Transcriptional Profile of Exercise-Induced Protection Against Relapse to Cocaine Seeking in a Rat Model

Eleanor Blair Towers; Daniel A Shapiro; Jean M Abel; Anousheh Bakhti-Suroosh; Kristyna Kupkova; David T Auble; Patrick A Grant; Wendy J Lynch

doi:10.1016/j.bpsgos.2023.01.007

Transcriptional Profile of Exercise-Induced Protection Against Relapse to Cocaine Seeking in a Rat Model

Biol Psychiatry Glob Open Sci. 2023 Feb 3;3(4):734-745. doi: 10.1016/j.bpsgos.2023.01.007. eCollection 2023 Oct.

Authors

Eleanor Blair Towers^{1

2}, Daniel A Shapiro³, Jean M Abel¹, Anousheh Bakhti-Suroosh¹, Kristyna Kupkova⁴, David T Auble⁴, Patrick A Grant⁵, Wendy J Lynch¹

Affiliations

¹ Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
² Medical Scientist Training Program, University of Virginia, Charlottesville, Virginia.
³ Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia.
⁴ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
⁵ Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida.

Abstract

Background: Exercise has shown promise as a treatment for cocaine use disorder; however, the mechanism underlying its efficacy has remained elusive.

Methods: We used a rat model of relapse (cue-induced reinstatement) and exercise (wheel running, 2 hours/day) coupled with RNA sequencing to establish transcriptional profiles associated with the protective effects of exercise (during early withdrawal [days 1-7] or throughout withdrawal [days 1-14]) versus noneffective exercise (during late withdrawal [days 8-14]) against cocaine-seeking and sedentary conditions.

Results: As expected, cue-induced cocaine seeking was highest in the sedentary and late-withdrawal exercise groups; both groups also showed upregulation of a Grin1-associated transcript and enrichment of Drd1-Nmdar1 complex and glutamate receptor complex terms. Surprisingly, these glutamate markers were also enriched in the early- and throughout-withdrawal exercise groups, despite lower levels of cocaine seeking. However, a closer examination of the Grin1-associated transcript revealed a robust loss of transcripts spanning exons 9 and 10 in the sedentary condition relative to saline controls that was normalized by early- and throughout-withdrawal exercise, but not late-withdrawal exercise, indicating that these exercise conditions may normalize RNA mis-splicing induced by cocaine seeking. Our findings also revealed novel mechanisms by which exercise initiated during early withdrawal may modulate glutamatergic signaling in dorsomedial prefrontal cortex (e.g., via transcripts associated with non-NMDA glutamate receptors or those affecting signaling downstream of NMDA receptors), along with mechanisms outside of glutamatergic signaling such as circadian rhythm regulation and neuronal survival.

Conclusions: These findings provide a rich resource for future studies aimed at manipulating these molecular networks to better understand how exercise decreases cocaine seeking.

Keywords: Cocaine seeking; Cocaine use disorder; Exercise; Extended-access cocaine self-administration; RNA sequencing; Treatment.

Abstract

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