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

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.