentam prejuízos cognitivos, além de todo quadro afetivo característico (Yaffe
1999; Ravnkilde 2002; Pardo 2006). Dentre esses prejuízos incluem-se alterações
nas funções de memória e aprendizado (Burt 1995; Weiland-Fiedler 2004). Esses
prejuízos cognitivos seriam revertidos através do tratamento com antidepressivos
(Austin et al. 2001; Castaneda et al. 2007) e evidências sugerem que essa melhora
está associada ao aumento de neurogênese (Duman & Monteggia 2006; Dranovsky
& Hen 2006; Nandam et al. 2007; Paizanis et al. 2007; Sahay & Hen 2007; Pittenger
& Duman 2008) e a modificações no sistema monoaminérgico (Lee et al. 2010).
Independente da presença de outros tipos de prejuízos cognitivos,
comumente as psicopatologias estão relacionadas a experiências e memórias
emocionais aversivas (APA 2000; Phelps & LeDoux 2005) e há muito se preconiza
que as vítimas desses transtornos poderiam se beneficiar com a diminuição dos
sintomas através de uma ressignificação da memória aversiva formada (Freud
1914). Sugere-se que a ressignificação dessas memórias ocorreria através de um
processo de extinção, que é dependente de mecanismos plásticos (Gabriele &
Packard, 2006). Extinção seria a formação de uma nova memória relacionada à
anteriormente formada, sem, contudo, substituir a memória anterior, passando a
existir paralelamente (Gabriele & Packard, 2006). Sendo assim, alterações no
processo normal de extinção de memórias aversivas poderiam estar relacionadas
com a fisiopatologia de alguns transtornos neuropsiquiátricos. Enquanto essa
relação já foi bem estudada para o transtorno do estresse pós-traumático (Rauch et
14
al. 2006; Krystal & Neumeister 2009), a participação de processos relacionados à
memória emocional e a fisiopatologia da depressão não está bem estabelecida
(Blaney 1986; Newman & Sweet 1992; Ilsley et al. 1995; Veiel 1997; Fava & Kendler
2000; Ravnkilde 2002). Apesar de prejuízos na memória serem comuns em diversos
transtornos
de
ansiedade
e
relatados
na
depressão,
a
conexão
entre
antidepressivos e memória permanece ainda não completamente elucidada (Austin
et al. 2001). Os resultados dos estudos prévios são bastante controversos, mesmo
em machos. Estudos que avaliam a extinção de memórias aversivas após a
administração
de
drogas
com
efeito
antidepressivo
mostram
resultados
contraditórios. Dentre estes estudos, alguns, utilizando machos, verificam os efeitos
do rolipram, uma droga com efeitos ansiolíticos e antidepressivos. Essa droga
diminuiu a extinção em um teste de medo condicionado e em um paradigma de
resposta de sobressalto potencializada pelo medo (Monti et al. 2006; Mueller et al.,
2010). Além disso, este fármaco melhorou o desempenho no labirinto aquático de
Morris, aumentando a distância e o tempo em que os animais nadam no quadrante
no qual previamente havia uma plataforma submersa; e ainda impediu a extinção
relacionada a uma tarefa de esquiva passiva (Cheng et al, 2010). Um outro estudo
foi realizado com um modelo animal para transtorno de estresse pós-traumático,
característico pela ausência de extinção da memória do evento traumático (APA
2000). Nesse estudo, a cicloserina-D (DCS), droga utilizada como auxiliar em
tratamentos antidepressivos, melhorou a extinção em testes de condicionamento de
medo em machos (Yamamoto et al. 2008).
Sabe-se que o mecanismo psicofisiológico de várias doenças (a depressão,
por exemplo) é diferente entre os sexos (Bekker & van Mens-Verhulst 2007; Kim et
al. 2010; Wooley et al. 2010). Em humanos, as mulheres são o gênero mais afetado
15
pelas doenças debilitantes funcionais e em grande parte dos transtornos
psicopatológicos a proporção dos indivíduos atingidos é de duas mulheres para cada
homem (Mahedran & Yap 2005; Bekker & van Mens-Verhulst 2007). Apesar de não
se descartar fatores culturais e sociais, diversas evidências indicam que a principal
origem dessas diferenças está relacionada aos hormônios esteróides gonadais
(Toufexis et al. 2006; Solomon & Herman 2009), que podem ter efeitos nas vias
neuroquímicas (Kelly et al. 1999). Além disso, aspectos do dimorfismo sexual no
funcionamento do sistema nervoso também podem estar relacionados a estas
diferenças (Bruder et al. 2001; Esel et al. 2005; Monteggia et al 2007; Elaković et al.
2011).
Apesar dos estudos sugerirem que diferenças sexuais são importantes, a
maioria dos estudos pré-clínicos utiliza somente machos ao invés de ambos os
sexos (Kim et al. 2010; Zucker & Beery 2010). Alguns estudos que comparam efeitos
entre machos e fêmeas no teste do nado forçado têm mostrado resultados
contraditórios. Dependendo da droga utilizada, machos respondem ao tratamento,
diminuindo o tempo de imobilidade, seguindo o esperado para o modelo, e fêmeas
não (Barros & Ferigolo 1998). Também foi demonstrado que a fase do ciclo pode ser
uma importante característica levando as fêmeas a ter desempenhos diferentes de
acordo com a fase do ciclo estral na qual se encontram (Gouveia Jr. et al 2008).
Deve-se também ressaltar que não apenas condições patológicas podem ser
diferentes entre os sexos, mas também mecanismos de atividades cognitivas
fisiológicas normais como a memória e a ansiedade. Ribeiro et al. (2010), por
exemplo, encontraram diferenças na extinção de uma tarefa de memória aversiva
entre machos e fêmeas, mostrando uma diminuição da extinção em fêmeas, que
16
pode ter relação com a predominância de psicopatologias em seres humanos do
sexo feminino.
No presente estudo, nós utilizamos o modelo utilizado por Ribeiro et al.
