NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats

Highlights

• The restraint stress-induced reinstatement of cocaine-CPP is dependent on the duration of restraint and the context.

• Systemic MK-801 blocks the development and expression of restraint stress-induced reinstatement of cocaine-CPP.

• Intra-Nac Core, but not shell, MK 801 administration blocks restraint stress-induced reinstatement of cocaine-CPP.

Abstract

Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30 min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP.

Introduction

Relapse to compulsive drug intake after a withdrawal period is considered a hallmark of the addiction process. 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 [25], [52], [51]. The conditioned place preference (CPP) test has been previously described as a useful protocol for studying relapse to drug-seeking in laboratory animals [36], [5], [29]. Drug relapse elicited by stressful life-events has been studied in rodents using a CPP paradigm by applying different stressors such as footshock, forced swimming or, as in the current study, restraint, in order to induce reinstatement of an extinguished cocaine-CPP [55], [46].

Since there are reported differences among the extinction protocols used to reinstate a drug-CPP response, the first interest of this study was to compare the two extinction procedures used so far for the reinstatement of extinguished drug-CPP. Specifically, we compared the effectiveness of a repeated test extinction procedure and a saline pairings extinction procedure to extinguish a CPP response to cocaine [36], [24].

Different lengths of intermittent or continuous exposure to either footshock or restraint stress, respectively, have also been used to elicit reinstatement of cocaine-CPP response [45], [30], [9], [3]. Nevertheless the restraint stress studies do not provide details about the place in which restraint stress occurs, in spite of the known relevance of environment to trigger the stress-induced reinstatement of extinguished cocaine self-administration behavior (see [48]). So, the second aim of the current study was to determine the length of exposure and the environment dependence of the restraint stress needed to induce reinstatement of extinguished cocaine-CPP.

In relation to the neuroanatomical substrates of these behaviors, it is well known that the nucleus accumbens (NAc) plays a major role in mediating the reinstatement of cocaine-seeking behavior [12], [26], [8]. This area is composed of two major subregions, NAc core and NAc shell, with differential anatomical afferents and efferent projections [22], which may account for different aspects of the drug-rewarding process [23]. The NAc shell seems to mediate several drug-related phenomena, such as the acute effects of drug reward [38], [23], the motor responses to addictive drugs [13], [31] and extracellular dopamine levels after an acute intravenous administration of cocaine [41]. The NAc core seems to be important for the processing of drug-associated cues and the drug-seeking behavior [23], [4], [40], [57], [15], [19].

Although several studies suggest that stress-induced reinstatement involves a specific limbic subcircuit [47], [48], it is well established that the glutamatergic projection from the medial prefrontal cortex (mPFC) to the NAc core represents a common mechanism underlying cocaine priming- [35], [26], cue- [18], [16], [42] and footshock- [11], [34] induced reinstatement of extinguished cocaine self-administration behavior. It has been consistently shown that the mPFC and NAc also participate in cocaine-priming and forced-swimming stress-induced reinstatement of extinguished cocaine-CPP [45], [58], [29]. Furthermore, [45] also demonstrated mPFC participation in restraint stress-induced reinstatement of cocaine-CPP. Interestingly, recent work from our lab has shown that a glutamatergic mechanism within the NAc core, but not shell, underpins the cross-sensitization to cocaine induced by restraint stress [17].

Regarding the involvement of the ionotropic glutamate receptors, AMPA/kainate and NMDA, it has been demonstrated that the AMPA receptors in the NAc are critically involved in the reinstatement of cocaine-seeking behavior [40], [56] and there is evidence that the NMDA receptors may also play a role in this behavior [6], [27], [15], [10]. For example, [10] reported that systemic administration of a non-competitive NMDA antagonist, MK 801, blocked cocaine-induced reinstatement of extinguished cocaine-CPP. Moreover, [4] demonstrated that by blocking the NMDA receptor within the NAc core, the cue-induced reinstatement of cocaine seeking is attenuated. However, the participation of NMDA receptors within the NAc core vs. shell has not been examined yet for restraint stress-induced reinstatement of extinguished cocaine-CPP. Therefore, the third and main aim of the present study was oriented to systematically examine the influence of a systemic, intra-core or shell administration of an NMDA receptor antagonist, i.e. MK 801, on restraint stress-induced reinstatement of extinguished cocaine-CPP.