Research reportMetabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking
Introduction
An extensive pre-clinical literature indicates that cocaine-induced alterations in limbic glutamate transmission play a critical role in the reinstatement of cocaine seeking, an animal model of relapse. However, these studies have focused primarily on the role of ionotropic glutamate receptors in the reinstatement of cocaine seeking [1], [2], [3], [4]. Examination of the role of metabotropic glutamate receptors (mGluRs) in cocaine reinstatement is of interest since these receptors also regulate neuronal excitability and plasticity [5], [6].
Eight different mGluR subunits have been identified to date and classified into three main groups based on sequence homology, pharmacology and coupling to intracellular effectors. For example, activation of group I mGluRs, which includes mGluR5 receptors, stimulates Gq/phospholipase C (PLC), resulting in the generation of diacylglycerol (DAG) and inositol triphosphate (IP3) [7], [8]. A growing body of evidence indicates that mGluR5 receptors, which are highly expressed in cortical and limbic nuclei including the nucleus accumbens [9], modulate cocaine-mediated behaviors. Initial evidence indicated that genetic deletion of mGluR5 in mice blocked the acquisition of cocaine self-administration without adversely affecting operant responding for food [10]. Subsequent pharmacological studies demonstrated that the systemic administration of the group I mGluR antagonist, MPEP, attenuated the expression of behavioral sensitization to cocaine [11], cocaine-induced conditioned place preference [12], [13] and reinforcing effects of cocaine [14], [15], [16], [17], [18], [19].
Relapse (or reinstatement) of cocaine seeking can be modeled in monkeys and rodents by re-exposure to cocaine-associated cues or the administration of a priming injection of cocaine among animals in which cocaine self-administration behavior has been extinguished [20]. Systemic injection of the mGluR5 antagonist, MPEP, attenuated both cue- [21] and priming- [17] induced reinstatement of cocaine seeking. The goal of the present experiments was to replicate these cocaine reinstatement studies and extend them by using MTEP, a non-competitive mGluR5 antagonist that is more potent and selective than MPEP [22], [23], [24]. Moreover, we also assessed the effect of administration of MPEP into the nucleus accumbens shell, a brain region known to play an important role in the reinstatement of cocaine seeking [25], [26], [27], [28].
Section snippets
Animals and housing
Male Sprague Dawley rats (Rattus norvegicus), weighing 250–300 g, were obtained from Taconic Laboratories (Germantown, NY, USA) and housed individually with food and water available ad libitum. The colony was maintained on a 12 h light/dark cycle with lights on at 7:00 am. All behavioral training and testing was done during the light cycle. All experimental protocols were conducted in accordance with guidelines from the National Institutes of Health (NIH) and approved by the Boston University
Cocaine priming- and cue-induced reinstatement of drug seeking
The data depicted in Fig. 1A and C show the last day of self-administration, extinction and reinstatement of drug seeking induced by either cocaine itself (panel A) or cocaine-associated cues (panel C). Following a total of 21 days of cocaine self-administration under an FR (cocaine-priming induced reinstatement group) (panel A) or 28 FR + 10 days under a second-order (cue-induced reinstatement group) (panel C) schedule of reinforcement, all subjects entered the extinction phase during which
Discussion
The present results indicate that systemic administration of mGluR5 antagonists attenuated cocaine priming-induced and cocaine cue-induced reinstatement of drug seeking. In addition, microinjection of MPEP directly into the nucleus accumbens shell significantly decreased drug seeking induced by a cocaine priming injection. These effects were reinforcer specific since neither of the mGluR5 antagonists (MPEP or MTEP) influenced the reinstatement of sucrose seeking. These data suggest that, at
Acknowledgements
This research was supported by grants from the National Institutes of Health (NIH) to RCP (R01 DA15214 and K02 DA18678). KRF was partially supported by a National Research Service Award (NRSA) from the NIH (F30 DA19304), as well as an NIH training grant (T32 GM008541-7). HDS was also partially supported by an NRSA from the NIH (DA16824). The authors thank Natasha D’Agostini for assistance with some of the sucrose reinstatement experiments and Audrey Pierce for administrative assistance.
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Current address: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, 125 South 31st Street, Philadelphia, PA 19106, United States.