(2010): a esquiva discriminativa em labirinto em cruz elevado (EDLC). A EDLC é um
método adequado para estudos concomitantes de memória/aprendizado e
medo/ansiedade em modelos animais. Consiste em um labirinto em cruz elevado
modificado, onde um dos braços fechados possui dois estímulos aversivos (sendo
um sonoro de intensidade equivalente a 80dB e um luminoso de 100W). Os animais
são submetidos a uma sessão de treino, na qual uma vez colocados individualmente
no centro do labirinto por 10 min, poderão explorar os braços, recebendo os
estímulos aversivos cada vez que o animal entrar com as quatro patas no braço
aversivo, até a saída do braço em questão. O tempo de permanência e o total de
entradas nos braços abertos e em cada braço fechado são quantificados. Decorridas
24 horas da sessão de treino é efetuada uma sessão de teste, na qual não se aplica
o estímulo aversivo. Dessa forma, ao longo da sessão pode-se também avaliar a
extinção da tarefa previamente aprendida, uma vez que os animais agora aprendem
que não há mais estímulos aversivos naquela localização. Este modelo foi
inicialmente descrito por Silva (1997) e Silva & Frussa-Filho (2000), que
padronizaram o modelo com machos e averiguaram que, usualmente os três
minutos iniciais são referentes à evocação da memória adquirida e os demais à
extinção.
Da mesma forma em que ocorre no labirinto em cruz elevado convencional, a
exploração dos braços abertos na EDLC reflete os níveis de ansiedade (Pellow et al.
1985; Pellow & File 1986), pois os ratos possuem medo inato de ambientes abertos
e de altura, o que fará com que eles evitem esses braços. De acordo com os níveis
17
de ansiedade a exploração desses braços poderá aumentar ou diminuir.
Considerando que alterações nos níveis de ansiedade podem afetar o perfil
comportamental dos animais em modelos animais de estudo de memória, o modelo
da EDLC apresenta a grande vantagem de permitir a avaliação simultânea destes
dois parâmetros (Calzavara et al. 2004; Silva & Frussa-Filho 2000). A diferenciação
entre os braços fechados (aversivo e não-aversivo) serve como parâmetro para
avaliação de memória e aprendizado. Esse modelo permite ainda a avaliação da
atividade locomotora que pode ser realizada por meio da exploração de todos os
braços e do centro, pelo total de passagens entre os braços (Silva et al. 2002) ou,
ainda, quantificando-se a distância total percorrida (Ribeiro et al., 2010).
Para avaliação do efeito de antidepressivos sobre a memória, o aprendizado,
a ansiedade e a atividade locomotora simultaneamente à depressão é preciso
associar a EDLC a um teste que possa avaliar comportamentos relacionados à
depressão. Dentre estes, o teste do nado forçado (TNF) é um modelo experimental
amplamente utilizado na comunidade científica mundial. O TNF tem sido utilizado
como modelo experimental em estudos sobre depressão, onde a imobilidade do
animal é interpretada como forma de desamparo aprendido, ou seja, o animal não
tenta mais escapar da situação aversiva (Porsolt 1977; 1978). Ou seja,
classicamente neste teste comportamental, antidepressivos causam a diminuição da
imobilidade dos animais no teste (Porsolt 1977). A escalada (climbing) é outra
medida que pode ser avaliada neste modelo comportamental. O tempo de escalada
ainda não está tão bem validada quanto o tempo de imobilidade, mas alguns autores
sugerem que antidepressivos tendem a aumentar este parâmetro comportamental,
como uma tentativa de fuga da situação (neste caso o cilindro com água). De
relevância para o presente trabalho, já foi observada uma diferença na ocorrência da
18
tentativa de fuga de situações aversivas, entre machos e fêmeas (Ribeiro et al.
2010), embora em outro tipo de tarefa comportamental. A diminuição da duração da
imobilidade e o aumento do tempo de escalada podem estar relacionados a uma
melhora dos sintomas tipo depressivos através da transmissão noradrenérgica
(Detke et al. 1995, 1997; Reneric & Lucki 1998; Page et al. 1999; Cryan & Lucki
2000; Lopez-Rubalcava & Lucki 2000; Cryan et al. 2002a; Reneric et al. 2002;
Consoni et al. 2006).
Com base em todas as evidências expostas, neste estudo, ratas foram
tratadas com três tipos diferentes de antidepressivos (fluoxetina, nortriptilina e
mirtazapina) de três classes farmacológicas diferentes (antidepressivos ISRS,
tricíclicos e atípicos) e testadas na EDLC. Até o presente momento, não existem
artigos
publicados
avaliando
a
ação
de
antidepressivos
nesse
aparato
comportamental. Adicionalmente, as ratas foram testadas no TNF, a fim de avaliar
comportamentos relacionados à depressão após o tratamento prolongado com
antidepressivos.
19
II.
Objetivos
Objetivo Geral
O presente estudo propôs-se a averiguar os efeitos de três antidepressivos
provenientes de classes farmacológicas distintas no aprendizado, memória,
extinção, ansiedade/emocionalidade e comportamento de desamparo aprendido em
ratas. Tendo em vista a prevalência dos transtornos relacionados à depressão e
ansiedade em mulheres e a pequena quantidade de pesquisas relacionando os
efeitos desses fármacos em processos cognitivos em indivíduos do sexo feminino, a
nossa proposta pretende contribuir no avanço da compreensão dos efeitos destas
classes de drogas em fêmeas.
Objetivos específicos
(a) Avaliar as diferentes etapas de memória (aquisição, consolidação, evocação e
extinção) em fêmeas tratadas com os antidepressivos na EDLC;
(b) Avaliar os comportamentos relacionados à ansiedade em fêmeas tratadas com
os antidepressivos na EDLC;
(c) Avaliar possíveis efeitos locomotores dos fármacos utilizados;
(d) Avaliar o efeito antidepressivo em ratas das drogas utilizadas nos esquemas de
tratamento e doses específicos aqui utilizados.
20
III.
