title: Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice.
abstract: BACKGROUND
  Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.
  
  
  OBJECTIVE
  To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.
  
  
  METHODS
  The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity.
  
  
  RESULTS
  In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake.
  
  
  CONCLUSIONS
  The present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.
authors.affiliation: Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen & Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sørensen
authors.forename: Morten
authors.initials: M
authors.lastname: Jensen
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.forename: Ditte
authors.initials: D
authors.lastname: Dencker
authors.forename: Søren H
authors.initials: SH
authors.lastname: Christiansen
authors.forename: Claus Juul
authors.initials: CJ
authors.lastname: Loland
authors.forename: Cecilie Hee
authors.initials: CH
authors.lastname: Bengtsen
authors.forename: Jørgen Holm
authors.initials: JH
authors.lastname: Petersen
authors.forename: Anders
authors.initials: A
authors.lastname: Fink-Jensen
authors.forename: Gitta
authors.initials: G
authors.lastname: Wörtwein
authors.forename: David P D
authors.initials: DP
authors.lastname: Woldbye
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000235:genetics; D012054:Reinforcement, Psychology; D012646:Self Administration; D014966:Xanthenes / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D003510:Cyclohexanes; D050483:Dopamine Plasma Membrane Transport Proteins; C410588:L 152804; D017476:Receptors, Neuropeptide Y; D014966:Xanthenes; C100568:neuropeptide Y5 receptor; D003042:Cocaine; D004298:Dopamine