Withdrawal from cocaine self-administration and yoked cocaine delivery dysregulates glutamatergic mGlu5 and NMDA receptors in the rat brain.

Lucyna Pomierny-Chamiolo,Joanna Miszkiel,Małgorzata Frankowska,Irena Smaga,Ewa Niedzielska,Fabio Fumagalli,Bartosz Pomierny,Małgorzata Filip

doi:10.1007/s12640-014-9502-z

Abstract

In human addicts and in animal models, chronic cocaine use leads to numerous alterations in glutamatergic transmission, including its receptors. The present study focused on metabotropic glutamatergic receptors type 5 (mGluR5) and N-methyl-D-aspartate receptor subunits (NMDAR: GluN1, GluN2A, GluN2B) proteins during cocaine self-administration and after 10-day of extinction training in rats. To discriminate the contingent from the non-contingent cocaine delivery, we employed the “yoked”-triad control procedure. Protein expression in rat prefrontal cortex, nucleus accumbens, hippocampus, and dorsal striatum was determined. We also examined the Homer1b/c protein, a member of the postsynaptic density protein family that links NMDAR to mGluR5. Our results revealed that cocaine self-administration selectively increased GluN1 and GluN2A subunit in the rat hippocampus and dorsal striatum, respectively, while mGluR5 protein expression was similarly increased in the dorsal striatum of both experimental groups. Withdrawal from both contingent and non-contingent cocaine delivery induced parallel increases in prefrontal cortical GluN2A protein expression, hippocampal mGluR5, and GluN1 protein expression as well as in accumbal GluN1 subunit expression, while the mGluR5 expression was reduced in the prefrontal cortex. Extinction training in animals with a history of cocaine self-administration resulted in an elevation of the hippocampal GluN2A/GluN2B subunits and accumbal mGluR5, and in a 50 % decrease of mGluR5 protein expression in the dorsal striatum. The latter reduction was associated with Homer1b/1c protein level decrease. Our results showed that both contingent and non-contingent cocaine administration produces numerous, brain region specific, alterations in the mGluR5, NMDA, and Homer1b/1c protein expression which are dependent on the modality of cocaine administration.

Highlights

Cocaine belongs to the most commonly used illicit stimulant drug in Europe with about 2.2 million young drug adults aged 15–34 in 2012 (EMCDDA, 2014)
The present study focused on metabotropic glutamatergic receptors type 5 and N-methyl-D-aspartate receptor subunits (NMDAR: GluN1, GluN2A, GluN2B) proteins during cocaine self-administration and after 10-day of extinction training in rats
Our results revealed that cocaine self-administration selectively increased GluN1 and GluN2A subunit in the rat hippocampus and dorsal striatum, respectively, while metabotropic glutamatergic receptors type 5 (mGluR5) protein expression was increased in the dorsal striatum of both experimental groups

Summary

Introduction

Cocaine belongs to the most commonly used illicit stimulant drug in Europe with about 2.2 million young drug adults aged 15–34 in 2012 (EMCDDA, 2014). The release of Glu during cocaine seeking elicits rapid postsynaptic changes in proteins regulating Glu signaling and surface spine morphology, while attenuation of Glu transmission reduces drug reinforcement and relapse-like behavior (McFarland et al 2003; Brebner et al 2005; Gipson et al 2013). The potentiation of Glu transmission, from prefrontal glutamatergic neurons to the accumbal core during drug-seeking behaviors, is critical to drug-associated memories (Kalivas 2009). Withdrawal from cocaine treatment alters the number of accumbal Glu synapses and spine density associated with a deteriorating actin cytoskeleton and a reduction in Glu signaling-related proteins (Shen et al 2009). These changes are the consequence of reduced basal accumbal extracellular Glu, together with changes in mechanisms responsible for Glu clearance (Pomierny-Chamiolo et al 2014)

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Results

Conclusion