Prophylactic efficacy of ketamine, but not the low-trapping NMDA receptor antagonist AZD6765, against stress-induced maladaptive behavior and 4E-BP1-related synaptic protein synthesis impairment

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 115; p. 110509
• Main Authors: Camargo, Anderson, Torrá, Ana Clara N.C., Dalmagro, Ana Paula, Valverde, Ana Paula, Kouba, Bruna R., Fraga, Daiane B., Alves, Eloise C., Rodrigues, Ana Lúcia S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 20.04.2022
• Subjects: Adaptor Proteins, Signal Transducing; Analgesics - pharmacology; Animals; Antidepressive Agents - pharmacology; Anxiety; AZD6765; Behavior, Animal; Cell Cycle Proteins; Depression; Hindlimb Suspension; Ketamine; Ketamine - pharmacology; Male; Mice; Phenethylamines - pharmacology; Prefrontal Cortex - drug effects; Prophylactic effect; Pyridines - pharmacology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Restraint, Physical - psychology; Depression; Anxiety; Prophylactic effect; Ketamine; AZD6765
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2022.110509

Ketamine enhances the resilience against stress-induced depressive-like behavior, but its prophylactic efficacy in anxiety-related behaviors remains to be elucidated. Moreover, there is a need for developing novel preventive strategies against depressive- and anxiety-like behavior. AZD6765, a low-trapping NMDA receptor antagonist, shares with ketamine common molecular targets and produces rapid-onset antidepressant effects, suggesting that it could be a prophylactic agent. Therefore, this study investigated the prophylactic effect of ketamine against the depressive- and anxiety-like behavior induced by chronic restraint stress (2 h/day, for 10 days) in mice. We also investigated if AZD6765 exerts a resilience-enhancing response against these maladaptive behaviors. The contribution of 4E-BP1-related synaptic proteins synthesis (PSD-95/GluA1) in the possible pro-resilience efficacy of ketamine and AZD6765 was investigated. A single administration of ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), given 1 week before the stress protocol, was effective in preventing stress-induced depressive-like behavior in the tail suspension test and splash test. Ketamine administered at 1 and 5 mg/kg (i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), prevented stress-induced anxiety-related self-grooming alterations. Stress-induced reduction on 4E-BP1 phosphorylation and PSD-95 and GluA1 immunocontent in the prefrontal cortex was prevented by ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.). The results indicate that ketamine, but not AZD6765, exerts a pro-resilience response against stress-induced maladaptive behavior, reinforcing that it could be a prophylactic agent to manage individuals at-risk to develop MDD and anxiety. •Ketamine promotes resilience against stress-induced depressive-like behavior.•Ketamine enhances the resilience against stress-induced anxiety-like behavior.•AZD6765 is not prophylactic against stress-induced maladaptive behavior.•Ketamine, but not AZD6765, prevents disturbances on 4E-BP1 and synaptic proteins.