Investigação das projeções Accumbens-Mesencefálica e Palidal na renovação do comportamento de busca de etanol induzida pelo contexto em ratos
Data
2023-05-24
Autores
Zaniboni, Caroline Riberti 
Orientadores
Cruz, Fabio Cardoso
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O consumo de drogas está diretamente relacionado ao curso da humanidade. Na atualidade o álcool é a
substância de abuso mais consumida no mundo. O uso abusivo e compulsivo desta droga é considerado um
grave problema de saúde pública e não há um tratamento efetivo, vide os altos índices de recaída. Um dos
principais fatores relacionados a recaída é a exposição do indivíduo ao ambiente associado ao uso da
substância. O Núcleo Accumbens é uma das principais estruturas encefálicas envolvidas na dependência de
drogas de abuso, desta forma o conhecimento acerca de suas projeções neurais é de grande importância para
elucidar os mecanismos envolvidos nos transtornos por uso de substâncias. As vias de saída do Núcleo
Accumbens para os gânglios da base estão envolvidas em comportamentos de aprendizado associativo e busca
por drogas. As principais projeções eferentes do Accumbens são para o Pálido Ventral (VP) e Mesencéfalo
Ventral (substância negra reticulada e área tegmental ventral - SNr/VTA) e os principais neurônios desta
estrutura são os neurônios espinhosos de projeção do tipo D1 e D2. Neste sentido, o objetivo geral desse projeto
foi investigar o papel das vias accumbens-palidal e accumbens-mesencefálica no comportamento de renovação
da busca de etanol induzida pelo contexto. Para isso, ratos Long Evans machos foram submetidos ao o modelo
de renovação contextual ABA e através de técnicas de imunoistoquímica, marcação retrógrada, desconexão
farmacológica e inibição quimiogenética investigamos a participação dessas vias no comportamento de
renovação da busca de etanol induzida pelo contexto. Os resultados demonstraram que no teste de renovação
da busca de álcool induzida pelo contexto houve maior ativação do pálido ventral e Núcleo Accumbens, mas
não da substância negra reticulada. Como também, foi observada ativação das vias accumbens-palidal e
accumbens-mesencefálica, por marcação retrógrada. Dando continuidade para um investigação mais funcional,
foi observado que a desconexão farmacológica da projeção accumbens-mesencefálica promoveu inibição da
busca de etanol induzida pelo contexto. A inibição de neurônios espinhosos de projeção do tipo D1 do núcleoaccumbens
por si só promoveu diminuição desse comportamento, no entanto, a inibição farmacológica da SNr
não promoveu nenhuma alteração na renovação da busca de etanol induzida pelo contexto. Por fim, foi
demonstrado que a inibição quimiogenética da via accumbens-palidal não bloqueou esse comportamento.
Desta forma, os resultados sugerem que a renovação do comportamento de busca de etanol induzida pelo
contexto parece ser coordenada por projeções do Núcleo Accumbens para a VTA/SNr de ambos os hemisférios.
Drug consumption is directly related to the course of humanity. Currently, alcohol is the most consumed substance of abuse in the world. The abusive and compulsive use of this drug is considered a serious public health problem, and there is no effective treatment, as evidenced by high relapse rates. One of the main factors related to relapse is the individual's exposure to the environment associated with substance use. The nucleus accumbens is one of the main brain structures involved in drug addiction, and knowledge of its neural projections is crucial to elucidate the mechanisms involved in substance use disorders. The efferent pathways from the nucleus accumbens to the basal ganglia are involved in associative learning and drug seeking behaviors. The main efferent projections of the Accumbens are to the Ventral Pallidum (VP) and Ventral Mesencephalon (reticular substantia nigra and ventral tegmental area - SNr/VTA), and the main neurons of this structure are the D1 and D2 projection spiny neurons. Therefore, the general objective of this project was to investigate the role of the accumbens-pallidal and accumbens-mesencephalic pathways in the relapse behavior induced by contextual alcohol seeking. Male Long Evans rats were subjected to the ABA contextual renewal model, and through immunohistochemistry, retrograde labeling, pharmacological disconnection, and chemogenetic inhibition, we investigated the participation of these pathways in relapse behavior induced by context. The results showed that during the reinstatement behavior induced by contextual alcohol seeking, there was greater activation of the ventral pallidum and nucleus accumbens, but not the reticular substantia nigra. It was also observed that the accumbens-pallidal and accumbens-mesencephalic pathways were activated through retrograde labeling. Continuing with a more functional investigation, pharmacological disconnection of the accumbens-mesencephalic projection promoted inhibition of contextual alcohol seeking, whereas inhibition of D1 projection spiny neurons in the nucleus accumbens alone led to a decrease in this behavior. However, pharmacological inhibition of SNr did not produce any changes in alcohol seeking induced by context. Finally, chemogenetic inhibition of the accumbens-pallidal pathway did not block this behavior. Thus, our results suggest that reinstatement of alcohol seeking induced by context appears to be coordinated by projections from the nucleus accumbens to the VTA/SNr of both hemispheres.
Drug consumption is directly related to the course of humanity. Currently, alcohol is the most consumed substance of abuse in the world. The abusive and compulsive use of this drug is considered a serious public health problem, and there is no effective treatment, as evidenced by high relapse rates. One of the main factors related to relapse is the individual's exposure to the environment associated with substance use. The nucleus accumbens is one of the main brain structures involved in drug addiction, and knowledge of its neural projections is crucial to elucidate the mechanisms involved in substance use disorders. The efferent pathways from the nucleus accumbens to the basal ganglia are involved in associative learning and drug seeking behaviors. The main efferent projections of the Accumbens are to the Ventral Pallidum (VP) and Ventral Mesencephalon (reticular substantia nigra and ventral tegmental area - SNr/VTA), and the main neurons of this structure are the D1 and D2 projection spiny neurons. Therefore, the general objective of this project was to investigate the role of the accumbens-pallidal and accumbens-mesencephalic pathways in the relapse behavior induced by contextual alcohol seeking. Male Long Evans rats were subjected to the ABA contextual renewal model, and through immunohistochemistry, retrograde labeling, pharmacological disconnection, and chemogenetic inhibition, we investigated the participation of these pathways in relapse behavior induced by context. The results showed that during the reinstatement behavior induced by contextual alcohol seeking, there was greater activation of the ventral pallidum and nucleus accumbens, but not the reticular substantia nigra. It was also observed that the accumbens-pallidal and accumbens-mesencephalic pathways were activated through retrograde labeling. Continuing with a more functional investigation, pharmacological disconnection of the accumbens-mesencephalic projection promoted inhibition of contextual alcohol seeking, whereas inhibition of D1 projection spiny neurons in the nucleus accumbens alone led to a decrease in this behavior. However, pharmacological inhibition of SNr did not produce any changes in alcohol seeking induced by context. Finally, chemogenetic inhibition of the accumbens-pallidal pathway did not block this behavior. Thus, our results suggest that reinstatement of alcohol seeking induced by context appears to be coordinated by projections from the nucleus accumbens to the VTA/SNr of both hemispheres.
Descrição
Citação
ZANIBONI, Caroline Riberti. Investigação das projeções Accumbens-Mesencefálica e Palidal na renovação do comportamento de busca de etanol induzida pelo contexto em Ratos. 2023. 176 f. Tese (Doutorado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo, 2023.