Cocaine Self-Administration and Abstinence Modulate NMDA Receptor Subunits and Active Zone Proteins in the Rat Nucleus Accumbens.

Irena Smaga,Małgorzata Filip,Fabio Fumagalli,Karolina Wydra,Małgorzata Frankowska,Marek Sanak

doi:10.3390/molecules25153480

Abstract

Cocaine-induced plasticity in the glutamatergic transmission and its N-methyl-d-aspartate (NMDA) receptors are critically involved in the development of substance use disorder. The presynaptic active zone proteins control structural synaptic plasticity; however, we are still far from understanding the molecular determinants important for cocaine seeking behavior. The aim of this study was to investigate the effect of cocaine self-administration and different conditions of cocaine forced abstinence on the composition of the NMDA receptor subunits and on the levels of active zone proteins, i.e., Ras-related protein 3A (Rab3A), Rab3 interacting molecules 1 (RIM1) and mammalian uncoordinated protein 13 (Munc13) in the rat nucleus accumbens. We found an up-regulation of the accumbal levels of GluN1 and GluN2A following cocaine self-administration that was paralleled by an increase of Munc13 and RIM1 levels. At the same time, we also demonstrated that different conditions of cocaine abstinence abolished changes in NMDA receptor subunits (except for higher GluN1 levels after cocaine abstinence with extinction training), while an increase in the Munc13 concentration was shown in rats housed in an enriched environment. In conclusion, cocaine self-administration is associated with the specific up-regulation of the NMDA receptor subunit composition and is related with new presynaptic targets controlling neurotransmitter release. Moreover, changes observed in cocaine abstinence with extinction training and in an enriched environment in the levels of NMDA receptor subunit and in the active zone protein, respectively, may represent a potential regulatory step in cocaine-seeking behavior.

Highlights

Glutamate is the major excitatory neurotransmitter, mediating nearly 70% of synaptic transmission within the central nervous system
We found that different conditions of cocaine abstinence abolished changes related to NMDA receptor subunits, while an increase in the mammalian uncoordinated protein 13 (Munc13) concentration was shown in rats housed in an enriched environment
The nucleus accumbens is the structure closely tied to motivational mechanisms [17] and receives excitatory glutamatergic inputs from the hippocampus, amygdala, and prefrontal cortex [18], as well as dopaminergic innervation from the ventral tegmental area, which modulates glutamatergic transmission and mediates the cocaine rewarding effects [5]

Summary

Introduction

Glutamate is the major excitatory neurotransmitter, mediating nearly 70% of synaptic transmission within the central nervous system. Glutamate is accumulated into synaptic vesicles and, upon depolarization of the presynaptic terminal is released into the synaptic cleft, glutamate binds to various specific ionotropic and metabotropic glutamate receptors localized in almost all brain areas [1]. The ionotropic group of glutamate receptors is composed of N-methyl-d-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors. NMDA receptors require binding of both glutamate and the co-agonist glycine, as well as membrane depolarization for removal of a magnesium block and activation of these receptors results in the opening of channel pore for sodium, magnesium and calcium [3]. Stimulation of the glutamatergic receptors drives synaptic phenomena including several intracellular signaling pathways, leading to neuronal plasticity

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