title: Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking.
abstract: Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets. In rats, we examined Fos expression during cue-induced reinstatement of cocaine- and sucrose-seeking in prelimbic cortex (PL), infralimbic cortex (IL), BLA, and vSub neurons that project to NAc core (NAcC) or NAc shell (NAcSh). Neurons in PL, BLA, and vSub that project to NAcC, but not NAcSh, expressed Fos during cue-induced cocaine seeking, but not sucrose seeking. However, only activation of the PL-NAcC pathway positively correlated with cocaine reinstatement behavior, unlike BLA or vSub inputs to NAcC. To confirm a functional role for the PL-NAcC pathway, and to test the hypothesis that this pathway is recruited in a dopamine-dependent manner, we used a pharmacological disconnection approach whereby dopamine signaling was blocked in PL and glutamate signaling was blocked in the contralateral NAcC. This disconnection attenuated cue-induced reinstatement of cocaine seeking but had no effect on reinstatement of sucrose seeking. Our results highlight a role for the PL-NAcC pathway in cocaine seeking and show that these glutamatergic projections are recruited in a dopamine-dependent manner to drive reinstatement.
  
  
  
  Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29403, Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.
authors.forename: Ellen M
authors.identifier: 0000-0001-6322-4165
authors.initials: EM
authors.lastname: McGlinchey
authors.affiliation: Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.
authors.forename: Morgan H
authors.identifier: 0000-0001-9298-8607
authors.initials: MH
authors.lastname: James
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29403, Department of Neurobiology and Behavior, University of California, Irvine, California 92697.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Mahler
authors.affiliation: Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and.
authors.forename: Caroline
authors.identifier: 0000-0002-7987-7053
authors.initials: C
authors.lastname: Pantazis
authors.affiliation: Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 08854, and aston.jones@rutgers.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Aston-Jones
mesh_terms: D000818:Animals; D002772:Cholera Toxin / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000494:pharmacology*; D004338:Drug Combinations; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004997:Ethinyl Estradiol; D005108:Extinction, Psychological / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009640:Norethindrone; D009714:Nucleus Accumbens / Q000187:drug effects*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D004338:Drug Combinations; D018377:Neurotransmitter Agents; D016761:Oncogene Proteins v-fos; C020416:norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; D004997:Ethinyl Estradiol; D013395:Sucrose; D002772:Cholera Toxin; D003042:Cocaine; D009640:Norethindrone; D004298:Dopamine
keywords: basolateral amygdala; cocaine; dopamine; nucleus accumbens; prelimbic cortex; ventral subiculum