Reconsolidation of appetitive instrumental memory and the metaplastic effects of NMDA receptors blockade in rats

Piva, Alessandro

Reconsolidation, Extinction, Instrumental Learning, Metaplasticity, MK-801, Rats
Obesity is one of the leading cause of death in world’s population, due to the comorbidity with pathologies like cardiovascular or mental disorders. Deviating from its role as a primary need, obese and overweight people tend to use food as a source of pleasure or to relieve from anxiety, typical of addiction to drugs. Thus, due to the commonality with drug abuse, like the impulsive-to-compulsive progression or the neurotransmitters release, overconsumption of high palatable food has been described as a form of addiction. As initially done for fear and drug maladaptive memories, food addiction has been investigated with memory reconsolidation studies. Reconsolidation theory stated that after stabilization, memory can return into a vulnerable state with re-exposure to stimuli previously associated to the initial learning and, once reactivated and destabilized, it needs reconsolidation to be restabilized. During the vulnerable phase, memory can strengthened or disrupted, and memory disruption could prevent relapse. The processes of memory destabilization and restabilization have been shown to depend on glutamatergic signaling. Moreover, glutamate receptor activity has been proposed as modulated by metaplasticity, a novel concept according to which neural stimulation could influence future synaptic activity even after disappearing of the acute effect. Thus, the goals of the present project was to investigate i) whether sucrose instrumental memory can undergo reconsolidation and ii) if it is possible to block reconsolidation with the NMDARs antagonist MK-801 given under a metaplasticity protocol. After 10 days of training to sucrose self-administration, rats were fasted for 14 days and finally treated with vehicle or MK-801 24 hours before retrieval. Then, rats were exposed to memory retrieval (Ret) or no-retrieval (No-Ret) and, 24 hours later, a reinstatement test evaluated sucrose seeking behaviour. Separate groups of rats were sacrificed 2 hours after memory Ret/No-Ret for the molecular analyses of Zif268, rpS6P and glutamate receptors levels in memory and reward key brain areas: nucleus accumbens (NAc) and amygdala (Amy). Results showed that sucrose instrumental memory undergo reconsolidation, as indicated by the increase of Zif268 and rpS6P in NAc and Amy. These results were further supported by the increased level of GluN2B (destabilization marker) and GluA1 (reactivation marker) in Amy, leading us to propose the Zif268/rpS6P two-component molecular assay as a valid and reliable method for the assessment of instrumental memory reactivation and reconsolidation. Furthermore, we demonstrated that the metaplastic treatment with MK-801 significantly decreased instrumental responding at the behavioural test only when administrated 24 hours before Ret, and this inhibition was associated to a significant decrease of Zif268 in NAc shell and of rpS6P in central Amy. Moreover, acute MK-801 significantly increased GluA1, GluN2B and mGluR5 in NAc and GluN2B in Amy. Here we demonstrated that NMDARs blockade affected sucrose instrumental memory, hypothesizing that the metaplasticity effect of MK-801 could have induced a switch from reconsolidation-to-extinction occurrence. However, it remains to be clarified the molecular mechanisms allowing for instrumental responding inhibition even at time MK-801 has been completely eliminated, and whether this inhibition is long-lasting, making it a possible therapeutic treatment for relapse on food addiction.
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