The involvement of PI3K/Akt/mTOR/GSK3β signaling pathways in the antidepressant-like effect of AZD6765

Autor: Priscila B. Rosa, Axel Fogaça Rosado, Isabel Werle, Morgana Moretti, Ana Lúcia S. Rodrigues, Vivian B. Neis, Fernanda Neutzling Kaufmann, Yasmim de Oliveira Dalsenter, Matheus Henrique Besen, Nicolle Platt
Rok vydání: 2020
Předmět:
Pyridines
Clinical Biochemistry
Pharmacology
Toxicology
Hippocampus
Biochemistry
Wortmannin
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Behavioral Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Stress
Physiological
Phenethylamines
medicine
Animals
Urea
LY294002
Phosphorylation
Protein kinase B
Biological Psychiatry
PI3K/AKT/mTOR pathway
Sirolimus
Glycogen Synthase Kinase 3 beta
Behavior
Animal
Depression
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
70-kDa
Psychotomimetic
Antidepressive Agents
Tail suspension test
030227 psychiatry
Drug Combinations
Thiazoles
Hindlimb Suspension
chemistry
Lanicemine
NMDA receptor
Female
Ketamine
Lithium Chloride
Open Field Test
Proto-Oncogene Proteins c-akt
030217 neurology & neurosurgery
Signal Transduction
medicine.drug
Zdroj: Pharmacology Biochemistry and Behavior. 198:173020
ISSN: 0091-3057
DOI: 10.1016/j.pbb.2020.173020
Popis: AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 μg/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, (0.01 μg/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3β signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr389) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3β.
Databáze: OpenAIRE
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