Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Jun 8:132:110998. doi: 10.1016/j.pnpbp.2024.110998. Epub 2024 Mar 27.

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.

Keywords: Chronic stress; Corticosterone; Depression; Ketamine; Rapid-acting antidepressants; Reelin.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Corticosterone* / metabolism
  • Depression / chemically induced
  • Depression / drug therapy
  • Female
  • Hippocampus / metabolism
  • Ketamine* / pharmacology
  • Ketamine* / therapeutic use
  • Rats
  • Rats, Long-Evans
  • Reelin Protein / pharmacology
  • Reelin Protein / therapeutic use

Substances

  • Antidepressive Agents
  • Corticosterone
  • Ketamine
  • Reelin Protein