Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.
Kaylene K A Scheil, Carla L Sánchez-Lafuente, Brady S Reive, Ciara S Halvorson, Jennifer Floyd, Hannah M O Reid, Jenessa N Johnston, Lisa E Kalynchuk, Hector J Caruncho
Progress in neuro-psychopharmacology & biological psychiatry June 8, 2024 DOI: 10.1016/j.pnpbp.2024.110998 via PubMed
Summary
AI-generated from the abstractChronic stress reduces reelin, a brain protein, in the hippocampus and causes depression-like behavior. A single dose of reelin or ketamine each reversed these behavioral and molecular effects within one hour, and the benefit lasted at least one week. When given together, reelin and ketamine showed additive effects after one week. The findings suggest that reelin-based treatments could become a new class of rapid-acting antidepressants.
Study at a glance
| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 120 |
| Population | Female Long Evans rats |
| Interventions | Reelin Ketamine |
| Dose | reelin 3μg; i.v., ketamine 10 mg/kg; i.p. |
| Duration | 21-day chronic corticosterone paradigm, with behavioral and biological evaluations at 1 h, 6 h, 12 h, and 1 week after treatment |
| Topics | Depression Ketamine |
| Keywords | Chronic stress Corticosterone Rapid-acting antidepressants Reelin |
| Citations | 5 |
| Key finding | Both reelin and ketamine individually reversed chronic stress-induced behavioral deficits and restored hippocampal reelin expression within one hour, with effects lasting at least one week, and their combination showed additive antidepressant-like effects at one week. |
Abstract
There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3μg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.