Cocaine Self-Administration Elevates GluN2B within dmPFC Mediating Heightened Cue-Elicited Operant Responding.

Karen K Szumlinski,Tod E Kippin,Bailey W Miller,Melissa G Wroten,Matan Cohen,Osnat Ben Shahar,Arianne D Sacramento

doi:10.21767/2471-853x.100022

Karen K Szumlinski, Tod E Kippin + Show 5 more

Open Access

https://doi.org/10.21767/2471-853x.100022

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Abstract

Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction-related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs. 30 days). Cocaine-seeking rats exhibited elevated GluN2B expression within the dorsomedial aspect of the PFC (dmPFC); this effect was apparent at both 3 and 30 days withdrawal and occurred in cocaine-experienced rats, regardless of experiencing an extinction test or not. Thus, elevated dmPFC GluN2B expression appears to reflect a pharmacodynamic response to excessive cocaine intake that is independent of the duration of drug withdrawal or re-exposure to drug-taking context. The functional relevance of elevated dmPFC GluN2B expression for drug-seeking was assessed by the local infusion of the prototypical GluN2B-selective antagonist ifenprodil (1.0 µg/side). Ifenprodil did not alter cue-elicited responding in animals with a history of saline self-administration. In contrast, ifenprodil lowered cue-elicited cocaine-seeking, while potentiating cue-elicited sucrose-seeking. Thus, the effects of an intra-dmPFC ifenprodil infusion upon cue reactivity are reinforcer-specific, arguing in favor of targeting GluN2B-containing NMDA receptors as a pharmacological strategy for reducing behavioral reactivity to drug-associated cues with the potential benefit of heightening the reinforcing properties of cues associated with non-drug primary rewards.

Highlights

The presentation of cocaine-associated cues to human cocaine addicts induces intense drug-craving, increasing the propensity for relapse to drug taking e.g., [1,2,3,4,5,6]
To determine whether or not cocaine self-administration experience alone was sufficient to elevate GluN2B levels within dorsomedial aspect of the PFC (dmPFC), we examined for time-dependent changes in dmPFC GluN2B expression in Coc6h and Sal6h rats that were left undisturbed in the home cage prior to tissue collection
This analysis revealed a time-independent elevation in dmPFC expression of GluN2b in Coc6h rats (Figure 1, right) [IV effect: F(1,57)=11.82, p=0.001; interaction: p=0.40]. These results indicate that a history of extended access to cocaine is sufficient to elevate dmPFC GluN2B expression and that this effect persists into protracted withdrawal

Summary

Introduction

The presentation of cocaine-associated cues to human cocaine addicts induces intense drug-craving, increasing the propensity for relapse to drug taking e.g., [1,2,3,4,5,6]. Selfreports of cocaine- craving upon the presentation of drug-related cues or imagery are associated with heightened activation of mPFC [1,2,3, 6,7,8,9]. Considerable evidence has accrued from studies of animal models of addiction to support the hypothesis that cocaine experience produces enduring anomalies in excitatory signaling within mPFC e.g., [14,15,16,17,18,19,20] that may be critical for cue-induced drug-seeking. Direct support for the mPFC in drug-seeking has been derived from neuropharmacological

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