Artigo para submissão
Date of submission:
ANTIDEPRESSANTS FLUOXETINE, NORTRIPTYLINE AND MIRTAZAPINE
MODIFIES THE EXTINCTION OF AN AVERSIVE MEMORY AND THE ANXIETY IN
FEMALE RATS
Thieza G. Melo, Geison S. Izídio, Luane S. Ferreira, Diego S. Silveira, Priscila
T. Macedo, Alícia Cabral, Alessandra M. Ribeiro, Regina H. Silva
Memory Studies Laboratory
Department of Physiology
Universidade Federal do Rio Grande do Norte
59.078-970, Natal, RN, Brazil·.
*Corresponding author: Regina H. Silva
Laboratório de Estudos da Memória
Departamento de Fisiologia - Centro de Biociências
Universidade Federal do Rio Grande do Norte
Av. Salgado Filho, s/n - Caixa Postal 1511 - CEP 59078-970 - Natal, RN, Brazil
fax: (55) 84 3211 9206
e-mail: [email protected]
Progress In Neuropsychopharmacology & Biological Psychiatry (Classificação
Qualis A2, em Fevereiro de 2011)
Keywords: discriminative avoidance task, sex differences, forced swimming
test, aversive memory, depression, anxiety.
21
Abstract
Treatment of major depression, posttraumatic stress disorder and other
psychopathologies with antidepressants can be associated with improvement of the
cognitive deficits related to these disorders. Although the mechanisms of these
effects are not completely elucidated, alterations in extinction of aversive memories
are believed to be present in these psychopathologies. Moreover, researches with
laboratory animals usually focus on male subjects, and we have recently verified that
extinction of an aversive task is reduced in female rats when compared to males. In
the present study, female rats were long-term treated with clinically used
antidepressants (fluoxetine, nortriptyline or mirtazapine) and tested in the plus-maze
discriminative avoidance and forced swimming tests in order to evaluate learning,
memory, extinction, anxiety and depression-related behaviors. All groups learned the
task, but learning was somewhat faster in nortriptyline and mirtazapine-treated
animals. Task retrieval was also showed by all experimental groups. Chronic
treatment with fluoxetine, but not with the other antidepressants, increased extinction
of the discriminative task. In the forced swimming test, animals treated with fluoxetine
and
mirtazapine
showed
decreased
immobility
duration.
In
conclusion,
antidepressants interfere with learning and female rats treated with fluoxetine
presented increased extinction of the aversive memory task. On the other hand, both
fluoxetine and mirtazapine were effective in the forced swimming test, suggesting
dissociation between the antidepressant effects and the extinction of aversive
memories.
22
1. Introduction
Psychopathological conditions such mood and anxiety disorders are frequently
related to aversive emotional experiences (APA, 2000) that could benefit from a
reframing of the aversive memory formatted, which is usually attempted in
psychotherapeutic procedures (Freud, 1914). It has also been suggested that the
cognitive deficits present in these disorders are reversed by treatment with
antidepressants (Austin et al., 2001; Castaneda et al., 2007), which are largely
indicated for both anxiety and mood disorders (Marks et al., 1998; Brunello et al.,
2001; Nandam et al., 2007). Several studies indicate that the improvement of these
cognitive deficits is associated with hippocampal neurogenesis (Santarelli et al.,
2003; Duman and Monteggia, 2006; Dranovsky and Hen, 2006; Nandam et al., 2007;
Paizanis et al., 2007; Sahay and Hen, 2007; Pittenger and Duman, 2008), which
would explain the delay of amelioration of depressive symptoms after the beginning
of clinical treatment. Despite memory deficits being common in many anxiety and
depression- related disorders the relationship between the improvement of
depression or anxiety symptoms by antidepressants treatment, as well as their effect
on memory, remains to be elucidated (Austin et al., 2001).
It is known that both the prevalence (Mahedran et al., 2006; Bekker and van
Mens-Verhulst,
2007)
and
the
psychophysiological
mechanisms
of
some
psychopathologies, including depression, differ between the sexes, being the
females the most affected gender (Kim et al., 2010; Wooley et al., 2010). The source
of these differences can be gonadal steroids (Toufexis et al., 2006; Solomon and
Herman, 2009) and their possible effects on neurochemical pathways (Kelly et al.,
1999).
23
Regardless the mentioned relevant gender differences, most of the preclinical
studies use males instead of females (Olivier et al., 2008; Kim et al., 2010; Zucker
and Beery, 2010). In this respect, it is important to mention that not only mechanisms
related to diseases, but also normal cognition has been shown to differ between
sexes. Specifically, studies with animal models usually show better spatial learning in
males and stronger emotional memory in females (Canli et al., 2002; Astur et al.,
2004; Rilea et al., 2004; Hamann, 2005; Jonassom, 2005; Blokland et al., 2006).
Interestingly, in a recent work, Ribeiro et al. (2010) found decreased extinction of an
aversive memory task in female rats when compared to males. It was suggested that
a diminished capacity of extinction of aversive memories could be related to the
predominance of certain psychopathological disorders in this gender. Although
several animal studies were held to investigate the effects of antidepressants on
memory (Marks et al., 1998; Austin et al., 2001; MacQueen et al., 2002; Nestler et
al., 2002; Castaneda et al., 2007; Schulz et al., 2007; Paizanis et al., 2007), they
were mostly conducted with male subjects. In addition, few studies have aimed to
study the effects of antidepressants specifically on the extinction of aversive
memories. Some studies were conducted investigating the effects of rolipram (which
has both antidepressant and anxiolytic effects) on male rodents. In these studies,
decrements in extinction of conditioned fear and in fear-potentiated startle paradigms
were shown (Monti et al. 2006; Mueller et al., 2010). The same drug also had
improved cognition related to the Morris water maze and impaired extinction in a
passive avoidance task (Cheng et al., 2010). In another animal study, D-cycloserine
(used as an adjuvant in antidepressant therapy), enhanced extinction in a
conditioned fear task (Yamamoto et al., 2008).
