Beyond Classical Reward Circuits: Dorsal Striatum Proteomic Alterations in an Adolescent Phencyclidine-Induced Mouse Model of Schizophrenia and Nicotine Use
- 1Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, 5 Andar—Vila Isabel, Rio de Janeiro 20550-170, RJ, Brazil
- 2Departamento de Ciências Biomédicas e Saúde, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Cabo Frio 28905-320, RJ, Brazil
- 3Departamento de Ciências, Faculdade de Formação de Professores, Universidade do Estado do Rio de Janeiro (UERJ), São Gonçalo 24435-005, RJ, Brazil
Abstract
Schizophrenia and nicotine misuse comorbidity frequently emerges during adolescence. Although the dorsal striatum has received less attention than mesolimbic regions in this context, growing evidence supports its involvement in both schizophrenia-related dysfunction and the transition to compulsive drug-seeking. Here, we investigated dorsal striatal proteomic alterations in adolescent male and female C57BL/6 mice modeled to schizophrenia (phencyclidine: 2.5 mg/kg, s.c., 15 days) with a history of nicotine exposure (nicotine: 24 mg/kg/day, minipump infusions, 7 days). Dorsal striatum samples were analyzed by label-free quantitative proteomics, followed by Reactome pathway enrichment and interactome map analyses. Co-exposure induced sex-dependent alterations. Females exhibited greater proteomic disruption, whereas in males, co-exposure amplified phencyclidine-associated alterations while attenuating nicotine-driven effects. Across sexes, convergent enrichment was observed in pathways related to immune signaling, metabolic regulation and signal transduction. Female interactome analysis identified glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as the most highly connected node linked to proteins involved in bioenergetics, RNA processing, and apoptosis, while the male network was centered on peptidyl-prolyl cis-trans isomerase (Fkbp1a) and associated with proteostasis-related processes. Our results identify the dorsal striatum as an emerging molecular target in an animal model combining schizophrenia-related and nicotine exposure-related insults and highlight pathways and candidate molecular markers to be further investigated and validated.
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BibTeX
@article{souza2026beyond,
title = {{Beyond Classical Reward Circuits: Dorsal Striatum Proteomic Alterations in an Adolescent Phencyclidine-Induced Mouse Model of Schizophrenia and Nicotine Use}},
author = {Thainá Pereira Souza and Andrés Rodríguez-Vega and Ana Carolina Dutra-Tavares and Keila Alves Semeão and Claudio Carneiro Filgueiras and Anderson Ribeiro-Carvalho and Alex Christian Manhães and Yael Abreu-Villaça},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209328},
url = {https://www.mdpi.com/1422-0067/27/20/9328},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond Classical Reward Circuits: Dorsal Striatum Proteomic Alterations in an Adolescent Phencyclidine-Induced Mouse Model of Schizophrenia and Nicotine Use
AU - Thainá Pereira Souza
AU - Andrés Rodríguez-Vega
AU - Ana Carolina Dutra-Tavares
AU - Keila Alves Semeão
AU - Claudio Carneiro Filgueiras
AU - Anderson Ribeiro-Carvalho
AU - Alex Christian Manhães
AU - Yael Abreu-Villaça
PY - 2026
DA - 2026/10/20
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209328
UR - https://www.mdpi.com/1422-0067/27/20/9328
AB - Schizophrenia and nicotine misuse comorbidity frequently emerges during adolescence. Although the dorsal striatum has received less attention than mesolimbic regions in this context, growing evidence supports its involvement in both schizophrenia-related dysfunction and the transition to compulsive drug-seeking. Here, we investigated dorsal striatal proteomic alterations in adolescent male and female C57BL/6 mice modeled to schizophrenia (phencyclidine: 2.5 mg/kg, s.c., 15 days) with a history of nicotine exposure (nicotine: 24 mg/kg/day, minipump infusions, 7 days). Dorsal striatum samples were analyzed by label-free quantitative proteomics, followed by Reactome pathway enrichment and interactome map analyses. Co-exposure induced sex-dependent alterations. Females exhibited greater proteomic disruption, whereas in males, co-exposure amplified phencyclidine-associated alterations while attenuating nicotine-driven effects. Across sexes, convergent enrichment was observed in pathways related to immune signaling, metabolic regulation and signal transduction. Female interactome analysis identified glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as the most highly connected node linked to proteins involved in bioenergetics, RNA processing, and apoptosis, while the male network was centered on peptidyl-prolyl cis-trans isomerase (Fkbp1a) and associated with proteostasis-related processes. Our results identify the dorsal striatum as an emerging molecular target in an animal model combining schizophrenia-related and nicotine exposure-related insults and highlight pathways and candidate molecular markers to be further investigated and validated.
SN - 1422-0067
ER -