Glutamate transporter-1 link astrocytes with heightened aggressive behavior induced by steroid abuse in male CF1 mice

The astrocytic glutamate transporter GLT-1 performs glutamate uptake thereby mediating NMDAr responses in neurons. Ceftriaxone (CEF) upregulates astrocytic GLT-1 expression/activity, which could counteract excessive glutamate levels and aggressive behavior induced by anabolic synthetic steroids such as nandrolone decanoate (ND). Here, adult male CF-1 mice were allocated to oil (VEH), ND, CEF, and ND/CEF groups. Mice were subcutaneously (s.c.) injected with ND (15 mg/kg) or VEH for 19 days, and received intraperitoneal (i.p.) injections of CEF (200 mg/kg) or saline for 5 days. The ND/CEF group received ND for 19 days plus coadministration of CEF in the last 5 days. On the 19th day, the aggressive phenotypes were evaluated through the resident-intruder test. After 24 h, cerebrospinal fluid was collected to measure glutamate levels, and the pre-frontal cortex was used to assess GLT-1, pGluN2B^Tyr1472, and pGluN2A^Tyr1246 by Western blot. Synaptosomes from the left brain hemisphere was used to evaluate mitochondrial function including complex II-succinate dehydrogenase (SDH), Ca²⁺ handling, membrane potential (ΔѰ_m), and H₂O₂ production. ND decreased the latency for the first attack and increased the number of attacks by the resident mice against the intruder, mechanistically associated with an increase in glutamate levels and pGluN2B^Tyr1472 but not pGluN2A^Tyr1244, and GLT-1 downregulation. The abnormalities in mitochondrial Ca²⁺ influx, SDH, ΔѰ_m, and H₂O₂ implies in deficient energy support to the synaptic machinery. The ND/CEF group displayed a decreased aggressive behavior, normalization of glutamate and pGluN2B^Tyr1472levels, and mitochondrial function at synaptic terminals. In conclusion, the pharmacological modulation of GLT-1 highlights its relevance as an astrocytic target against highly impulsive and aggressive phenotypes.