24
In the present study, we investigated the effects of three antidepressants
(fluoxetine, nortriptyline and mirtazapine) of different pharmacological classes on
learning, memory and extinction of an aversive task in female rats, as well as anxiety
and depression-related behaviors in the same subjects. Fluoxetine is a selective
serotonin reuptake inhibitor (SSRI), the most prescribed class of antidepressants
(Dunlop and Davis, 2008). Nortriptyline is a tricyclic antidepressant, an older class of
drugs, and act by nonselective inhibition of monoaminergic reuptake. Although these
compounds are no longer largely prescribed, they are still an option to individuals
which are non-responsive to other antidepressants and to subjects susceptible to the
serotonin syndrome (Dagtekin et al., 2010). Finally, the atypical antidepressant
mirtazapine is used to treat both mood and anxiety disorders (Rauggi et al., 2005;
Gambi et al., 2005) and enhances central noradrenergic and serotonergic
neurotransmission through inhibition of the noradrenergic α2-autoreceptor and α2heteroreceptor in serotonergic synapses (Bengtsson et al., 2000; Gambi et al., 2005).
We used the plus-maze discriminative avoidance task (PMDAT) to evaluate
concomitantly memory and anxiety-related behaviors. Several studies performed with
this task have shown the effects of memory-enhancing or amnestic drugs,
procedures that modify anxiety-like behaviors and/or locomotor activity (Silva et al.,
1997; Silva and Frussa-Filho, 2000; Silva et al., 2002a; Silva et al., 2002b). It also fits
for the evaluation of learning and extinction processes, by the evaluation of aversive
arm avoidance across the behavioral sessions (Silva et al., 2004; Ribeiro et al., 2010;
see Methods). Additionally, female rats were also tested in the forced swimming test
(FST) in order to evaluate depression-related behaviors.
2. Materials and Methods
25
2.1 Animals
Three-month-old female Wistar rats (120–230g), from our own colony were
housed in groups of 4 animals in plastic cages (30 x 37 x 16 cm) in a room with
acoustic isolation, airflow and controlled conditions of temperature (24 – 26 °C),
humidity and luminosity (12h light: 12h dark, lights on 06h30). Food and water were
available ad libitum throughout the experiments. Animal care was according to
Brazilian law nº 11.794/2008 for the use of animals in research, and all experiments
were approved by the local ethical committee (CEUA-UFRN). All efforts were made
to minimize animal pain, suffering or discomfort as well as the number of animals
used.
2.2 Procedures and drugs
Animals were allocated to one of four groups (n=8 - 10): (a) treated with
fluoxetine (20mg/ml/kg daily; Medley, Brazil), (b) nortriptyline (20mg/ml/kg daily;
Novartis, Brazil), (c) mirtazapine (10mg/ml/kg daily; Torrent, India), or (d) vehicle
(physiological saline with Tween 20%), all injected intraperitoneally, once a day, for
20 days. The drugs were dilluted in physiological saline containing three drops of
Tween-20 per 1ml. The duration of treatments and doses were chosen based on
previous studies (Dazzi et al., 2001; Dulawa et al., 2003; Rauggi et al., 2005; Gambi,
2005; Rógòz, 2005; Consoni et al., 2006; Miyamoto et al., 2010; McNamara et al.,
2010; Rógòz, 2010). During the treatment period, injections were held simultaneously
with estrous cycle control (through vaginal smears) at 6 p.m. There was no
26
predominance of any stage among the experimental groups during the experiments
(data not shown). Rats were handled for the whole injection period, for 5 minutes per
day. From the 17th day of treatment onwards, behavioral tests started at 1:30 p.m.
and injections and cycle control continued at 6 p.m., after the behavioral procedure.
2.3 Plus-maze discriminative avoidance task (PMDAT)
In order to evaluate the effects of the antidepressants on learning, memory,
extinction and anxiety, we used the PMDAT. The apparatus is a modified elevated
plus-maze made of wood with two open arms (50 cm lenght x 15 cm width) and two
closed arms (50 cm lenght x 15 cm width x 40 cm high), in one of which aversive
stimuli (light and noise) were presented in the training session, as described
previously (Ribeiro et al., 2010). The animals were placed individually in the center of
the maze, for 10 minutes in each session, with the head turned to the intersection
between the open arms, to explore the maze. In the training session the aversive
stimuli (100-watt light and an 80 dB noise applied through a lamp and a speaker
placed over the aversive enclosed arm) were given every time the animal entered
this closed arm, remaining until the animal left the arm. In the testing/extinction
session, 24h later, the animal was allowed to explore the apparatus without the
stimuli (the lamp and the speaker were still present over the aversive arm, but turned
off). In both sessions the animals were also evaluated for other measures related to
anxiety. The other parameters used were risk assessment and head dipping. The risk
assessment behavior is defined by body stretching to look into the locations of the
apparatus before entering (or not) them (Rodgers et al., 1997). The head dipping was
characterized by an attempt to look ―under‖ the maze with the head pointing the floor
27
(Rodgers et al., 1997). A decrease in risk assessment behavior and an increase in
head dipping indicate less anxious behavior (Rodgers and Dalvi, 1997; Rodgers et
al., 1997). Distance traveled in the apparatus, percent time spent in the aversive
enclosed arm (time spent in aversive enclosed arm / time spent in both enclosed
arms) and percent time spent in open arms (time spent in open arms / time spent in
both open and enclosed arms) were registered min by min throughout the sessions
and used to evaluate motor activity, learning/memory/extinction and anxiety,
respectively. The behavior of the animals was monitored and analyzed by the videotracking software ANY-maze, Stoelting, USA.
2.4 Forced Swimming Test (FST)
For evaluation of the depression-related behaviors we used the FST (Porsolt
et al., 1977). This test consists in placing the animal in a cylinder (40 cm high, 25 cm
diameter) with water (30 cm deep) in a temperature of 24 to 27°C, for two
consecutive days. On the first day, animals were submitted to 15 min of forced
exposure (pre-test session) with no behavioral observation. In the second day, 24 h
after the pre-test session, rats were placed once again in the water tank (test
session) in the same conditions described above and total immobility duration,
climbing behavior and the latency to engage in immobility were registered for 5 min.
