title: Infralimbic GluN2A-Containing NMDA Receptors Modulate Reconsolidation of Cocaine Self-Administration Memory.
abstract: Addiction is characterized by high relapse susceptibility, and relapse can be triggered by drug-associated cues. Cue presentation induces retrieval of the drug-cue memory, which becomes labile and must be reconsolidated into long-term storage. Repeated unpaired cue presentation, however, promotes extinction. Cue-reactivity can be reduced by blocking reconsolidation or facilitating extinction, which are mediated by NMDA receptors (NMDArs). However, the role of NMDArs in either process following self-administration is unclear. Thus, to determine their role in extinction, rats learned to self-administer cocaine before receiving injections of the NMDAr antagonist CPP immediately after four 45-min extinction sessions. During a subsequent 90-min extinction retention test, CPP-treated rats lever pressed less than saline-treated rats indicating that NMDAr blockade facilitated extinction or disrupted drug-cue memory reconsolidation. In addition, infusing CPP into the infralimbic medial prefrontal cortex (IL-mPFC), a structure implicated in extinction, before four 45-min or immediately after four 30min extinction sessions, had similar results during the extinction retention tests. Next, the GluN2A-selective antagonist NVP or GluN2B-selective antagonist Ro25 was infused into IL-mPFC or nucleus accumbens (NAc) shell, another structure implicated in extinction, after four 45-min extinction sessions. Blocking GluN2A-, but not GluN2B-, containing NMDArs, in IL-mPFC or NAc shell reduced lever pressing during the extinction retention tests. Finally, to dissociate reconsolidation from extinction, NVP was infused into IL-mPFC after four 10-min reactivation sessions, which resulted in reduced lever pressing during the retention test. These results indicate that IL-mPFC GluN2A-containing NMDArs modulate reconsolidation, and suggest a novel treatment strategy, as reducing cue reactivity could limit relapse susceptibility.
authors.affiliation: Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Madalyn
authors.initials: M
authors.lastname: Hafenbreidel
authors.affiliation: Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Carolynn
authors.initials: C
authors.lastname: Rafa Todd
authors.affiliation: Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.|Department of Basic Sciences, Ponce Health Sciences University-School of Medicine/Ponce Research Institute, Ponce, Puerto Rico.
authors.forename: Devin
authors.initials: D
authors.lastname: Mueller
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects* / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology*; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012646:Self Administration
chemical_list: D003042:Cocaine; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid