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

• Published in: Molecular neurobiology Vol. 56; no. 6; pp. 4061 - 4071
• Main Authors: Agrawal, Juhee, Ludwig, Birgit, Roy, Bhaskar, Dwivedi, Yogesh
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2019; Springer Nature B.V
• Subjects: Abuse; Adrenergic receptors; Amygdala; Animals; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Cell Biology; Enzyme-linked immunosorbent assay; Gene Expression Regulation - drug effects; Go/no-go discrimination learning; Hippocampus; Impulsive behavior; Impulsive Behavior - drug effects; Impulsivity; Kinases; Limbic system; Male; Mental disorders; Mood; Neurobiology; Neurology; Neurosciences; Prefrontal cortex; Protein kinase A; Proteins; Rats; Rats, Long-Evans; Receptors, Adrenergic, alpha-2 - genetics; Receptors, Adrenergic, alpha-2 - metabolism; Regulatory subunits; Signal transduction; Signal Transduction - drug effects; Social behavior; Suicide; Testosterone; Testosterone - administration & dosage; Testosterone - blood; Testosterone - pharmacology; Transcription; Transcription, Genetic - drug effects; Testosterone; Impulsivity; Noradrenergic system; Alpha-2A adrenergic receptor; Rodent model
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-1350-z

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-G
αs
[
Gnas
], inhibitory subunit-G
iα
[
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
G
αs
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.