title: Cell-type specific expression of p11 controls cocaine reward.
abstract: BACKGROUND
  The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10), specifically in the NAc, elicits depressive-like behaviors in mice, but its role in drug addiction is unknown.
  
  
  METHODS
  We combined mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (six to eight mice per group) and molecular correlates (three experiments, five to eight mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (five to eight mice per group).
  
  
  RESULTS
  We demonstrated that p11 knockout mice have enhanced cocaine conditioned place preference, which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine conditioned place preference. Finally, we identified dopamine receptor-1 expressing medium spiny neurons as key mediators of the effects of p11 on cocaine reward.
  
  
  CONCLUSIONS
  Our data provide evidence that disruption of p11 homeostasis in the NAc, particularly in dopamine receptor-1 expressing medium spiny neurons, may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Schwarz
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Mary
authors.initials: M
authors.lastname: Vernov
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wilkinson
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bradbury
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Akira
authors.initials: A
authors.lastname: Feliz
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Roberta
authors.initials: R
authors.lastname: Marongiu
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Gelfand
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Warner-Schmidt
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Psychiatry and Pharmacology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: mik2002@med.cornell.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009714:Nucleus Accumbens / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D012201:Reward; D009418:S100 Proteins / Q000378:metabolism / Q000502:physiology*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D003042:Cocaine; D017447:Receptors, Dopamine D1; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10
keywords: Cocaine reward; conditional knock down; nucleus accumbens; p11 (s100a10); striatonigral pathway; striatopallidal pathway
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