title: Nandrolone-induced aggressive behavior is associated with alterations in extracellular glutamate homeostasis in mice.
abstract: Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is interconnected with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of the NMDAr antagonists, memantine or MK-801, shortly before the intruder test decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Kalinine
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Eduardo Rigon
authors.initials: ER
authors.lastname: Zimmer
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Kamila Cagliari
authors.initials: KC
authors.lastname: Zenki
authors.affiliation: Laboratory of Exercise Physiology and Human Performance, Federal University of Santa Maria (UFSM), Rio Grande do Sul, Santa Maria, Brazil.
authors.forename: Iouri
authors.initials: I
authors.lastname: Kalinine
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kazlauckas
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Clarissa Branco
authors.initials: CB
authors.lastname: Haas
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Hansel
authors.affiliation: Pharmaceutical Sciences Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Aline Rigon
authors.initials: AR
authors.lastname: Zimmer
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, University of Extremo Sul Catarinense (UNESC), Criciúma, Santa Catarina, Brazil.
authors.forename: Alexandre Pastoris
authors.initials: AP
authors.lastname: Müller
authors.affiliation: Department of Biochemistry, Post-Graduation Program in Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: roskaportela@gmail.com.
authors.forename: Luis Valmor
authors.initials: LV
authors.lastname: Portela
mesh_terms: D000374:Aggression / Q000187:drug effects*; D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009277:Nandrolone / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
chemical_list: D045930:Anabolic Agents; D027341:Excitatory Amino Acid Transporter 1; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D009277:Nandrolone
keywords: Aggressive behavior; Glutamate transporter 1 (GLT-1); MK-801; Memantine; N-methyl-d-aspartate receptor (NMDAr); Nandrolone decanoate