Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats.
BACKGROUND
Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity.


OBJECTIVE
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.
Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave., Garland Hall 224, Milwaukee, WI, 53211, USA.
Madalyn
M
Hafenbreidel
Carolynn
C
Rafa Todd
Robert C
RC
Twining
Jennifer J
JJ
Tuscher
Devin
D
Mueller
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration
D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D003042:Cocaine