Elsevier

Brain Research

Volume 1215, 18 June 2008, Pages 173-182
Brain Research

Research Report
Contributions of nucleus accumbens core and shell GluR1 containing AMPA receptors in AMPA- and cocaine-primed reinstatement of cocaine-seeking behavior

https://doi.org/10.1016/j.brainres.2008.03.088Get rights and content

Abstract

Glutamate signaling in the nucleus accumbens influences reinstatement of previously extinguished cocaine-seeking behavior in rats. Whether or not region specific glutamate signaling in the nucleus accumbens contributes to reinstatement of cocaine-seeking behavior is not known. We investigated whether directly stimulating ionotropic glutamate receptors (GluRs) within the nucleus accumbens core or shell would differentially influence renewed cocaine-seeking behavior following extinction training. We also tested the hypothesis that GluR1 subunit (GluR1) containing alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors in the nucleus accumbens core and not the shell regulate reinstatement of previously extinguished cocaine-seeking behavior. Microinjection of AMPA into the nucleus accumbens shell and the nucleus accumbens core dose-dependently elicited significant cocaine-seeking behavior. Administration of antisense oligonucleotides (AS) directed against GluR1 subunit mRNA into the core and shell disrupted AMPA- and cocaine-primed reinstatement—with the most pronounced effects seen in the nucleus accumbens shell. These results demonstrate that GluRs in the nucleus accumbens core and shell influence AMPA- and cocaine-primed reinstatement, yet the nucleus accumbens shell exerts a prepotency over the nucleus accumbens core.

Introduction

Relapse to cocaine intake of following abstinence is a problematic obstacle in treatment of cocaine addiction (Kreek and Koob, 1998). The role of glutamate signaling in reinstatement of cocaine-seeking behavior in preclinical models of cocaine relapse is emerging (Baker et al., 2003, Cornish et al., 1999, Kruzich and Xi, 2006, Sun et al., 2005, Suto et al., 2004). Inhibition of GluRs in the ventral tegmental area dampens cocaine-primed reinstatement of previously extinguished cocaine-seeking behavior (Sun et al., 2005). Direct stimulation of GluRs in the nucleus accumbens (Cornish et al., 1999, Suto et al., 2004) and more specifically nucleus accumbens core (Kruzich and Xi, 2006) leads to significant reinstatement of previously extinguished cocaine-seeking behavior in rats. While it has been demonstrated that dopamine receptors in the nucleus accumbens shell and not the nucleus accumbens core influence cocaine-primed reinstatement (Anderson et al., 2006, Schmidt et al., 2006), determination of whether or not glutamate signaling in the nucleus accumbens shell is also involved in reinstatement of cocaine-seeking behavior has not been demonstrated.

In the present study we hypothesized that stimulation of GluRs in the nucleus accumbens core and not shell would lead to significant reinstatement of previously extinguished cocaine-seeking behavior. This hypothesis was based on a prior study showing inactivation of the nucleus accumbens shell with GABA-A and GABA-B agonists does not disrupt cocaine-primed reinstatement in rats (McFarland and Kalivas, 2001). We also sought to test the hypothesis that the specific ionotropic GluR subtype, type 1 (GluR1), regulates AMPA- and cocaine-primed reinstatement of cocaine-seeking behavior. We investigated GluR1 subunit because prior studies demonstrated robust increases of GluR1 subunits and not GluR2/3 expression in the nucleus accumbens of rats displaying behavioral sensitization to cocaine (Churchill et al., 1999, Boudreau et al., 2007). Currently, there are no commercially available specific GluR1 subunit agonists or antagonists. We therefore targeted GluR1 subunit receptor mRNA with antisense oligonucleotides (AS) in order to decrease GluR1 subunit protein expression in the nucleus accumbens core or shell of the nucleus accumbens.

Section snippets

Histology of subjects used for data analysis

Fig. 1 depicts representative photomicrographs from animals with appropriate cannula placement in the nucleus accumbens core (Figs. 1A and B) and nucleus accumbens shell (Figs. 1C and D). The group numbers used for statistical analyses were: nucleus accumbens core 0.3 nmol/side n = 7, nucleus accumbens core 0.6 nmol/side n = 7, nucleus accumbens shell 0.3 nmol/side n = 8, and nucleus accumbens shell 0.6 nmol/side n = 6.

Active lever responding

Fig. 2 depicts the behavioral data for experiment #1. There was not an overall

Discussion

The present study demonstrates that the nucleus accumbens core and shell play significant roles in AMPA- and cocaine-primed reinstatement—with the shell showing a level of ascendancy that was not anticipated. This study also supports very recent findings showing the specific role of GluR1 subunits in the nucleus accumbens shell in reinstatement of cocaine-seeking behavior and a partial role of GluR1 subunits in the nucleus accumbens core in AMPA-primed reinstatement (Anderson et al., 2008).

The

Experimental animals and surgery

Male Fischer 344 (F344) rats (Harlan, Indianapolis, IN, USA) were used in this experiment. Animals weighed on average 275 g at the beginning of the experiment and were individually housed and maintained on a 12-h light/dark cycle (lights on 0700 h) in a temperature and humidity controlled vivarium. Rats were kept at 90% of their individual ad libidum weights during food training and sessions 1–7 of cocaine self-administration by feeding them approximately 20 g of food/day. Following

Acknowledgment

This research was funded by the State of Georgia (PJK).

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