Agmatine potentiates antidepressant and synaptic actions of ketamine: Effects on dendritic arbors and spines architecture and Akt/S6 kinase signaling

• Published in: Experimental neurology Vol. 333; p. 113398
• Main Authors: Freitas, Andiara E., Heinrich, Isabella A., Moura, Tainara M., Fraga, Daiane B., Costa, Ana P., Azevedo, Dayane, Brocardo, Patricia S., Kaster, Manuella P., Leal, Rodrigo B., Rodrigues, Ana Lúcia S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2020
• Subjects: Agmatine; Agmatine - pharmacology; Akt/p70S6K signaling; AMPA receptor subunit GluR1; Animals; Antidepressive Agents - pharmacology; Dendrites - drug effects; Dendrites - ultrastructure; Dendritic arbor; Dendritic spine; Dendritic Spines - drug effects; Dendritic Spines - ultrastructure; Drug Synergism; Hindlimb Suspension; Ketamine; Ketamine - pharmacology; Male; Mice; Motor Activity - drug effects; Oncogene Protein v-akt - drug effects; Prefrontal Cortex - drug effects; Ribosomal Protein S6 Kinases - drug effects; Signal Transduction - drug effects; Synapses - drug effects; Akt/p70S6K signaling; AMPA; p70S6K; Agm; PKB; i.p; Dendritic arbor; MDD; p.o; GSK-3β; Ketamine; PSD95; PI3K; TST; AMPA receptor subunit GluR1; ANOVA; Dendritic spine; mTOR; NMDA; GluA1; Ket; Agmatine; mTORC1; ERK
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113398

We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.
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•The synergism of agmatine and ketamine produces an antidepressant-like effect.•Agmatine potentiates ketamine's dendritic arbors and spines remodeling effects.•Agmatine's enhancer effects of ketamine involves Akt/S6K signaling activation.•Agmatine augments ketamine's effects in a time-dependent manner.