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Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats.

ABSTRACT: The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30?pg/0.3?µl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3?µg/0.3?µl /hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity or food-reinforced instrumental behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

SUBMITTER: Xie X

PROVIDER: S-EPMC4384648 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats.

Xie Xiaohu X Lasseter Heather C HC Ramirez Donna R DR Ponds KaiCee L KL Wells Audrey M AM Fuchs Rita A RA

Addiction biology 20110426 2

The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement ...[more]

PMID: 21521425

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Project description:Impaired glutamate homeostasis is a key characteristic of the neurobiology of drug addiction in rodent models and contributes to the vulnerability to relapse to drug seeking. Although disrupted astrocytic and presynaptic regulation of glutamate release has been considered to constitute with impaired glutamate homeostasis in rodent model of drug relapse, the involvement of endocannabinoids (eCBs) in this neurobiological process has remained largely unknown. Here, using cocaine self-administration in rats, we investigated the role of endocannabinoids in impaired glutamate homeostasis in the core of nucleus accumbens (NAcore), which was indicated by augmentation of spontaneous synaptic glutamate release, downregulation of metabotropic glutamate receptor 2/3 (mGluR2/3), and mGluR5-mediated astrocytic glutamate release. We found that the endocannabinoid, anandamide (AEA), rather than 2-arachidonoylglycerol elicited glutamate release through presynaptic transient receptor potential vanilloid 1 (TRPV1) and astrocytic cannabinoid type-1 receptors (CB1Rs) in the NAcore of saline-yoked rats. In rats with a history of cocaine self-administration and extinction training, AEA failed to alter synaptic glutamate release in the NAcore, whereas CB1R-mediated astrocytic glutamate release by AEA remained functional. In order to induce increased astrocytic glutamate release via exogenous AEA, (R)-methanandamide (methAEA, a metabolically stable form of AEA) was chronically infused in the NAcore via osmotic pumps during extinction training. Restoration of mGluR2/3 function and mGluR5-mediated astrocytic glutamate release was observed after chronic methAEA infusion. Additionally, priming or cue-induced reinstatement of cocaine seeking was inhibited in methAEA-infused rats. These results demonstrate that enhancing endocannabinoid signaling is a potential pathway to restore glutamate homeostasis and may represent a promising therapeutic strategy for preventing cocaine relapse.

Dataset Information

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats.

Publications

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats.

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