The metaplastic effects of ketamine on sucrose renewal and contextual memory reconsolidation in rats

Metaplastic effects of the NMDARs blocker ketamine at the neural and behavioural levels have been described as potential mechanisms underlying the beneficial effects in treatment-resistant depression. However, ketamine effects on addictive behaviours are still unexplored. In the present study, we investigated the effects of ketamine given under a "metaplasticity-inducing dose regimen" on sucrose-related renewal and contextual memory reconsolidation in rats. After a molecular analysis of ketamine modulation of GluN2B, GluA1 and mGluR5 receptors levels in nucleus accumbens, hippocampus and amygdala, two behavioural models were used to investigate ketamine effects: i) context-induced renewal of sucrose-seeking, and ii) sucrose memory reconsolidation. Ketamine was administrated 24 h before the renewal test or the retrieval. At the molecular level, ketamine i) decreased GluN2B, GluA1 and mGluR5 receptors in hippocampus, ii) decreased GluA1 and mGluR5 but increased GluN2B in nucleus accumbens and iii) increased GluN2B and mGluR5 in amygdala. At the behavioural level, ketamine given prior to renewal significantly inhibited responding compared to vehicle, while no significant effects were observed on reconsolidation of contextual memory. In conclusion, the molecular analysis of ketamine metaplastic effects in key brain areas suggest a possible involvement of glutamatergic receptors in the inhibition of sucrose renewal but not of contextual memory reconsolidation. The inhibition of renewal could be correlated to hippocampal and accumbal decreased levels of GluA1 and mGluR5, whereas, the lack of effect on contextual memory reconsolidation could be correlated to decreased GluN2B expression in hippocampus, landmark of destabilization-insensitive state.