Role of hippocampal NF-\u03baB and GluN2B in the memory acquisition impairment of experiences gathered prior to cocaine administration in rats

Rosa López-Pedrajas,Francisco J Romero,María V Sánchez-Villarejo,Jorge M Barcia,María Muriach,Borja Muriach,Inmaculada Almansa

doi:10.1038/s41598-021-99448-w

Abstract

Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.

Highlights

Cocaine abuse induces severe neurobehavioral changes that modify neuronal circuits, among others, the ones involved in learning and memory processes
Among the neuroadaptations triggered by cocaine, we find dopamine (DA) hypoactivity[11,12,13] and a significantly lower dopamine D2 receptor (D2R) binding after chronic consumption[11,12,14]
We must consider that the two major kinds of hippocampal-based synaptic plasticity are long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD)[20,21,22] and both, require NMDA receptors (NMDAR) activation[20]

Summary

Introduction

Cocaine abuse induces severe neurobehavioral changes that modify neuronal circuits, among others, the ones involved in learning and memory processes. We aimed to deep into the transcriptional cascades accounting for the memory impairment of experiences acquired prior to drug administration In this regard, among the neuroadaptations triggered by cocaine, we find dopamine (DA) hypoactivity[11,12,13] and a significantly lower dopamine D2 receptor (D2R) binding after chronic consumption[11,12,14]. Kaltschmidt et al reported that loss of neuronal NF-κB impairs spatial long-term memory formation and suggested a transcriptional cascade where NF-κB could control the CREB signaling pathway[18]. This transcription factor possesses an essential role in long-term memory formation, as well as in the neuroadaptative mechanisms associated to drug a ddiction[19]. Calcium entry through the above mentioned extra-synaptic NMDARs, activates a general and dominant CREB shut-off pathway[25]

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