Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence

Érika Kestering-Ferreira; Bernardo Aguzzoli Heberle; Francisco Sindermann Lumertz; Pedro Henrique Gobira; Rodrigo Orso; Rodrigo Grassi-Oliveira; Thiago Wendt Viola

doi:10.1016/j.neulet.2024.137898

Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence

Érika Kestering-Ferreira, Bernardo Aguzzoli Heberle, Francisco Sindermann Lumertz, Pedro Henrique Gobira, Rodrigo Orso, Rodrigo Grassi-Oliveira, Thiago Wendt Viola^*

^*Corresponding author for this work

Department of Clinical Medicine - Translational Neuropsychiatry Unit

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. Materials and methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. Results: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. Conclusions: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

Original language	English
Article number	137898
Journal	Neuroscience Letters
Volume	837
ISSN	0304-3940
DOIs	https://doi.org/10.1016/j.neulet.2024.137898
Publication status	Published - Aug 2024

Keywords

Adolescence
Dopamine
Epigenetics
Fentanyl
Opioids
Sex differences

Access to Document

10.1016/j.neulet.2024.137898

Cite this

@article{d7069a2cf9ac4b21a79205db992f0144,

title = "Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence",

abstract = "Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. Materials and methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. Results: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. Conclusions: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.",

keywords = "Adolescence, Dopamine, Epigenetics, Fentanyl, Opioids, Sex differences",

author = "{\'E}rika Kestering-Ferreira and Heberle, {Bernardo Aguzzoli} and {Sindermann Lumertz}, Francisco and Gobira, {Pedro Henrique} and Rodrigo Orso and Rodrigo Grassi-Oliveira and Viola, {Thiago Wendt}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = aug,

doi = "10.1016/j.neulet.2024.137898",

language = "English",

volume = "837",

journal = "Neuroscience Letters",

issn = "0304-3940",

publisher = "Elsevier Ireland Ltd.",

}

Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence. / Kestering-Ferreira, Érika; Heberle, Bernardo Aguzzoli; Sindermann Lumertz, Francisco et al.
In: Neuroscience Letters, Vol. 837, 137898, 08.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Sex differences in sensitivity to fentanyl effects in mice

T2 - Behavioral and molecular findings during late adolescence

AU - Kestering-Ferreira, Érika

AU - Heberle, Bernardo Aguzzoli

AU - Sindermann Lumertz, Francisco

AU - Gobira, Pedro Henrique

AU - Orso, Rodrigo

AU - Grassi-Oliveira, Rodrigo

AU - Viola, Thiago Wendt

PY - 2024/8

Y1 - 2024/8

N2 - Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. Materials and methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. Results: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. Conclusions: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

AB - Purpose: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. Materials and methods: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the μ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. Results: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. Conclusions: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

KW - Adolescence

KW - Dopamine

KW - Epigenetics

KW - Fentanyl

KW - Opioids

KW - Sex differences

UR - http://www.scopus.com/inward/record.url?scp=85198751473&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2024.137898

DO - 10.1016/j.neulet.2024.137898

M3 - Journal article

C2 - 39013536

AN - SCOPUS:85198751473

SN - 0304-3940

VL - 837

JO - Neuroscience Letters

JF - Neuroscience Letters

M1 - 137898

ER -

Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this