2.5 Statistical Analyses
Data from behavioral tests were analyzed with one- or two-way analysis of
variance (ANOVA) with Bonferroni‘s tests for post-hoc comparisons. In addition to the
28
total length of the sessions in the PMDAT, behavioral sessions were divided in 5
blocks of 2 minutes each. Comparison among these blocks was used to evaluate
learning (training) or extinction (test) of the task. ANOVAs with repeated measures
were used to compare the percent time spent in the aversive and open arm
throughout PMDAT sessions and pairwise comparisons was used. We used the
software SPSS (version 17) to perform the statistical analysis. Differences were
considered significant at p<0.05.
3. Results
Plus-maze discriminative avoidance task:
Groups of all treatments presented similar percentage of time spent in the
aversive enclosed arm in the training session, suggesting that all groups learned the
task [F (3,34) = 0.32; p = 0.811] (Fig. 1A). The analysis of the percent time in the
aversive arm with repeated measures ANOVA revealed a time (2 minutes session
blocks) effect [F (2,87) = 20.80; p < 0.001], but not treatment [F (3,31) = 0.73; p =
0.54] or time x treatment interaction effects [F (8,63) = 1.34; p = 0.226] (Fig. 1B).
Indeed, paired samples t-test showed that all groups presented significant
decrements in aversive arm exploration (comparing to first block), starting in the
second block for nortriptyline (t = 4.93; p = 0.002) and mirtazapine (t = 4.92; p =
0.002). From the third block onwards all groups showed significant decrements
(Block 3: vehicle t = 4.77, p < 0.001; fluoxetine t = 3.58, p = 0.007; nortriptyline t =
4.17, p = 0.004; mirtazapine t = 3.74, p = 0.007. Block 4: vehicle t = 3.56, p = 0.006;
fluoxetine t = 1.95, p = 0.08; nortriptyline t = 3.86, p = 0.006; mirtazapine t = 4.80, p =
0.002. Block 5: vehicle t = 5.05, p < 0.001; fluoxetine t = 2.33, p = 0.04; nortriptyline t
= 4.71, p < 0.002; mirtazapine t = 4.60, p = 0.002) compared to the percent time in
29
the aversive arm during the first session block (paired samples t-test) (Fig. 1B). The
ANOVA for the 2 minutes session blocks showed no difference between the groups
for each session (for the first block [F (3,34) = 0.58; p = 0.62], second [F (3,34) =
1.00; p = 0.40], third [F (3,34) = 1.04; p = 0.38], fourth [F (3,34) = 1.30; p = 0.29] and
fifth [F (3,34) = 2.03; p = 0.13]).
Comparison of the exploration of the aversive arm was marginally significant in
the test session [F (3,34) = 2.52; p = 0.07], and pos hoc analysis with Bonferroni‘s
test indicated no difference between the groups (p > 0.05) (Fig. 1C). The analysis of
the percent time in the aversive arm in two-minute session blocks throughout the test
session with repeated measures ANOVA revealed a time effect [F (3,68) = 3.57; p =
0.01] and time x treatment interaction [F (3, 31) = 53.72; p < 0.001] , but not a
treatment effect [F (8,63) = 1.34; p = 0.22] (Fig. 1D). Only vehicle- and fluoxetinetreated groups presented significant increases in aversive arm exploration compared
to the first block throughout the session [fluoxetine from the third block onwards
(block 3: t = -3.22, p = 0.01; block 4: t = -2.54, p = 0.03; block 5: t = -3.28, p = 0.01
and vehicle in the fourth and fifth blocks (t = -2.78, p = 0.02 and t = -3.32, p = 0.009,
respectively)]. None of the groups have shown significant changes in the second
block, and nortriptyline- mirtazapine-treated animals did not modify aversive arm
exploration across the session blocks (Block 2: vehicle t = -0.96, p = 0.35; fluoxetine t
= -1.74, p = 0.12; nortriptyline t = 0.42, p = 0.68; mirtazapine t = 1.60, p = 0.15. Block
3: vehicle t = -1.67, p = 0.12; nortriptyline t = 0.56, p = 0.58; mirtazapine t = 1.37, p =
0.21. Block 4: nortriptyline t = 0.29, p = 0.77; mirtazapine t = 0.49, p = 0.63. Block 5:
(nortriptyline t = -0.95, p = 0.37; mirtazapine t = 0.61, p = 0.56) compared to the
percent time in the aversive arm during the first session block (paired samples t-test)
(Fig. 1D).
30
Percentage of time spent in the open arms did not differ between different
treatments, suggesting that animals did not present anxiety-related differences
[training session: F (3,34) = 0.060; p = 0.98; test session: F (3,34) = 0.50; p = 0.68]
(Fig. 2). Similarly, no differences were found in the frequency of head dipping
[training session: F (3,34) = 1.352; p = 0.276; test session: F (3,34) = 0.060; p = 0.98]
(Fig.3C and D). A treatment effect was found for time spent in risk assessment in the
test [F (3,34) = 3.876; p = 0.018] (Fig. 3B), but not in the training session [F (3,34) =
0.278; p = 0.841] (Fig. 3A). In the test session, the post hoc with Bonferroni‘s test
showed a significant difference between vehicle and fluoxetine (p = 0.04), while the
comparison between vehicle and nortriptyline almost reached significance (p = 0.05).
When the whole sessions were considered for analysis, ANOVA revealed a
treatment effect in the distance traveled in the apparatus [F (3,34) = 4.56; p < 0.01]
and [F (3,34) = 3.86; p < 0.05] in training and test, respectively. Post hoc with
Bonferroni‘s test showed that animals treated with mirtazapine exhibited a
significantly decreased locomotor activity compared to the other groups (Table 1).
