When administered into the nucleus accumbens core or shell, the NMDA receptor antagonist AP-5 reinstates cocaine-seeking behavior in the rat

Abstract

Cocaine craving in human addicts can be elicited by three major factors: environmental cues associated with drug taking, a stressful life-event or re-exposure to cocaine [26]. Drug craving is modeled in rodents and non-human primates using the reinstatement model of cocaine seeking [13,19,39]. The nucleus accumbens plays a major role in mediating the reinstatement of cocaine seeking [27,36]. The nucleus accumbens receives a major dopaminergic projection from the ventral tegmental area (VTA) and glutamatergic projections from the prefrontal cortex, hippocampus and amygdala [5,34,43]. The accumbens is composed of two major subregions, the core and the shell, which have differential afferent and efferent anatomical projections [7,20,21,44]. Functionally, the accumbens shell is considered the more limbic subregion, mediating the acute effects of drug reward [8,35]. In contrast, the core is more involved in the compulsivity of drug addiction [16] and the effects of drug-associated cues [14,18,25]. In terms of cocaine priming-induced reinstatement of drug seeking, dopamine receptors play differential roles in the shell versus the core [2][3][4]. For example, infusion of dopamine receptor antagonists into the accumbens shell, but not the core, attenuates the reinstatement of cocaine-seeking behavior [2][3][4]. Similarly, dopamine receptor agonists promote the reinstatement of cocaine seeking when microinjected into the shell, but not core [4,37]. Collectively, these studies demonstrate that increased dopamine transmission in the nucleus accumbens shell, but not the core, critically mediates the reinstatement of cocaineseeking behavior.The glutamatergic projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens is one of the key anatomical substrates underlying cocaine priming-induced reinstatement of drug seeking [27,37]. There are two major classes of ionotropic glutamate receptors: AMPA/kainate and NMDA. While AMPA receptors in the nucleus accumbens are critically involved in the reinstatement of cocaine-seeking behavior [9,10,30,32,40], there is evidence that NMDA receptors may also play a role. For example, systemic administration of MK-801, an NMDA receptor channel blocker, robustly reinstated cocaine seeking, without an increase in nonspecific operant responding [12, but see also 6]. In a subsequent study, it was found that intra-accumbal administration of the competitive NMDA receptor antagonist, CPP, had no effect on the reinstatement of cocaine seeking when administered either alone or prior Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. to a systemic...

Infralimbic Prefrontal Cortex Is Responsible for Inhibiting Cocaine Seeking in Extinguished Rats

“…These data support the infralimbic cortex and NAshell as participants in a functional network that mediates extinction-induced inhibition of cocaine seeking. Although this finding is consistent with a previous finding that NMDA blockade in the NAshell reinstates cocaine seeking (Famous et al, 2007), bilateral NAshell inactivation elicited motor activity, as reported previously (Maldonado-Irizarry and Kelley, 1994;Kelley, 2004). This poses the possibility that the Figure 3.…”

“…The infralimbic cortex projection to the NAshell is hypothesized to contribute to the inhibitory regulation of cocaine seeking, but the NAshell is also directly regulated by structures that trigger cocaine seeking, such as the BLA. Thus, glutamate transmission in the NAshell may either inhibit or facilitate cocaine seeking depending on whether it is derived from infralimbic or BLA afferents, respectively, perhaps accounting for why studies have identified both facilitatory and inhibitory roles for the NAshell in drug seeking and other motivated behaviors (Kelley, 2004;Reynolds and Berridge, 2003;Anderson et al, 2006;Famous et al, 2007).…”

Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior

“…It is noteworthy that, like sensitization, conditioned cues reduce AMPA receptor surface expression 24 h after exposure to these cues (Conrad et al, 2008). In contrast to the consistent findings regarding nucleus accumbens AMPA receptors and reinstatement, injection of the NMDA agonist 1-aminocyclobutane-cis-1,3-dicarboxylic acid into the core reinstates cocaine seeking, whereas injection of 2-amino-5-phosphonovaleric acid, an NMDA antagonist, into the core or shell either blocks, has no effect on, or reinstates cocaine seeking (Cornish et al, 1999;Cornish and Kalivas, 2000;Bä ckström and Hyytiä , 2007;Famous et al, 2007). Finally, injections of the group II mGluR agonist LY379268 into the nucleus accumbens blocks 1) context-induced heroin seeking and 2) cocaine-primed drug seeking (Bossert et al, 2006;Peters and Kalivas, 2006).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Infusion of AP5 in the NAcore or NAshell also enhances context-induced, cocaine-conditioned locomotion (Rodríguez-Borrero et al, 2006). Interestingly, contradictory evidence for the role of AP5 infusion on reinstated cocaine seeking exists, with one report demonstrating that AP5 infusion into the NAcore or NAshell induces reinstated cocaine seeking, with the NAshell infusion having the stronger effect (Famous et al, 2007), and the other group demonstrating that NMDAR blockade via AP5 infusion into the NAcore dose-dependently inhibits cue-induced cocaine seeking (Bäckström and Hyytiä, 2007). One important consideration is that Famous et al (2007) used a higher dose of AP5 (3 and 30 mg) to promote reinstated cocaine seeking, whereas Bäckström and Hyytiä (2007) found that lower doses of AP5 (1 and 2 mg) inhibit cue-induced cocaine seeking.…”

“…Interestingly, contradictory evidence for the role of AP5 infusion on reinstated cocaine seeking exists, with one report demonstrating that AP5 infusion into the NAcore or NAshell induces reinstated cocaine seeking, with the NAshell infusion having the stronger effect (Famous et al, 2007), and the other group demonstrating that NMDAR blockade via AP5 infusion into the NAcore dose-dependently inhibits cue-induced cocaine seeking (Bäckström and Hyytiä, 2007). One important consideration is that Famous et al (2007) used a higher dose of AP5 (3 and 30 mg) to promote reinstated cocaine seeking, whereas Bäckström and Hyytiä (2007) found that lower doses of AP5 (1 and 2 mg) inhibit cue-induced cocaine seeking. Infusion of AP5 into the accumbens (no distinction made between the NAcore and NAshell) also decreases the potentiation of conditioned reinforcement caused by D-amphetamine (Burns et al, 1993) and decreases oral ethanol self-administration (Rassnick et al, 1992).…”