title: Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence.
abstract: In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse.
  
  
  CONCLUSIONS
  In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence.
authors.affiliation: Behavioral Neuroscience Branch, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, 2337 Australia, nathan.marchant@nih.gov yavin.shaham@nih.gov.
authors.forename: Nathan J
authors.identifier: http://orcid.org/0000-0002-6583-4802
authors.initials: NJ
authors.lastname: Marchant
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, University of Newcastle, the Priority Research Centre for Translational Neuroscience and Mental Health and the Hunter Medical Research Institute, Newcastle, 2308, Australia.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Campbell
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Whitaker
authors.affiliation: Optogenetics and Transgenic Technology Core, and.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Konstantin
authors.identifier: http://orcid.org/0000-0002-1577-109X
authors.initials: K
authors.lastname: Kaganovsky
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Sweta
authors.initials: S
authors.lastname: Adhikary
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Hope
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Heins
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Merck Pharmaceuticals, Kenilworth, New Jersey 07033, and.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Cellular Neurobiology Research Branch, National Institute on Drug Abuse-IRP, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Behavioral Neuroscience Branch.
authors.forename: Jennifer M
authors.identifier: http://orcid.org/0000-0001-5636-4071
authors.initials: JM
authors.lastname: Bossert
authors.affiliation: Behavioral Neuroscience Branch, nathan.marchant@nih.gov yavin.shaham@nih.gov.
authors.forename: Yavin
authors.identifier: http://orcid.org/0000-0002-8242-3319
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D064829:Alcohol Abstinence / Q000523:psychology*; D000428:Alcohol Drinking / Q000503:physiopathology / Q000523:psychology*; D000818:Animals; D002772:Cholera Toxin / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D045785:Diterpenes, Clerodane; D000431:Ethanol / Q000008:administration & dosage; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism; D011678:Punishment; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D012008:Recurrence; D012054:Reinforcement, Psychology; D012646:Self Administration; D014161:Transduction, Genetic
chemical_list: D004224:Diterpenes; D045785:Diterpenes, Clerodane; D016761:Oncogene Proteins v-fos; D017473:Receptors, Opioid, kappa; C508456:salvinorin B; D049452:Green Fluorescent Proteins; D000431:Ethanol; D002772:Cholera Toxin
keywords: alcohol; chemogenetics; nucleus accumbens; punishment; relapse; ventral subiculum