In the forced swimming test, ANOVA revealed a treatment effect in immobility
duration [F (3,33) = 13.64; p < 0.001]. Post hoc with Bonferroni‘s test showed that
animals treated with fluoxetine and mirtazapine had decreased immobility duration
compared with the control and nortriptyline groups (Fig. 4A). The latency to start
immobility was not different among the groups (data not shown). Moreover, ANOVA
revealed a treatment effect on climbing behavior [F (3,33) = 4.17; p = 0.014]. Post
hoc with Bonferroni‘s test showed that fluoxetine group had an increased time in
climbing behavior (p = 0.009) compared with nortriptyline group (Fig. 4B).
31
32
Figure 1. Percent time spent in the aversive arm (%TAV) of the plus-maze
discriminative avoidance task by female rats repeatedly treated with vehicle (vehi),
20mg/kg fluoxetine (fluox), 20 mg/kg nortriptyline (nort) or 10 mg/kg mirtazapine
(mirt): (A) The whole training session; (B) Blocks of two minutes across the training
session; (C) The whole test session; (D) Blocks of two minutes across the test
session. ANOVA with repeated measures revealed time effects (session blocks) in
training and test sessions; #p < 0.05 compared to first block (paired samples t-test).
33
Figure 2. Percent time spent in the open arms (%TAB) of the plus-maze
discriminative avoidance task by female rats repeatedly treated with vehicle (vehi),
20mg/kg fluoxetine (fluox), 20 mg/kg nortriptyline (nort) or 10 mg/kg mirtazapine
(mirt): (A) Training session; (B) Test session.
34
35
Figure 3. Time spent in risk assessment and frequency of head dipping on the plusmaze discriminative avoidance task by female rats repeatedly treated with vehicle
(vehi), 20mg/kg fluoxetine (fluox), 20 mg/kg nortriptyline (nort) or 10 mg/kg
mirtazapine (mirt): (A) Training session for risk assessment; (B) Test session for risk
assessment; (C) Training session for head dipping behavior; (D) Test session for
head dipping behavior. ANOVA revealed a treatment effect on risk assessment test
session; *p < 0.05 compared to vehicle; +p = 0.05 compared to vehicle (ANOVA
followed by Bonferroni‘s test).
36
Figure 4. Time spent in immobility and climbing behavior on the forced swim test by
female rats repeatedly treated with vehicle (vehi), 20mg/kg fluoxetine (fluox), 20
mg/kg nortriptyline (nort) or 10 mg/kg mirtazapine (mirt): (A) The time spent in
immobility on test session; (B) The time spent in climbing behavior on test session; *p
< 0.05 compared to vehi; §p < 0.05 compared to fluox and mirt; ¥p < 0.05 compared
to nort (ANOVA followed by Bonferroni‘s test).
37
Treatment
Training
Test
Vehicle
19,0±2,4
21,1±1,9
Fluoxetine
20,0±3,0
21,6±4,4
Nortriptyline
22,9±3,1
16,8±4,4
Mirtazapine
10,4±0,5*
8,5±2,3*
Table 1. Distance travelled in meters in both training and test session by female rats
repeatedly treated with vehicle, 20mg/kg fluoxetine, 20 mg/kg nortriptyline or 10
mg/kg mirtazapine; *p<0.05 compared to all other groups (ANOVA followed by
Bonferroni‘s test).
4. Discussion
In summary, our data showed that some antidepressants could interfere on
both learning and memory processes, more specifically on the acquisition and, more
importantly, extinction of an aversive task. The nortriptyline- and mirtazapine-treated
groups learned the task faster than the vehicle and fluoxetine counterparts, as
demonstrated by a significant decrease in the aversive arm exploration earlier in the
training session (see figure 1B). During the test session, vehicle and fluoxetine
groups have shown extinction of the task, i.e., significant increases in aversive arm
exploration across the session blocks, what did not occur in the other groups (see
figure 1D). Moreover, the extinction was anticipated by treatment with fluoxetine. The
treatment with fluoxetine and nortriptyline also reduced one of the anxiety-related
behaviors in the elevated plus-maze discriminative avoidance task (risk assessment
behavior, see figure 3B). Results obtained in the forced swimming test showed that
38
treatment with fluoxetine and mirtazapine reduced the immobility time, which is
consistent with the antidepressant-like effects of these drugs (see figure 4A).
As mentioned above, the analysis of the aversive arm exploration throughout
the test session of the PMDAT provides indication of both task retrieval (beginning of
session) and extinction (subsequent session blocks) (Ribeiro et al., 2010). Indeed,
with the aversive stimuli no longer present, the animals avoid the aversive arm at
first, but eventually realize the arm is now safe and increase its exploration, reaching
the amount they would explore a regular enclosed arm by chance (or even more,
since this arm is almost novel for them in the test session). This pattern is usually
observed in males, but in a previous study we have shown that female rats keep
avoiding the aversive arm until the end of the test, or even at a subsequent retest
(Ribeiro et al., 2010). The lack of extinction by females points out to stronger
consolidation and/or impaired extinction of aversive memories, which is in line with
the better emotional memory usually reported for women (Canli et al., 2002;
Hamann, 2005). In particularly, this lack of extinction is similar to what occur in some
anxiety disorders, as for example, the posttraumatic stress disorder (PTSD), and it
could be related to the greater prevalence of depression and anxiety disorders
among female gender (Kendler et al., 2001; Mahedran, 2005; Rauch et al., 2006;
Bekker and van Mens-Verhulst, 2007).
In the present study, however, females did show extinction of the task. The
amount of aversive arm exploration by the end of the test was still lower than that
previously observed for males, but this result suggests that the lack of extinction of
this task by females may not be unequivocal. Further, and more importantly, the
presented data indicated that the SSRI fluoxetine was capable of increasing or
speeding up the process of extinction in females. Although speculative, one might
39
raise the hypothesis that fluoxetine could exert its therapeutic action by modulating
the extinction of aversive memories. In line with this reasoning, this drug has been
shown potential benefits in the treatment of PTSD, which has a close relationship
with deficits in extinction of traumatic memories (APA, 2000; Quirk et al., 2006;
Yamamoto et al., 2008; 2009). Moreover, despite the effects of fluoxetine treatment
on males in the same test has not been investigated yet, these results, taking
together with previous extinction studies performed with males (see Introduction)
suggest an important role of gender in the ability of antidepressants in modifying
extinction.
