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Chronic Testosterone Increases Impulsivity and Influences the Transcriptional Activity of the Alpha-2A Adrenergic Receptor Signaling Pathway in Rat Brain

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Abstract

Testosterone is an anabolic androgenic steroid hormone involved in brain development, reproduction, and social behavior. Several studies have shown that testosterone can cause impulsivity in humans, which in turn, is linked with mood-related psychiatric disorders and higher risk of death by suicide. The mechanisms by which testosterone abuse influences impulsivity are unclear. The present study aims to understand how testosterone influences impulsivity in a rodent model both at behavioral and molecular levels. In this study, rats were either only gonadectomized or gonadectomized and injected with supraphysiological doses of testosterone. Their relative impulsivity levels were assessed using the go/no-go task. Serum level of testosterone was measured using ELISA. Transcript levels of alpha-2A adrenergic receptor (Adra2a), G proteins (stimulatory subunit-Gαs [Gnas], inhibitory subunit-Giα [Gnai1 and Gnai2]), and catalytic and regulatory subunits of protein kinase A (PKA) were examined using quantitative PCR (qPCR) in brain areas associated with limbic system (prefrontal cortex (PFC), hippocampus, and amygdala). The testosterone-treated (T) group showed significantly higher level of serum testosterone and displayed a lower go/no-go ratio, indicating greater impulsivity compared to the gonadectomized (GDX) group. The transcript levels Adra2a and Gαs genes and PKA subunits encoded by Prkar1a, Prkar1b, Prkar2a, and Prkaca genes were significantly upregulated in PFC of testosterone treated rats. The expression levels of these genes were not significantly altered in hippocampus. On the other hand, amygdala showed changes only in Gnas and Prkar2a. These results suggest that chronic testosterone influences impulsivity possibly via hyperactive alpha-2A adrenergic receptor-PKA signaling axis, specifically in the PFC.

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Acknowledgments

We would like to acknowledge Kevin Prall and Lauren Allen for technical assistance.

Funding

The research was supported by grants from the National Institute of Mental Health (R01MH082802, 1R01MH101890, R01MH100616, 1R01MH107183-01) to Dr. Dwivedi. The sponsoring agency had no role in study design, collection, analysis, interpretation of data, and in the writing of the manuscript.

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  1. Juhee Agrawal and Birgit Ludwig contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, SC711 Sparks Center 1720 7th Avenue South, Birmingham, AL, 35294, USA

    Juhee Agrawal, Birgit Ludwig, Bhaskar Roy & Yogesh Dwivedi

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  1. Juhee Agrawal
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  2. Birgit Ludwig
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Correspondence to Yogesh Dwivedi.

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Agrawal, J., Ludwig, B., Roy, B. et al. Chronic Testosterone Increases Impulsivity and Influences the Transcriptional Activity of the Alpha-2A Adrenergic Receptor Signaling Pathway in Rat Brain. Mol Neurobiol 56, 4061–4071 (2019). https://doi.org/10.1007/s12035-018-1350-z

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