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Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats

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Abstract

Rationale

Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity.

Objectives

We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci.

Methods

Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal.

Results

Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction.

Conclusions

Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.

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Acknowledgments

This research was supported by DA027870 and a grant from the University of Wisconsin—Milwaukee Research Growth Initiative to DM. We thank John Schneider, Dr. Ashley Fortress, Dr. Tim Jarome, and Jake Burkard for their technical assistance, and Dr. Karyn Frick for generous use of equipment.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave., Garland Hall 224, Milwaukee, WI, 53211, USA

    Madalyn Hafenbreidel, Carolynn Rafa Todd, Robert C. Twining, Jennifer J. Tuscher & Devin Mueller

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  1. Madalyn Hafenbreidel
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  2. Carolynn Rafa Todd
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  3. Robert C. Twining
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  4. Jennifer J. Tuscher
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  5. Devin Mueller
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Correspondence to Devin Mueller.

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Hafenbreidel, M., Rafa Todd, C., Twining, R.C. et al. Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats. Psychopharmacology 231, 4585–4594 (2014). https://doi.org/10.1007/s00213-014-3607-1

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  • DOI: https://doi.org/10.1007/s00213-014-3607-1

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