The SSRIs are one of most commonly prescribed drugs for treating mood and
anxiety disorders (Marks et al., 1998; Brunello et al., 2001; Nandam et al., 2007).
Their action includes an improvement on cognitive deficits caused by the disease
(Austin et al., 2001; Castaneda et al., 2007) through the stimulation of the
neurogenesis in males (Duman and Monteggia, 2006; Dranovsky and Hen, 2006;
Nandam et al., 2007; Paizanis et al., 2007; Sahay and Hen, 2007; Pittenger and
Duman, 2008), which is also needed for the extinction process (Gabriele and
Packard., 2006). Treatment with fluoxetine also induces an increase in BDNF
releasing, which may cause reactivation of the neuronal plasticity (Castrén and
Rantamäki, 2010).
In addition, another study has shown that brain-derived
neurotrophic factor (BDNF) is also needed for the extinction of a memory (Gabriele
and Packard, 2006). However, further clarification is needed about the role of BDNF
in depression, because antidepressant effects of nortriptyline and escitalopram
appear to be unrelated to hippocampal BDNF expression in female rats, (Hansson et
al., 2011). Previous studies have demonstrated that antidepressants may induce
synaptic reorganization in the amygdala (McEwen and Chattarji, 2004). For example,
40
fluoxetine administered chronically to adult rats reduces, in the amygdala, the
polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule
involved in the synaptogenesis (Varea et al. 2007; Homberg et al., 2011). It has also
been proposed that some types of antidepressants could elicit an increase on the
perception of the threat cues and improve the trace of the formatted memory
avoiding or decreasing its extinction (Rawlings et al., 2010). In summary, it seems
plausible that the clinical action of antidepressants could be related to a modulation
of plastic processes related to extinction of aversive memories.
On the other hand, in the present study, both mirtazapine and nortriptyline
groups were not able to extinguish the task. This lack of extinction of the aversive
memory could be related to the disturbance on emotional processing and persistence
of the negative events instead of the neutral and good events (Beck et al., 1979;
Harmer, 2010). That could be due to the modulation promoted by these drugs of the
perception of the threat cues (Rawlings et al., 2010) and to the decrease of
perception of aversive and rewarding stimuli seen in clinical studies (Harmer et al.,
2006; McGabe et al., 2010). One of the effects of mirtazapine and nortriptyline is a
decrease on HPA axis activity (Schüle et al., 2002; 2006), which we expected would
improve the extinction, oppositely to what happened. An increase in HPA axis activity
could damage the extinction process, as shown in a study with post-sepsis rats which
received dexamethasone in low doses, and were tested on the inhibitory avoidance
task (Cassol-Jr et al., 2010). In addition, it is known that the higher the sensitivity to
cortisol, higher is the response to stressful events in the amygdala (Morgan and
LeDoux, 1995), and lower is the activation of hippocampus and prefrontal cortex
(Lebrón et al., 2004). As a result of these effects, a damage of the extinction of any
41
aversive memory formatted could appear (Morgan and LeDoux, 1995; Lebrón et al.,
2004; Quirk et al., 2006).
The hypolocomotor effects observed here in females treated with mirtazapine
have already been found in other studies in this same dose range (Reneric et al.,
2002) or not (Rauggi et al., 2005). It is interesting to note that, in the present study,
the hypolocomotor effects were specifically found in the plus-maze discriminative
avoidance task, i.e. they were not present in the forced swimming test. It is known
that mirtazapine enhances both 5-HT and NA neurotransmissions, yet differently
from monoamine reuptake inhibitors since its antidepressant effects are mediated
through the direct antagonism of both α2 and 5-HT2C receptors (de Boer et al., 1996;
Haddjeri et al., 1996). It has been shown that this mediation can cause
hypolocomotor effects (Franowicz et al., 2002). Mirtazapine also induces blockage of
histamine-H1 receptors, other possible mechanism that may produce sedation and
decrease the exploratory activity (Schüle et al., 2003; 2006; Gambi et al., 2005).
Usually, the clinical treatment with antidepressants, although possibly inducing
an increase in anxiety at the beginning of the treatment, has overall an anxiolytic
effect (for a review see Borsini et al., 2002; Drapier et al., 2006). Studies with male
rodents also have shown that the antidepressants could have an anxiolytic effect
acutely (Silva et al., 1999; Kurt et al., 2000; Holmes and Rodgers 2003; Drapier et
al., 2006). The treatment with antidepressants fluoxetine and nortriptyline reduced
the anxiety-related behaviors at least in one of the evaluated ethological parameters.
However, this effect was observed only in the test session. A possible explanation
would be that the presence of a stressful context (the aversive stimuli) in the training
session would interfere with evaluation of the anxiety-like behavior. Indeed, in the
test session the animals could explore more freely the apparatus and we could have
42
a better evaluation of the parameters. On the other hand, some authors argue that
the evaluation of anxiety-related behaviors in a re-exposition to the conventional
elevated plus-maze is not adequate, because the reasoning of the paradigm implies
novelty (File, 1990).
Still regarding possible anxiolytic effects of antidepressant drugs in animal
models, despite the fact that most of anxiety and mood disorders are twice more
frequent in females than in males (Bekker and van Mens-Verhulst, 2007) there is a
strong bias towards the use of male animals to study these phenotypes (Wald and
Wu, 2010; Zucker and Beery, 2010). This type of bias is not rare once most of drugs
are tested in males and most of behavioral apparatus were developed using male
rats. Thus it, is very important taking into account not only classical variables, but
also the ethopharmacological parameters, when studying females in elevated plusmaze and their derived apparatus Cruz et al. (1994) showed that classical variables,
like time spent in and number of entries into the open arms, which express ―anxiety‖
levels, loaded together with end-exploring, head dipping and risk assessment in a
principal components analysis. In addition, Carobrez and Bertoglio (2005)
emphasized the advantages of using this ethopharmacological measures for the
purpose of avoid false negative results, what normally occur if we consider only
classical parameters. To our knowledge, there were a few studies evaluating the
effects of chronic treatment with nortriptyline in behavioral tests related to anxiety.
