Avaliação de alterações na cascata intracelular de sinalização dopaminérgica no núcleo accumbens relacionadas com a escalada da autoadministração de cocaína em ratos
Arquivos
Data
2023-07-11
Autores
Costa, Giovanna Victória Lopes 
Orientadores
Cruz, Fábio Cardoso
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A cocaína é uma das drogas ilícitas mais utilizadas mundialmente e seu uso vem aumentando nos últimos anos. Quando utilizada repetidamente, essa substância pode causar dependência, o que pode ocasionar consequências adversas para o usuário e para a sociedade. Sabe-se que apenas uma pequena, mas significativa, parcela de usuários de cocaína evolui para um quadro de dependência. Apesar de sua relevância, os mecanismos envolvidos na transição do uso ocasional para o compulsivo não estão totalmente elucidados. Evidências sugerem que neuroplasticidades no núcleo accumbens, promovidas pelo uso repetido de cocaína, podem desempenhar papel fundamental no desenvolvimento da dependência. O objetivo do presente estudo foi analisar alterações na cascata intracelular de sinalização da neurotransmissão dopaminérgica, que envolve receptores D1 e D2, fatores de transcrição CREB/CREB-P, DARPP-32 e a enzima tirosina hidroxilase (TH), no núcleo accumbens de ratos submetidos a diferentes protocolos de cocaína que predizem o uso ocasional ou compulsivo. Para isso, ratos Wistar machos foram treinados a autoadministrar cocaína intravenosamente por 12 dias consecutivos. Foram empregados dois modelos de acesso à autoadministração dessa substância: acesso restrito (1 hora/dia), modelo animal associado ao uso ocasional e acesso estendido (6 horas/dia), modelo associado com o uso compulsivo da droga. Como controle, dois grupos de animais autoadministraram sacarose 6% (m/v) nas mesmas condições de acesso descritas anteriormente. Imediatamente após a última sessão de autoadministração, os animais foram anestesiados, submetidos a eutanásia e seus encéfalos foram coletados. O núcleo accumbens foi dissecado para análise posterior das proteínas citadas acima, utilizando a técnica de Western Blotting. Nossos resultados para a autoadministração de cocaína mostram que os animais com acesso estendido à cocaína apresentam maior número de respostas na barra ativa em comparação com animais do grupo de acesso restrito. Por outro lado, não foram observadas diferenças entre os animais do grupo que autoadministraram sacarose no acesso restrito em comparação com os animais do grupo de acesso estendido. Nossos dados, para o Western Blotting mostram que os grupos com acesso estendido, independentemente do reforço, e os grupos de cocaína, independentemente do acesso, quando comparados aos respectivos grupos sacarose, apresentam diminuição na expressão de TH, D1, DARPP-32 constitutiva e tendência de diminuição de CREB-P e CREB. Assim, nossos resultados sugerem que a escalada no consumo de cocaína está associada a neuroadaptações no núcleo accumbens na via dopaminérgica.
Cocaine is one of the most widely used illicit drugs worldwide, and its use has been increasing in recent years. When used repeatedly, this substance can cause dependence, which can lead to adverse consequences for the user and society. It is known that only a small but significant portion of cocaine users develop a dependency. Despite its relevance, the mechanisms involved in the transition from occasional to compulsive use are not fully understood. Evidence suggests that neuroplasticity in the nucleus accumbens, promoted by repeated cocaine use, may play a key role in the development of addiction. The aim of this study was to analyze changes in the intracellular signaling cascade of dopaminergic neurotransmission, involving D1 and D2 receptors, CREB/CREB-P transcription factors, DARPP-32, and the enzyme tyrosine hydroxylase (TH), in the nucleus accumbens of rats subjected to different cocaine protocols that predict occasional or compulsive use. Male Wistar rats were trained to self-administer intravenous cocaine for 12 consecutive days. Two models of access to self-administration were employed: restricted access (1 hour/day), an animal model associated with occasional use, and extended access (6 hours/day), a model associated with compulsive drug use. As a control, two groups of animals self-administered 6% (w/v) sucrose under the same access conditions described earlier. Immediately after the last self-administration session, the animals were anesthetized, euthanized, and their brains were collected. The nucleus accumbens was dissected for further analysis of the aforementioned proteins using the Western blotting technique. Our results for cocaine self-administration show that animals with extended access to cocaine exhibit a higher number of active lever responses compared to animals in the restricted access group. On the other hand, no differences were observed between animals in the sucrose self-administration group under restricted access compared to animals in the extended access group. Our Western blotting data show that both the extended access groups, regardless of reinforcement, and the cocaine groups, regardless of access, exhibit a decrease in the expression of TH, D1, constitutive DARPP-32, and a tendency towards a decrease in CREB-P and CREB when compared to their respective sucrose groups. Thus, our results suggest that the escalation in cocaine consumption is associated with neuroadaptations in the nucleus accumbens in the dopaminergic pathway.
Cocaine is one of the most widely used illicit drugs worldwide, and its use has been increasing in recent years. When used repeatedly, this substance can cause dependence, which can lead to adverse consequences for the user and society. It is known that only a small but significant portion of cocaine users develop a dependency. Despite its relevance, the mechanisms involved in the transition from occasional to compulsive use are not fully understood. Evidence suggests that neuroplasticity in the nucleus accumbens, promoted by repeated cocaine use, may play a key role in the development of addiction. The aim of this study was to analyze changes in the intracellular signaling cascade of dopaminergic neurotransmission, involving D1 and D2 receptors, CREB/CREB-P transcription factors, DARPP-32, and the enzyme tyrosine hydroxylase (TH), in the nucleus accumbens of rats subjected to different cocaine protocols that predict occasional or compulsive use. Male Wistar rats were trained to self-administer intravenous cocaine for 12 consecutive days. Two models of access to self-administration were employed: restricted access (1 hour/day), an animal model associated with occasional use, and extended access (6 hours/day), a model associated with compulsive drug use. As a control, two groups of animals self-administered 6% (w/v) sucrose under the same access conditions described earlier. Immediately after the last self-administration session, the animals were anesthetized, euthanized, and their brains were collected. The nucleus accumbens was dissected for further analysis of the aforementioned proteins using the Western blotting technique. Our results for cocaine self-administration show that animals with extended access to cocaine exhibit a higher number of active lever responses compared to animals in the restricted access group. On the other hand, no differences were observed between animals in the sucrose self-administration group under restricted access compared to animals in the extended access group. Our Western blotting data show that both the extended access groups, regardless of reinforcement, and the cocaine groups, regardless of access, exhibit a decrease in the expression of TH, D1, constitutive DARPP-32, and a tendency towards a decrease in CREB-P and CREB when compared to their respective sucrose groups. Thus, our results suggest that the escalation in cocaine consumption is associated with neuroadaptations in the nucleus accumbens in the dopaminergic pathway.