Elsevier

Neuroscience

Volume 93, Issue 4, August 1999, Pages 1359-1367
Neuroscience

A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior

https://doi.org/10.1016/S0306-4522(99)00214-6Get rights and content

Abstract

This study investigated the effect of ionotropic glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration and the reinstatement of cocaine-seeking behavior. The stimulation of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or N-methyl-d-aspartate glutamate receptors in the nucleus accumbens with either α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or 1-aminocyclobutane-cis-1,3-dicarboxylic acid, respectively, decreased the number of cocaine-reinforced responses, suggesting an enhancement in the rewarding properties of cocaine. In contrast, blockade of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors with N-methyl-d-aspartate, or N-methyl-d-aspartate receptors with dizocilpine maleate or 2-amino-5-phosphonovaleric acid had no selective effect on the maintenance of cocaine self-administration. Following one week of extinction from the reinforcing cue of the drug-paired lever, both α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid and 1-aminocyclobutane-cis-1,3-dicarboxylic acid treatment in the nucleus accumbens reinstated cocaine-seeking behavior. However, α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid treatment increased responding only on the drug-paired lever, while 1-aminocyclobutane-cis-1,3-dicarboxylic acid increased responding on both the drug-paired and non-drug-paired levers.

These results suggest that stimulation of glutamate receptors in the nucleus accumbens augments the reinforcing effect of cocaine, yet glutamate transmission is not required to maintain cocaine self-administration. In addition, increased glutamate transmission in the nucleus accumbens may be involved in facilitating the relapse to cocaine-seeking behavior.

Section snippets

Subjects

All experiments were conducted according to specifications of the National Institute of Health guide for the Care and Use of Laboratory Animals. Male Sprague–Dawley rats (Simmonsen, Gilroy, CA) weighing 300–350 g at the beginning of the experiment were housed under a 12 h light-dark cycle and had ad libitum access to food and water, except where food restrictions applied as outlined below. Animals were individually housed after surgery and all experiments were performed during the light cycle.

Drugs

Results

Figure 1 shows the effect of glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration. All groups analysed showed significant discrimination between the infusion and inactive levers (P<0.003). Neither saline nor DMSO (20%) treatment significantly altered infusion lever responses and the data have been pooled (Fig. 1A, B). Figure 1A and B shows that pretreatment with either AMPA (0.4 nmol/side) or cis-ACDA (3 nmol/side)

Discussion

The present results describe a role for AMPA or NMDA receptor activation in the nucleus accumbens in maintaining cocaine self-administration or for initiating the relapse to cocaine-seeking behavior. AMPA or NMDA receptor stimulation in the nucleus accumbens during the maintenance of cocaine self-administration caused a significant leftward shift of the cocaine dose–response curve to suggest an enhancement of cocaine reward. In addition, the intra-accumbens administration of AMPA or NMDA

Conclusions

This study demonstrates a facilitatory effect of increased glutamate transmission in the nucleus accumbens on the rewarding efficacy of cocaine and on the reinstatement of cocaine-seeking behavior. These results imply that changes in glutamate transmission detected in rats sensitized to non-contingent cocaine administration at least in part parallel those alterations which are observed in animals withdrawn from contingent cocaine-taking. Therefore, changes in nucleus accumbens glutamate

Acknowledgements

We thank Jenny Baylon for her assistance in the preparation of this manuscript and Anastasia J. Romanides and Mathew Edwards for their technical assistance. This research was supported in part by the Washington State Alcohol and Drug Abuse Program and USPHS grants MH-40817 and DA-03906, and a Research Career Development Award DA-00158 (PWK).

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