For example, Brocco et al. (2002) showed that mice exposed to a novel environment
failed to elevate the locomotion suggesting absence of anxiolytic effect. In opposite,
the effects of chronic fluoxetine treatment were already been evaluated in the
literature with some studies demonstrating anxiolytic (Griebel et al., 1995; Durand et
43
al. 1999; Mirza et al., 2007) while others showed anxiogenic effects (File et al., 1999;
Robert et al., 2011).
The forced swimming test is normally used in the screening of antidepressant
drugs, with immobility duration levels being used to measure indices of ―behavioral
despair‖ (Borsini and Meli, 1988). Moreover, the immobility presented by the animal
is reversed by repeated antidepressant treatment and for this reason it is used as an
index of ‗depressive-like‘ state (Cryan et al., 2005; Porsolt et al., 1978). In the present
study, animals treated with fluoxetine and mirtazapine, as expected, showed
decreased time of immobility duration in the forced swimming test. However, females
treated with nortriptyline did not exhibit this decrease, at a dose that was previously
shown to be effective in a study with males (Consoni et al., 2006). They also showed
less climbing behavior than fluoxetine–treated animals, suggesting that nortriptyline
group were less active in this behavioral test. However, the possibility that these
effects were only due to alterations in locomotion seems unlikely, because in the
plus-maze discriminative avoidance task there were no significant decreases in
ambulation of nortriptyline-treated animals.
An important issue to consider when studying female rodents behavior is the
significant variation across the phases of the estrous cycle (Marcondes et al., 2001;
Milad et al., 2009). In the present study, the estrous cycle stage was determined daily
throughout treatment and behavioral procedures. In the behavioral test days, we did
not found any predominance of phase in the experimental groups. In this respect, it is
known that females in proestrous present low immobility duration in the forced
swimming test (Contreras et al., 1998). In addition, progesterone chronically
administered
at
low
doses
reverted
depressive-like
behaviors
and
had
antidepressant effects during the diestrous phase (Andrade et al., 2010). In the
44
present study it was not possible to separate the animals according to the cycle
phase in each behavioral experiment. Moreover, the relevance of this separation
would be jeopardized by the fact that a prolonged drug treatment was performed, i.e.,
all rats received drug treatment at all phases. Even so, more experiments are needed
to investigate if the lack of effect of nortriptyline group could be dependent on the
estrous cycle stage. In conclusion, data reported in the present study showed that
the treatment with antidepressant drugs modified the learning and extinction of an
aversive task of females. Groups treated with nortriptyline and mirtazapine
accelerated the learning of an aversive task compared to fluoxetine and vehicle. The
fluoxetine promoted an improvement on extinction of the discriminative task,
antecipating the process when compared to the vehicle counterparts. These results
contribute to the investigation of sex differences in the neurobiology of anxiety and
depression-related
disorders,
as
well
as
the
possibitily
of
gender-based
pharmacotherapy in the near future.
45
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Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international
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84
IV.
Considerações finais e conclusões
Os presentes resultados demonstraram que o grupo tratado com fluoxetina
manteve o aprendizado e a evocação da tarefa nos mesmos níveis que os
desempenhados pelo grupo veículo; porém exibiu uma aceleração no processo de
extinção da memória aversiva. A nortriptilina e a mirtazapina aumentaram a
velocidade de aprendizado da tarefa aversiva, o que pode ser relacionado a uma
ênfase aos estímulos aversivos, um efeito inesperado resultante do uso de
antidepressivos (Harmer et al. 2006; McGabe et al. 2010; Rawlings et al. 2010). Já
na sessão teste essas drogas impediram a extinção da tarefa. A nortriptilina
demonstrou efeitos na redução da ansiedade apenas sob um dos aspectos
etológicos, o que pode sugerir uma necessidade de maior dosagem para que
possam ser observados efeitos ansiolíticos mais expressivos em fêmeas. Essa
ausência de diferenças nos parâmetros mais clássicos do labirinto em cruz elevado
no tocante a ansiedade atenta para a importância da observação dos aspectos
etológicos no modelo utilizado. Além disso, as fêmeas tratadas com mirtazapina
exibiram uma menor atividade locomotora no treino e teste da EDLC, sugerindo um
efeito hipolocomotor da dose da droga utilizada, apesar de o mesmo não ocorrer
com machos nas mesmas condições (Rauggi 2005). Por fim, no TNF os grupos de
fêmeas tratados com fluoxetina e mirtazapina apresentaram decréscimo de
imobilidade, um resultado que sugere um efeito antidepressivo destas drogas neste
teste comportamental. O grupo tratado com fluoxetina ainda apresentou aumento do
tempo de escalada. Já a nortriptilina apresentou um resultado atípico no TNF,
sugerindo uma possível necessidade de aumento de dosagem para observação de
efeitos antidepressivos.
85
Estes resultados sugerem que a fluoxetina pode exercer sua ação terapêutica
facilitando a extinção de memórias aversivas, correlatas ou não a transtornos de
humor e ansiedade. A mirtazapina apesar de promover um efeito antidepressivo em
animais submetidos ao teste do nado forçado, não foi capaz de promover a extinção
da memória aversiva, o que sugere uma dissociação entre a melhora dos sintomas
depressivos e possíveis efeitos sobre a extinção da memória para esse fármaco.
Estudos como o nosso sugerem que a investigação das diferenças sexuais na
neurobiologia da ansiedade e transtornos associados à depressão pode contribuir
com a melhora na escolha mais adequada para o tratamento farmacológico mais
específico, com melhores efeitos em curto prazo e com menores efeitos colaterais
baseados no gênero. Além disso, nossos dados corroboram a premissa de que os
efeitos terapêuticos de ISRS podem estar relacionados à facilitação da extinção de
memórias aversivas. Mais estudos são necessários para o esclarecimento dos
mecanismos relacionados a esse efeito.
86
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